INVESTIGATIONS IN TITANIUM-CATALYZED AND -MEDIATED BOND FORMING REACTIONS By Seokjoo Lee A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry – Doctor of Philosophy 2023 ABSTRACT Nitrogen containing compounds, such as isoxazoles, enamines, amines, and a variety of heterocycles have incredible values and potentials in pharmaceutical industry.1 These compounds are prevalent in many pharmaceuticals, organic dyes, solar cells, and natural products. However, conventional pyridine syntheses often have limitation, such as limited substrate scope, low regioselectivity, or harsh reaction conditions. Therefore, new synthetic routes into these nitrogen containing compounds are highly desirable. Our group has been exploring synthetic routes using titanium metal reagents or catalysts to synthesize a wide variety of nitrogen containing compounds. One of the synthetic routes developed in our group is titanium-mediated pyridine synthesis via inverse electron-demand hetero-Diels-Alder reaction (Chapter 2). Also, our group previously developed a tool to help us evaluate ligand effects to high valent metal, and with this tool we have been exploring and developing new asymmetric ligands for titanium catalysts (Chapter 3). To My Family and Friends iii ACKNOWLEDGEMENTS First, I would like to thank Professor Aaron L. Odom. I appreciate the opportunity to be part of your group during this program. Your guidance, encouragement, and motivation provide invaluable assistance to me. I have gained tremendous knowledge and found great joy in chemistry in the Odom group. I would also like to thank all my committee members as well. Professor Thomas Hamann, Professor Xuefei Huang, and Professor Kevin Walker have provided me with support and advice throughout my studies. Your guidance has been invaluable to me throughout my candidacy exam. Also, I appreciate your time to reviewing this dissertation and providing valuable corrections. In addition, I would like to thank Dr. Daniel Holmes and Dr. Li Xie for all help with our NMR studies. I would also like to thank Robert R. Rasico Jr. for always helping me with any facility issues in the lab. In the department of chemistry, I was very fortunate to go through the program with some amazing people. These people provided support and motivation. Special thanks to Dr. Po-Jen Hsiao, Dr. Zhilin Hou, and Rashmi Jena for being amazing friends throughout graduate school and providing me with advice along the way. I also met amazing people outside of the chemistry department. I would like to thank everyone for being valued friends. These people made each day enjoyable at Michigan State University Finally, I wanted to thank my family back in Korea. I am extremely fortunate to have such a great parent (Eunjo Lee and Hyunsoon Yang) and a sister (Bomin Lee). Without my family's love and support, I could not have made it through graduate school. I was able to continue pushing forward and complete this program because of their love and encouragement from back home in Korea, as well as their faith in me. I really appreciate their understanding and patience during this journey. iv TABLE OF CONTENTS LIST OF SYMBOLS AND ABBREVIATIONS ....................................................................... vi Chapter 1. Introduction to Synthesis and Catalysis Using Titanium Metal Complexes ........ 1 1.1 Background .......................................................................................................................... 1 1.2 Titanium-Mediated N-Heterocycle Synthesis ................................................................... 1 1.3 Titanium Catalysis for C-N Bond formation .................................................................... 3 1.4 Titanium-Catalyzed iminoamination for N-Heterocycle Synthesis ................................ 7 1.5 Titanium Catalyst Development: Asymmetric Ancillary Ligands for Titanium Catalysis ................................................................................................................................... 11 1.6 Conclusion .......................................................................................................................... 14 REFERENCES ........................................................................................................................ 15 Chapter 2. Titanium-Mediated Pyridine Syntheses from Isoxazoles via inverse electron- demand hetero-Diels-Alder reaction (IEDDA) ......................................................................... 17 2.1 Introduction ....................................................................................................................... 17 2.2 Experimental Results and Discussion .............................................................................. 20 2.3 Computational Results and Discussion ........................................................................... 25 2.4 Conclusions ........................................................................................................................ 30 2.5 Experimental Details ......................................................................................................... 32 REFERENCES ........................................................................................................................ 70 Chapter 3. Investigation of Asymmetric Ancillary Ligand Effect for Titanium-Catalyzed Hydroamination .......................................................................................................................... 73 3.1 Introduction ....................................................................................................................... 73 3.2 Investigation of Symmetric Ligand Effects in Titanium Catalysis ............................... 82 3.3 Conclusion .......................................................................................................................... 92 3.4 Experimental Details ......................................................................................................... 92 REFERENCES ...................................................................................................................... 117 APPENDIX: COMPUTATIONAL DETAILS IN CHAPTER 2: TITANIUM-MEDIATED PYRIDINE SYNTHESES FROM ISOXAZOLE VIA INVERSE ELECTRON-DEMAND HETERO-DIELS-ALDER REACTION ................................................................................. 120 v LIST OF SYMBOLS AND ABBREVIATIONS %Vbur Percent Buried Volume 3CC Boc dtbpy CHO DMF DME DMSO Et2O Equiv. GC/FID GC/MS h IEDDA H2dpm H2dpma Ind LDP min MSU M.W. NMR OAc RT s TFA THF Three-Component Coupling tert-Butoxycarbonyl 4,4′-tert-butyl-2,2′-bipyridine Aldehyde Dimethylformamide Dimethoxyethane Dimethyl sulfoxide Diethyl ether Equivalent Gas Chromatography Flame Ionization Detector Gas Chromatography Mass Spectrometry Hour(s) Inverse-Electron Demand Diels-Alder 5,5-dimethyldipyrrolylmethane N,N-(dipyrrolyl-α-methyl)-N-methylamine Indole Ligand Donor Parameter Minute(s) Michigan State University Molecular weight Nuclear magnetic resonance Acetate Room temperature Second(s) Trifluoroacetic acid Tetrahydrofuran vi Chapter 1. Introduction to Synthesis and Catalysis Using Titanium Metal Complexes 1.1 Background Heterocyclic frameworks containing nitrogen atoms are crucial due to a diverse range of applications, such as organic dyes for solar cells and natural products. In particular, N-heterocycles are significant structural components in pharmaceuticals.1 In 2018, Douguet and colleagues published datasets of FDA-Approved drugs with a molecular weight less than 20002, revealing that nitrogen-heterocycles continue to play a significant role in the pharmaceutical industry. As of July 2022, the database has 2056 drugs including many drugs with N-heterocycles, such as pyridines (223), piperidines (216), pyrimidines (190), and pyrazoles (18). FDA-Approved Drugs (total 2056) Pyridines (223, 10.8%) Piperidines (216, 10.5%) Other Pyrimidines (190, 9.2%) Figure 1.1 Classification of U.S. FDA-Approved drugs in 2022.1 The formation of heterocyclic scaffolds through chemical reactions, such as C-C and C-N bond forming reactions, has been explored using rare and late transition metals like palladium, iridium, rhodium, and etc. However, the high production costs associated with low natural abundance of these late transition metals bring high cost to produce heterocycles. In contrast, early transition metals are more readily available and less expensive. From this perspective, the development of chemical reactions using early transition metals is important. 1.2 Titanium-Mediated N-Heterocycle Synthesis Titanium, the second most abundant transition metal and ninth most abundant element in crustal rocks, is non-toxic as well as highly available.3 Due to these reasons, titanium complexes are also highly attractive reagents or catalysts in a view of green chemistry. Consequently, titanium 1 chemistry has attracted significant attention, leading to the development of essential reactions such as olefin polymerization and Sharpless epoxidation. Titanium chemistry has contributed to the synthesis of N-heterocycles, as demonstrated by many examples of titanium-mediated C-N and C- C bond formation for N-heterocycle synthesis. a) R3 + O N R4 R5 R2 R1 NR2 R2 R1 R3 N O R4 R5 TiCl4 Zn dust R3 R2 R1 N R4 R5 b) R2 c) R1 + R3 Ti(OiPr)4 iPrMgCl R1 R2 Ti(OiPr)2 R3 TolSO2CN R3 H+ R2 R1 N NO2 R1 R2 TiCl3 O N R1 R2 R2 O N R1 TiCl3 HN R2 R1 Scheme 1.1 Examples of titanium-mediated N-heterocycle synthesis. In 1989, Ohta and coworkers discovered the IEDDA (Inverse Electron Demand hetero- Diels-Alder) reaction of isoxazoles and enamines for synthesizing substituted pyridines in the presence of TiCl4 and Zn (Scheme 1.1a).4 In this reaction, the isoxazole undergoes [4 + 2]- cycloaddition with the enamine. It was proposed that subsequent steps after cycloaddition lead to pyridine-N-oxide as an intermediate, and this pyridine-N-oxide is then reduced by TiCl4 and Zn in the reaction to produce substituted pyridines. With this strategy, all substituents on pyridines can be controlled with excellent regioselectivity. A titanium-mediated multi-component coupling reaction to form pyridines was reported by Urabe and coworkers in 2005 (Scheme 1.1b).5 The coupling of two acetylenes with a reduced Ti species generates titanocyclopentadiene, the titanocyclopentadiene reacts with nitriles and forms substituted pyridines. An efficient synthesis of 2,3-disubstituted indoles from 2-nitrophenyl-substituted alkenes by aqueous TiCl3 was recently reported (Scheme 1.1c).6 This is an intramolecular reaction between a nitro group and an alkene on the same aromatic ring. Once TiCl3 reduces the nitro group on the benzene rings, the alkene 2 attacks nitrogen to form indole-N-oxide in situ. The indole-N-oxide is reduced by TiCl3 again to produce 2,3-disubstituted indoles. These synthetic methods include simple coupling reactions or reduction but are very effective for the synthesis of N-heterocycles. Other than classic titanium- mediated reactions, many novel synthetic methods utilizing titanium redox chemistry also have been developed in recent years.7 The research in the Odom group has been focused on C-N bond forming reactions and N- heterocycle synthesis. I have conducted a study on the IEDDA reaction of isoxazoles and enamines originally reported by the Ohta group.4 The reaction conditions are optimized using various reagents to broaden the substrate scope, and a mechanistic study was conducted using DFT calculations (Chapter 2).8 The Odom research group developed various titanium catalysts and their applications in catalysis, such as hydroamination and iminoamination reactions, that prove to be advantageous in N-heterocycle synthesis as well.3 1.3 Titanium Catalysis for C-N Bond formation Titanium-catalyzed reactions have been investigated and applied in academia and industry for various purposes; however, they are not as extensively utilized as late transition metal catalysts in terms of the diversity of catalytic chemistry. Therefore, the Odom research group has focused on studying titanium catalysis forming C-N bonds. These C-N bond forming reactions are important starting points for N-heterocycle synthesis. The hydroamination of alkynes using titanium catalysts has been a very important topic of interest for our group. Our group found that Ti(NMe2)4, a commercially available compound, proved to be effective as a precatalyst for hydroamination of alkynes.9 This transformation is a 100% atom-economical process to generate imines from alkynes and amines. Since, our group has been designing ligands for titanium(IV) catalysts to achieve faster reaction rates as well as broader substrate scope. Furthermore, the Odom group developed titanium-catalyzed multicomponent coupling reactions from anilines, alkynes, and isonitriles to produce α,β-unsaturated imines.10 3 H2NR1 R2 R3 tBu C N R1HN N NC R2 R3 2-aminopyridines N N R4 R5 NR2 TiCl4(THF)2 Ti powder R4 N R5 R3 R2 pyridines ON R2 NH2OH R3 isoxazoles Alkyne Iminoamination Titanium Catalyst H2N NHR R2 R3 R N N H pyrazoles NR1 NHtBu R2 R3 R1 = aryl HOAc NH N R2 R3 quinoliines R N H CO2Et X NH2 R2 R3 R N CO2Et H pyrroles X N N R2 R3 pyrimidines Figure 1.2 The multicomponent coupling reaction and various N-heterocycle synthesis developed in the Odom group. Thsese α,β-unsaturated imines, accessed via multicomponent coupling strategies, have similar reactivity with 1,3-dicarbonyl compounds and are employed as intermediates for various N-heterocycle syntheses developed in the Odom group. This multicomponent coupling reaction has enabled the synthesis of various N-heterocycles, branching out into many different pathways.3 4 1.3.1 Titanium-Catalzyed Intermolecular Hydroamination of Alkynes (a) Proposed Mechanism for Titanium-Catalyzed Intermolecular hydroamination R2 R3 N Ti R1 X X H2NR1 R3 R2 TiX2A2 H2NR1 − 2 HA Dimerization N Ti R1 X X X X R1 Ti N N Ti R1 X X R2 R1 R3 N H H enamine R2 R3 R1HN R1 X N X R2 N Ti R3 R1H2N R1 X X R ate D etermining Step (b) Synthesis for Titanium Precatalysts from the Odom group + H N O H H H2NMe•HCl (0.5 equiv) EtOH/H2O H N N H N N N N Ti N N Ti(NMe2)4 ether − 35 °C to r.t H N + O 10 mo % TFA H H 5 min, r.t H2dpma Ti(NMe2)2(dpma) HN H N H2dpm Ti(NMe2)4 ether − 35 °C to r.t N Ti N NMe2 NMe2 Ti(NMe2)2(dpm) Figure 1.3 Proposed mechanism for titanium-catalyzed intermolecular hydroamination and synthetic routes for titanium precatalysts with H2dpma and H2dpm. In 2001, the Odom group discovered that the commercially available reagent Ti(NMe2)4 is a catalyst for hydroamination of alkynes, which is cheaper and more stable than previously reported precatalysts, such as zirconocene- and titanocene-based catalysts.9 Comparing to titanocene-based catalysts, Ti(NMe2)4 provides faster reaction rates in many cases. The reaction 5 mechanism (Figure 1.4) is originally established by Bergman and coworkers for zirconocene- based catalysts.11,12 The titanium precatalyst reacts with an amine to form a titanium imido complex, the active catalyst, and the titanium imido complex and alkyne undergo [2 + 2]- cycloaddition to form a four-membered titanium metallacycle. Lastly, another amine binds to the metal center and protons from the amines are transferred to release the enamine product. The protonolysis of the titanium-carbon bond is believed to be the rate determining step in the catalytic cycle. Also, dimerization of the titanium imido complex, the active catalyst, is believed to be inhibiting the catalysis. Although Ti(NMe2)4 provides relatively good reactivity and substrate scope, multiple pyrrole-based ancillary ligands have been developed to improve the catalytic activity. The first pyrrole-based ancillary ligand in the Odom group was H2dpma (N,N-di(pyrrolyl-a-methyl-N- methylamine), synthesized via Mannich condensation of pyrrole, formaldehyde and methylamine hydrochloride.12 Another representative pyrrole-based ancillary ligand in the Odom group is H2dpm (5,5-dimethyldipyrrolylmethane), synthesized via Friedel-Crafts reaction of pyrrole and acetone with a catalytic amount of trifluoroacetic acid (Figure 1.5).14 With our titanium catalysts, hydroamination between primary amines and alkynes provide good regioselectivity to produce Markovnikov products in the most cases.13,14 However, the regioselectivity varies depending on precatalyst. For example, hydroamination between aniline and 1-hexyne with Ti(dpma)(NMe2)2 is higly selective for the Markonikov product (>50:1), whereas the same reaction with Ti(dpm)(NMe2)2 provide a selectivity of 6:1. Moreover, these precatalysts brought the opposite results in terms of regioselectivity for hydroamination between aniline and 1-phenylproypne. The reaction with Ti(dpma)(NMe2)2 is selective for the anti- Markonikov product (1:19) however, Ti(dpm)(NMe2)2 provides an excellent regioselectivity of 50:1. Other than H2dpma and H2dpm, various pyrrole-, indole-, or phenol-based bidentate ancillary ligands were synthesized in the Odom group to investigate ligand effects on titanium-catalyzed hydroamination of alkynes. 1.3.2 Titanium-Catalyzed Iminoamination According to the Bergman hydroamination mechanism, the protonolysis of the titanium- carbon bond is slow from the four-membered titanium metallacycle from [2 + 2]-cycloaddition. The titanium metallacycle has a reactive titanium-carbon bond, and our group tried to utilize the bond to form another compound with an isonitrile before the slow step of proton transfer to release 6 the enamine product. This led to the discovery of a three-component coupling reaction, which forms a new C-C and C-N bond by using a primary amine, an alkyne, and an isonitrile.10 R2 R3 N Ti R1 X X R3 R2 TiX2A2 H2NR1 − 2 HA N Ti R1 X X R4 N NH R1 R2 R3 α,β-unsaturated imines R1 N Ti X X R2 NHR1 R3 R4 N R4NC R1 X X N Ti R2 R3 N R4 R2 R3 R1 X X N Ti N R4 H2NR1 H2NR1 Scheme 1.2 Proposed mechanism for titanium-catalyzed iminoamination. The mechanism of the three-component coupling reaction involves a titanium metallacycle as one of intermediates. It is proposed that isonitrile 1,1-inserts into the reactive titanium-carbon bond of the titanium metallacycle. Then protonolysis produces the 1,3-diimine product. The final product is produced through the formal addition of an iminyl and amino group to the C-C triple bond, resulting in iminoamination. Ti(NMe2)2(H2dpma) and Ti(NMe2)2(H2dpm) are employed for iminoamination, and with these catalysts, iminoamination usually gives around 70% yield. 1.4 Titanium-Catalyzed iminoamination for N-Heterocycle Synthesis The 1,3-diimines from alkyne iminoamination offer a convenient route to synthesize complex structures that would otherwise require multiple steps using alternative methods. These versatile 1,3-diimines find extensive use in the synthesis of various N-heterocyclic compounds. Typically, the iminoamination product is not isolated but instead used in a one-pot procedure to build N-heterocycles, enabling the fast and convenient synthesis of various heterocyclic cores in an one-pot reaction sequence. 7 H2NR1 R3 + + R2 R4NC Ti(dpm)(NMe2)2 or Ti(dpma)(NMe2)2 R4 N NH R1 R2 R3 4th component N-Heterocycles Figure 1.4 Synthetic route for N-heterocycles using titanium-catalyzed iminoamination. These 1,3-diimines, with amines as leaving groups on both ends, exhibit comparable reactivity to 1,3-dicarbonyl compounds. As a result, they are utilized as intermediates in the synthesis of various N-heterocycles. Typically, reagents utilized as the 4th component in the synthesis of N-heterocycles contain functional groups that facilitate cyclization, which connect to each end of 1,3-diimines. 1.4.1 [3 + n]-Heterocyclizations: Isoxazole, Pyrimidine, and Pyrazole Synthesis The process of (3+n)-heterocyclizations involves utilizing 1,3-diimines as a three-carbon backbone and a fourth component as a linker to connect the 1- and 3-positions of the backbone. This results in the formation of heterocyclic products by removing two amines from the 1,3- diimine as leaving groups. With this strategy, pyrazoles, pyrimidines, and isoxazoles can be easily prepared by a one-pot titanium catalyzed iminoamination reactions (Figure 1.6). Pyrazoles can be prepared by a one-pot iminoamination reaction followed by addition of hydrazine hydrate or monosubstituted hydrazines in pyridine as a solvent and base in the reaction. Although the yields from the one-pot synthesis for pyrazoles are not high, various pyrazoles are easily prepared from simple and common reagents compared to other multistep synthesis. 8 H2NR1 R3 + + R2 NC R4 Ti(dpm)(NMe2)2 or Ti(dpma)(NMe2)2 R4 N NH R1 R2 R3 R N N R3 R2 H2NNH2 or H2NNHR H2NOH X NH2 NH R N N R2 R3 N O R2 R3 X X X R2 R3 Figure 1.5 Synthetic routes for isoxazoles, pyrimidines, pyrroles, and pyrazoles using titanium- catalyzed iminoamination. In this reaction, a mixture of two regioisomers could be produced as final products if internal alkynes are used for iminoamination and monosubstituted hydrazine is used as 4th component. However, the unsubstituted NH2 group prefers to attack on the sterically less hindered carbon of the backbone so that 1,4,5-trisubstituted pyrazole is produced as the major product with good regioselectivity. For example (Eq 1.1), a one-pot synthesis (using aniline, 1-phenylpropyne, and tert-butyl isocyanide for imminoamination and phenylhydrazine as 4th component) gives 1,4- diphenyl-3-methylpyrazole as a major product (9:1).15 Ph Me tBu N HN H2NNHPh Ph pyridine, 150 °C 24 h Me Ph N N Ph N N Ph Ph Me 9 : 1 (Eq 1.1) (Eq 1.1) Pyrimidines and isoxazole can be prepared in a similar manner to the pyrazole synthesis but, instead of hydrazines, amidine and hydroxylamine are used as 4th component.16 In the isoxazole synthesis, products were synthesized in a regioselective manner because the NH2 group of hydroxylamine selectively attacks the sterically less hindered carbon of 1,3-diimines.17 Moreover, symmetric amidines do not bring any issue in regioselectivity in the pyrimidine synthesis. 9 1.4.2 [4 + 2]-Heterocyclizations: Pyridine and Quinoline Synthesis The process of [4 + 2]-heterocyclizations also involves utilizing 1,3-diimines as a three- carbon backbone and a fourth component as a linker to connect the 1- and 3-positions of the backbone. However, this process only loses one amine, and the other amine becomes a part of six- membered heterocycle product. With this strategy, various quinolines and 2-amino-3- cyanopyridines can be easily synthesized by a one-pot titanium-catalyzed iminoamination reaction. H H2N R2 R R3 + + R4NC 10 mol % Ti(dpm)(NMe2)2 toluene, 100 °C 24 h R H R4 N NH R2 R3 AcOH R 150 °C, 24 h N R3 R2 Figure 1.6 Synthesis of substituted quinolines using a one-pot titanium-catalyzed iminoamination. In the case of quinoline synthesis, an aniline is used as a primary amine to produce 1,3- diimine, and electrophilic cyclization leads to quinoline derivatives in the presence of acetic acid.18 The only byproduct from this reaction is the amine derived from isonitrile. In this reaction, anilines should have at least one ortho-hydrogen for cyclization. Moreover, this synthetic method is not only limited to quinolines but also other fused-ring systems including other heterocycles, such as thiophenes, pyrroles. Another one-pot synthesis was developed for the synthesis of 2-amino-3-cyanopyridines.19 The reaction between imminoamination and malononitrile in the presence of DBU produced 1,2- dihydro-2-imino-3-pyridinecarbonitrile intermediate. A Dimroth rearrangement occurs from this intermediate to synthesize 2-amino-5-cyanopyridines as the final products (Figure 1.8). The intermediate can be isolated using triethylamine instead of DBU as well. More than twenty examples of 2-amino-3-cyanopyridines were synthesized using this method. The exploration of NRF2 inhibitors was sparked by one of the products in this project.20,21 10 (a) Synthesis of 2-amino-3-cyanopyridines using an one-pot titanium catalyzed iminoamination H2NR1 R3 10 mol % Ti(dpm)(NMe2)2 R4 NH N R1 R2 toluene, 100 °C 24 h R3 + + R2 NC R4 N N (2 equiv.) DBU (0.5 equiv.) EtOH, 80 °C, 2 h R1 N R2 NH CN R3 R1 HN Rearrangement N CN R2 R3 (b) Proposed Mechanism for pyridine synthesis from 1,3-diimine and malononitrile R4 NH N R1 R2 R3 N N − H2NR4 R1 NH R2 N R3 CN 6-exo dig NH CN H R1 N R2 R3 NHR1 CN N R2 NR1 CN NH R2 NH2 CN N R1 B R2 NH2 CN N R1 B R2 R3 R3 R3 R3 NH2 CN R3 NH2 CN R1 N R2 N N N R1 B R2 R3 (B = DBU) Figure 1.7 Synthesis of 2-amino-3-cyanopyridines using a one-pot titanium-catalyzed iminoamination and proposed mechanism for pyridine synthesis from 1,3-diimines and malononitrile. In conclusion, the utilization of titanium-catalyzed iminoamination products allowed for the synthesis of a diverse range of heterocycles in one-pot syntheses. These syntheses efficiently transform commercially accessible starting materials to various N-heterocyclic compounds. Now our group’s research has focused on the improvement in the activity of titanium catalysts by modifying ligand properties as well as the application of N-heterocycles. 1.5 Titanium Catalyst Development: Asymmetric Ancillary Ligands for Titanium Catalysis The most common approach for catalyst development involves modifying ligands to alter reactivity. Nonetheless, quantified data is necessary to make this process effective since ligand design involves multiple variables, including electronic and steric effects, which can make it 11 challenging. To provide a better approach to investigate electronic effects of anionic ligands, the Odom group developed an experimentally-defined parameter for the electron donation of ancillary ligands towards a high oxidation state transition metal center. Figure 1.8 Chromium system for the measurement of LDP of ligand X, and a space-filling model of the chromium complex with a pyrrole(red) for X ligand.24 The blue sphere is positioned 3.5 Å away from the metal center, while the overlapped region(purple) between the blue sphere and the red area (representing pyrrole) is the volume occupied by pyrrole within the 3.5 Å sphere. To parameterize donor effects of ligands, the Odom group synthesized chromium(VI) complexes, NCr(NiPr2)2X, with mono-anionic ligands X.22 In this system, the electron donation competition between the amido ligand and the X ligand influences the Cr-NiPr2 bond's single or double bond character. When X is a good donor ligand, the amide ligand donates less electron to the metal, and the Cr-N bond will have more single bond character. In contrast, a poor donating X ligand provides an amide ligand with more double bond character. As a result, the rotational enthalpic barrier of the Cr-N bond can be used as a parameter for the X ligand's donor ability towards the metal center. Using Spin-Saturation Transfer (SST), the Cr-N bond rotation rate can be determined. The enthalpic barrier for rotation (ΔH‡) can be obtained from this rate. This value of ΔH has been referred to as the Ligand Donation Parameter (LDP), allowing direct and quantitative comparison of the electronic donor ability between various ligands towards an early transition metal. A high LDP indicates weak donor ability to the metal center by the ligand, while a low LDP suggests that 12 the ligand is a strong donor. In the previous study from the Odom group, donor abilities of various ligands were evaluated with this technique (Figure 1.10).22 Figure 1.9 Ligand Donor Parameters (kcal/mol) for various X in NCr(NiPr2)2X.22 To quantify the ligand steric effects, web-based software made by Cavallo and coworkers is used.23 With crystal structure data of chromium(VI) complexes, the percentage of the coordination sphere taken up by the ligand within 3.5 angstrom radius from the metal can be measured. Considering a sphere with a radius of 3.5 Å around the metal, the software demonstrates a strong correlation with Tolman's cone angle in some cases. Using this tool, the steric effect is taken into account by using this measured volume (percent buried volume or %Vbur). This %Vbur steric effect was used with LDP in a simple model (Eq. 1.2). "!"# × 10$ = 1.34 + 1.61(-./) − 2.25(%5"%&) (Eq. 1.2) The Odom group studied a series of catalysts with using these techniques, LDP and %Vbur.24 Various titanium catalysts were synthesized with symmetric ancillary ligands, and experimental reaction rates for hydroamination with these catalysts were successfully modelled 13 using LDP and %Vbur. Based on the model, catalysts with electron-deficient and small ligands provide faster reaction rates than those with electron-rich and sterically bulky ligands. With this model, it is possible to predict reaction rates of catalysts with only LDP and %Vbur values. Furthermore, the database of LDP and %Vbur can be useful to improve other early transition metal catalysis with ancillary ligands. Despite successfully modeling the titanium-catalyzed reaction, one limitation in improving catalysts is that all ancillary ligands were symmetric in the previous study. To investigate the ligand effects of asymmetric ancillary ligands, multiple titanium catalysts were synthesized and a new model was obtained (vide infra). 1.6 Conclusion Titanium, an Earth abundant transition metal, is non-toxic and provides attractive reagents or catalysts, and various synthetic methods for N-heterocycle synthesis using titanium reagents were developed. Using these synthetic methods, various nitrogen-containing heterocyclic compounds are easily accessed. Taking advantage of properties of titanium complexes, the Odom group has been focusing on titanium-catalyzed and titanium-mediated reactions for nitrogen- containing heterocyclic compounds. During my doctoral study, I have studied titanium-mediated Diels-Alder reactions from isoxazoles and enamines, and unsymmetrical ancillary ligand effect for titanium-catalyzed hydroamination to improve titanium catalysis. Furthermore, I have worked on exploration and development of NRF2 inhibitors derived from titanium-catalyzed iminoamination reactions. 14 REFERENCES 1. Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57 (24), 10257–10274. 2. Douguet, D. Data Sets Representative of the Structures and Experimental Properties of FDA- Approved Drugs. ACS Med. Chem. Lett. 2018, 9 (3), 204–209. 3. Odom, A. L.; McDaniel, T. J. Titanium-Catalyzed Multicomponent Couplings: Efficient One- Pot Syntheses of Nitrogen Heterocycles. Acc. Chem. Res. 2015, 48 (11), 2822–2833. 4. Ohta, K.; Iwaoka, J.; Kamijo, Y.; Okada, M.; Nomura, Y. Formation of Pyridines by the Reaction of Isoxazoles with Enamines. NIPPON KAGAKU KAISHI 1989, 1989 (9), 1593– 1600. 5. Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.; Takayama, Y.; Sato, F.; Urabe, H. One-Pot Synthesis of Metalated Pyridines from Two Acetylenes, a Nitrile, and a titanium(II) Alkoxide. J. Am. Chem. Soc. 2005, 127 (21), 7774–7780. 6. Tong, S.; Xu, Z.; Mamboury, M.; Wang, Q.; Zhu, J. Aqueous Titanium Trichloride Promoted Reductive Cyclization of O-Nitrostyrenes to Indoles: Development and Application to the Synthesis of Rizatriptan and Aspidospermidine. Angew. Chem. Int. Ed Engl. 2015, 54 (40), 11809–11812. 7. (a) Hao, W.; Wu, X.; Sun, J. Z.; Siu, J. C.; MacMillan, S. N.; Lin, S. Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of N-Acylaziridines and Alkenes. J. Am. Chem. Soc. 2017, 139 (35), 12141–12144. (b) Tarantino, K. T.; Miller, D. C.; Callon, T. A. Bond- Weakening Catalysis: Conjugate Aminations Enabled by the Soft Homolysis of Strong N–H Bonds. J. Am. Chem. Soc. 2015, 137 (20), 6440–6443. 8. Lee, S.; Jena, R.; Odom, A. L. Substituted Pyridines from Isoxazoles: Scope and Mechanism. Org. Biomol. Chem. 2022, 20 (33), 6630–6636. 9. Shi, Y.; Ciszewski, J. T.; Odom, A. L. Ti(NMe2)4 as a Precatalyst for Hydroamination of Alkynes with Primary Amines. Organometallics 2001, 20 (19), 3967–3969. 10. Cao, C.; Shi, Y.; Odom, A. L. A Titanium-Catalyzed Three-Component Coupling to Generate Alpha,beta-Unsaturated Beta-Iminoamines. J. Am. Chem. Soc. 2003, 125 (10), 2880–2881. 11. Walsh, P. J.; Baranger, A. M.; Bergman, R. G., J. Am. Chem. Soc. 1992, 114, 1708-1719. 12. Baranger, A. M.; Walsh, P. J.; Bergman, R. G., J. Am. Chem. Soc. 1993, 115, 2753-2763. 13. Cao, C.; Ciszewski, J. T.; Odom, A. L. Hydroamination of Alkynes Catalyzed by a Titanium Pyrrolyl Complex. Organometallics 2001, 20, 5011–5013. 14. Shi, Y.; Hall, C.; Ciszewski, J. T.; Cao, C.; Odom, A. L. Titanium Dipyrrolylmethane Derivatives: Rapid Intermolecular Alkyne Hydroamination. Chem. Commun. 2003, No. 5, 586–587. 15 15. Majumder, S.; Gipson, K. R.; Staples, R. J.; Odom, A. L. Pyrazole Synthesis Using a Titanium- Catalyzed Multicomponent Coupling Reaction and Synthesis of Withasomnine. Adv. Synth. Catal. 2009, 351 (11-12), 2013–2023. 16. Majumder, S.; Odom, A. L. Titanium Catalyzed One-Pot Multicomponent Coupling Reactions for Direct Access to Substituted Pyrimidines. Tetrahedron 2010, 66 (17), 3152–3158. 17. Dissanayake, A. A.; Odom, A. L. Regioselective Conversion of Alkynes to 4-Substituted and 3,4-Disubstituted Isoxazoles Using Titanium-Catalyzed Multicomponent Coupling Reactions. Tetrahedron 2012, 68 (3), 807–812. 18. Majumder, S.; Gipson, K. R.; Odom, A. L. A Multicomponent Coupling Sequence for Direct Access to Substituted Quinolines. Org. Lett. 2009, 11 (20), 4720–4723. 19. Dissanayake, A. A.; Staples, R. J.; Odom, A. L. Titanium-Catalyzed, One-Pot Synthesis of 2- Amino-3-Cyano- Pyridines. Adv. Synth. Catal. 2014, 356 (8), 1811–1822. 20. Hou, Z.; Lockwood, L.; Zhang, D.; Occhiuto, C. J.; Mo, L.; Aldrich, K. E.; Stoub, H. E.; Gallo, K. A.; Liby, K. T.; Odom, A. L. Exploring Structural Effects in a New Class of NRF2 Inhibitors. RSC Med Chem 2023, 14 (1), 74–84. 21. Zhang, D.; Hou, Z.; Aldrich, K. E.; Lockwood, L.; Odom, A. L.; Liby, K. T. A Novel Nrf2 Pathway Inhibitor Sensitizes Keap1-Mutant Lung Cancer Cells to Chemotherapy. Mol. Cancer Ther. 2021, 20 (9), 1692–1701. 22. Bemowski, R. D.; Singh, A. K.; Bajorek, B. J.; DePorre, Y.; Odom, A. L. Effective Donor Abilities of E-T-Bu and EPh (E = O, S, Se, Te) to a High Valent Transition Metal. Dalton Trans. 2014, 43 (32), 12299–12305. 23. Falivene, L.; Credendino, R.; Poater, A.; Petta, A.; Serra, L.; Oliva, R.; Scarano, V.; Cavallo, L. SambVca 2. A Web Tool for Analyzing Catalytic Pockets with Topographic Steric Maps. Organometallics 2016, 35 (13), 2286–2293. 24. Billow, B. S.; McDaniel, T. J.; Odom, A. L. Quantifying Ligand Effects in High-Oxidation- State Metal Catalysis. Nat. Chem. 2017, 9 (9), 837–842. 25. DiFranco, S. A.; Maciulis, N. A.; Staples, R. J.; Batrice, R. J.; Odom, A. L. Evaluation of Donor and Steric Properties of Anionic Ligands on High Valent Transition Metals. Inorg. Chem. 2012, 51 (2), 1187–1200. 16 Chapter 2. Titanium-Mediated Pyridine Syntheses from Isoxazoles via inverse electron- demand hetero-Diels-Alder reaction (IEDDA) 2.1 Introduction Pyridines, six-membered heterocyclic aromatic compounds containing one nitrogen atom, attract significant attention in various fields. Pyridine scaffolds occur in many important compounds, including agrochemicals, pharmaceuticals, and vitamins (Figure 2.1).1 According to the database published by Douguet and colleagues, 223 drugs have pyridine moieties among 2056 drugs approved by FDA as of July 2022.2 S NH O O O N O N O S N HN O Pigolitazone (Anti-diabetic medication) Esomeprazole (Proton pump inhibitor) Cl Cl N Cl S P OEt OEt Chlorpyrifos (insecticide) HO HO OH N Vitamin B6 Figure 2.1 Examples of bioactive substituted pyridines. Pyridines (or bipyridines) have been widely used as ligand for various catalysts due to their robust redox stability and ease of functionalization. For instance, various types of pyridine or bipyridine ligands are predominantly used in such reactions as iridium-catalyzed C-H borylation, and photocatalysis.4,5 Given the importance of substituted pyridines, chemists have been studying preparation of highly substituted pyridines for over a century. For example the Hantzsch synthesis was published in 1881.6 17 2.1.1 Condensation Strategy to Substituted Pyridines (a) Condensation of 1,5-dicarbonyl O R2 O NH3 R1 R3 R2 R2 [O] R1 N H R3 R1 N R3 (b) Hantzsch Synthesis O + O O NH3 H R1 R2 OR3 2 equiv. O R1 O [O] O R1 O R3O OR3 R3O OR3 R2 N H R2 R2 N R2 Figure 2.2 Preparation of substituted pyridines using a condensation approach. One of the most common synthetic methods for substituted pyridines is the condensation of carbonyl compounds. In the case of condensation of 1,5-dicarbonyl and Hantzsch synthesis6 (Figure 2.2), ammonia reacts with ketones or aldehydes, and generates 1,4-dihydropyridines as intermediates. These intermediates can be oxidized to generate substituted pyridines. Although these methods are widely used, limitations still exist. For example, pyridines generated from Hantzsch synthesis must have ester groups in the 3- and 5-positions on the pyridine. 2.1.2 Cycloaddition Strategy to Substituted Pyridines O O + N NMe2 O H MeCN, ultrasound, 0.5 h 88% N Me2N H O Air, r.t, 24h 92% N O O Figure 2.3 Preparation of substituted pyridines using cycloaddition of 1-azadiene.7 Cycloaddition between 1-azadiene and an alkene or alkyne, followed by subsequent oxidation is a straightforward synthetic route to access substituted pyridines. In 1994, Menendez and coworkers published a reaction between 1-azadienes and electron-deficient dienophiles to form pyridines using ultrasound.7 In the case of the reaction between 1-azadiene and dienophile, 1-azadiene undergoes [4 + 2]-cycloaddition with a dienophile, and 1,4-dihydropyridine is formed. Subsequent oxidation leads to pyridines from 1,4-dihydropyridines by losing amine. Many of Diels-Alder reactions with 1-azadiene have developed. However, this pathway often requires harsh reaction conditions and is disfavored because conformational (s-cis ⇋ s-trans) and tautomeric 18 equilibria (imine ⇋ enamine) of 1-azadienes lower the concentration of reactive species. In addition, the high electronegativity of the nitrogen in 1-azadiene lowers the reactivity of 1- azadiene in the case of “normal” electron demand Diels-Alder reactions.7 2.1.3 Inverse-Electron Demand Diels-Alder (IEDDA) Reactions to Substituted Pyridines IEDDA with cyclic 1- or 2-azadienes is a rapid synthetic pathway to substituted pyridines. Isoxazole and oxazole are cyclic 1- and 2-azadienes, respectively. In 1984, Weinreb and coworkers published a paper including a IEDDA reaction between oxazole and olefin for the Kondrat'eva synthesis.8 In the case of the reaction with oxazole, oxazole undergoes [4 + 2]-cycloaddition, and a norbornene-like intermediate is formed. Depending on the reaction conditions, it is suggested that three distinct final products may be generated from the same intermediate. Although cycloaddition with oxazole is a less energy demanding reaction than isoxazole, this reaction might not be selective to form a single product.9 (a) Inverse Electron Demand Diels-Alder reaction with oxazole O N R1 + R2 R3 R3 R2 O N R1 R2 R2 R3 HO R3 HO R3 R1 N R1 N R1 N (- H2O) (- HR2) (- H2) (b) Inverse Electron Demand Diels-Alder reaction with Isoxazole R3 R2 R1 + O N R2N R4 R5 R2 R1 R3 O N R4 R5 NR2 R2 R1 R3 N O R4 R5 normally not observed R3 R2 R1 N R4 R5 Figure 2.4 Preparation of substituted pyridines using IEDDA of cyclic 1- and 2-azadienes. Another pathway to build substituted pyridines is an IEDDA reaction with isoxazole. This reaction was first reported by Ohta and coworkers in 1989 using titanium tetrachloride (TiCl4) and zinc as reductant.10 In this work, it is proposed that isoxazole undergoes [4 + 2]-cycloaddition to form the [2.2.1]-oxazabicyclic intermediate, and then amine loss and reduction from this intermediate leads to substituted pyridines. This reaction of isoxazoles with electron-rich olefins not only changes isoxazoles to pyridines with removal of the oxygen atom in isoxazole but also 19 adds new substituents in a regioselective manner in the pyridine core. This type of “scaffold hopping” reaction is an appealing synthetic method because the core structure of heterocycles can be switched to another core structure while leaving the substituents the same or adding complexity to it.15-19 For instance, one can change the core structure by adding or deleting a nitrogen atom to convert cyclic compounds to other cyclic compounds.20-22 These “scaffold hopping” reactions enable rapid exploration of structural relationships to biological activity.17 The Odom group has been exploring a novel class NRF2 (Nuclear factor-erythroid factor 2-related factor 2) inhibitors with 2-amino-3-cyanopyridines.23,24 This synthetic approach could be highly efficient to generate diverse pyridine compounds that function as NRF2 inhibitors, particularly when combined with our group's established synthetic method for 3,4-disubstituted isoxazoles.25,26 The previous work showed that IEDDA reaction between isoxazoles and enamines has an excellent regioselectivity so that substituents at all positions of pyridines can be utilized.10,11 However, this method still has limitations such as air-sensitive reagents and poor yields, and the substrate scope was limited to isoxazoles with simple alkyl groups. Therefore, I have re-visited this chemistry to reoptimize the reaction conditions and to develop a more reliable method using bench-stable reagents with an easier reaction setup.12 In addition, we put effort to understand the mechanism of the reaction using Density Function Theory (DFT), the effects of solvents on the reaction using the Solvent Model based on the SMD method, and the role of TiCl4 as a possible Lewis acid in the reaction. 2.2 Experimental Results and Discussion The previous work by Ohta and coworkers proposed that pyridine-N-oxide is a possible intermediate and can be reduced to form pyridines in the presence of TiCl4 and zinc dust,10 however, TiCl4 is known to be highly corrosive and reactive. It readily undergoes rapid hydrolysis through a vigorous exothermic reaction. Instead of reactive TiCl4, commercially available and more bench stable TiCl4(THF)2 was used for optimization of this reaction. In addition, various reductants were employed in the optimization process, apart from zinc dust. 20 Table 2.1 Optimization of pyridine synthesis using TiCl4(THF)2 and reductants.12 O + N N 1a 2a x equiv TiCl4(THF)2 (y equiv) Ti powder (z equiv) dioxane, 100 °C N 3a Entry 1 2 3 4 5 6 7 8 9 10 11 12 x / y / z 4 / 1 / 1 3 / 1 / 1 2 / 1 / 1 4 / 2 / 1 4 / 1 / 2 2 / 1 / 1 2 / 1 / 1 2 / 1 / 2.2 4 / 1 / 1 4 / 2 / 1.5 4 / 2 / 1.2 4 / 2 / 1.2 Reductant GC % Yield Ti powder Ti powder Ti powder Ti powder Ti powder Zn dust Al pellets Mg turning Sn powder Rieke Zn Ti powder Zn dust 80 69 58 69 68 61 45 38 65a 53a 53a 46a aTHF was used in place of dioxane as solvent. For the optimization reaction, isoxazole and 1-pyrrolidino-1-cyclohexene were used. In this reaction, 1 equivalent of TiCl4(THF)2, 1 equivalent of titanium powder, and 4 equivalent of enamine in dioxane gave the highest yield (Table 2.1, Entry 1). With these conditions, various isoxazoles and enamines were investigated. To see the substrate scope of isoxazoles, a large series of isoxazoles were reacted with 1-pyrrolidino-1-cyclohexene (Scheme 2.1). These reactions gave good yields in general. Many common functional groups in the 3- and 4-positions of the isoxazoles are tolerated in this reaction, such as alkyls, aryls, acylamines, and halides. Furthermore, 3,4- dimethyl-1,2,5-oxadiazole (dimethylfurazane) was also employed for this reaction to produce 2,3- dimethylpyrazine. 21 R3 O + N R2 R1 N 4 equiv TiCl4(THF)2 (1 equiv) Ti powder (1 equiv) R2 R3 dioxane, 100 °C 12 h R1 N Br N 70% N N 76% N N 19% 82% N 41% N S 72% O N H N N 21% Trace amount O OEt N N 73% Trace amount Scheme 2.1 Pyridine synthesis with 1-pyrrolidino-1-cyclohexene. Isolated yields are reported. Unfortunately, the yield is significantly reduced when isoxazoles have substituents in the 5-position(R3) or large substituents in the 4-position(R2). In this reaction, enamine attacks into 5- position of isoxazole and undergoes [4 + 2]-cycloaddition; therefore, it is assumed that steric protection from the 5-position or a bulky group in the 4-position of isoxazole leads to reduced yield. Only a trace amount of product was formed from the reaction with an ester group in either the 3- or 5-position of isoxazole, and no product from 3,5-dimethylisoxazole was observed by GC- MS. In previous reports, the IEDDA of isoxazoles showed excellent regioselectivity with a single product formed.10,11 In order to study the regioselectivity as well as substrate scope of enamines in the reaction, a few monoaryl enamines were investigated, such 2-phenyl-1-(1-pyrrolidinyl)ethene (2b) and 2-methyl-1-phenyl-1-(1-pyrrolidinyl) (2b) (Scheme 2.2). Reactions with these enamines produced products selectively with excellent regioselectivity. 22 R2 R1 R3 O + N N R4 R5 4 equiv R3 TiCl4(THF)2 Ti powder R2 dioxane, 100 °C 12 h R1 N R4 R5 N Br 84% N 84% Br N 86% N 77% N 80% O N H N 65% N 67% Scheme 2.2 Pyridine synthesis with monoaryl enamines. Isolated yields are reported. These monoaryl enamine reactions include 1-phenyl-1-(1-pyrrolidinyl)ethene (2c) as well. Considering steric effects from substituents in the 2-position of enamine, 1-phenyl-1-(1- pyrrolidinyl)ethene (2c) was expected to be more reactive than 2-phenyl-1-(1-pyrrolidinyl)ethene (2b); however, 1-phenyl-1-(1-pyrrolidinyl)ethene (2c) did not give any pyridine products. Similarly, reaction between 4-bromoisoxazole and 1-methyl-1-(1-pyrroldinyl)ethene generates 3- bromo-5-methylpyridine in 50% GC yield. However, the reaction between 4-bromoisoxazole and 2-methyl-1-(1-pyrroldinyl)ethene did not give the corresponding pyridine. (Scheme 2.6 in Experimental Details). This result aligns with the findings from Mayr and colleagues regarding the nucleophilicity of enamines in relation to their substitution patterns in 2003.13 These results suggested that internal alkenes (e.g. 2-phenyl-1-(1-pyrrolidinyl)ethene) have higher nucleophilicity than terminal alkenes (e.g. 1-(1-pyrrolidinyl)ethene) Enamines with higher nucleophilicity are more reactive for this reaction. 23 (a) (b) TiCl4(THF)2 Ti powder Ph Ph O Electrophile Relative reactivities krel of enamines N + N dioxane, 100 °C 12 h 1a 2b O N + Me TiCl4(THF)2 Ti powder N Ph dioxane, 100 °C 12 h 1a 2c N 84% Me N Ph 67% (reaction condition) Ph NR2 Ph NR2 (mpa)2CH+ 1 16 (CH2Cl2, 20 °C) (mfa)2CH+ 1 15 (CH2Cl2, 20 °C) NR2 = N O N + N Ph 1a 2d TiCl4(THF)2 Ti powder dioxane, 100 °C 12 h N Ph No product observed N mpa = mfa = N CF3 lil = N Figure 2.5 (a) Reactions between isoxazole12 (a) and monoaryl enamines (2b, 2c, and 2d). (b) Relative reactivity between internal and terminal alkenes (1-phenyl-1-(1-piperidinyl)ethene vs. 2- phenyl-1-(1- piperidinyl)ethene).13 Moreover, pyrrolidine-based enamines provide higher nucleophilicity than piperidine- and morpholine-based enamines. These results are consistent with our findings for this reaction. In addition, in 2013, Houk and coworkers published a computational study on the mechanism of 1,3- dipolar cycloaddition of phenyl azides with enamines, showing that the energy barrier with internal alkene is slightly lower than terminal alkene.14 R2 R1 R3 O + N N R4 R5 4 equiv R3 TiCl4(THF)2 Ti powder R2 dioxane, 100 °C 12 h R1 N R4 R5 Br Br N N N N N 90% 88% 91% 67% 84% Scheme 2.3 Pyridine synthesis with diaryl enamines. Isolated yields are reported. 24 A couple of diaryl enamines were investigated as well. Reactions with 1-(1,2- diphenylvinyl)pyrrolidine and 1-(1,2-di-p-tolylvinyl)pyrrolidine gave excellent yields (Scheme 2.3). Using this method, multi-arylated pyridines were synthesized with excellent regioselectivity. Lastly, the mechanism of the reaction was also experimentally investigated. In 1992, Nesi and coworkers reported [4 + 2]-cycloaddition of 4-nitro-3-phenylisoxazole-5-carboxylates with enamines, and it is shown that pyridine-N-oxide was isolated as an intermediate and then reduced to generate pyridines.11 In our reaction conditions, pyridine-N-oxides were not observed by any means; therefore, it was hypothesized that tetrahydroquinoline-N-oxide, the intermediate of the reaction, was produced for reduction. Therefore, ethereal solvents that are likely to act as a radical donor was removed from the reaction to prevent radical reaction. TiCl4 and benzene were used in place of TiCl4(THF)2 and dioxane, respectively. However, 5,6,7,8-tetrahydroquinoline (3a) was only observed by GCMS and GCFID (Scheme 2.4, Eq. 2.1). Another possible assumption is that enamine acts as reductant. Therefore, an excess of isoxazole was employed in case some enamine is used in side reactions (Scheme 2.4, Eq. 2.2). However, pyridine-N-oxide intermediate were never observed. O N 1a TiCl4 N benzene, 100 °C 2a (4 equiv) N 3a (31%) (Eq. 2.1) O N 1a (4 equiv) N 2a TiCl4 benzene, 100 °C N N O (Eq. 2.2) 3a observed by GCMS not observed by GCMS Scheme 2.4 The reaction of isoxazole and 1-(1-cyclohexenyl)pyrrolidine with TiCl4 in benzene. 2.3 Computational Results and Discussion The investigation of the reaction mechanism was not only conducted using experimental methods but also computational methods. Density Functional Theory, B3LYPD3 with aug-cc- pVDZ, was employed to study the mechanism. The investigation was initiated by gas phase calculations and using the Solvent Model based on Density (SMD) method to study the effects of 25 solvents on the reaction was modelled for the experimental solvent, 1,4-dioxane. In addition, the effect of Lewis acids on the reaction were investigated using TiCl4. R3 + O N R4 R5 R2 R1 R3 O N R2 R1 [4 + 2] NR2 Pathway A R3 O N R2 R1 − HNR2 R4 R5 R3 R2 R1 N R4 R5 reductant R2 R1 R3 N O R3 O N NR2 R5 R4 R4 R5 NR2 or R2 R1 Pathway B R2 R1 R3 N O − HNR2 R4 R5 R4 NR2 R5 R3 R2 R5 R1 R4 N not observed Scheme 2.5 The IEDDA (inverse-electron demand hetero-Diels Alder) reaction of isoxazole with enamine produces substituted pyridines after in situ reduction in the presence of reductant.12 Depending on whether ring-opening or amine loss occurs first, the reaction mechanism can be divided into two main pathways after cycloaddition. 2.3.1 Cycloaddition Despite the proposal of two potential pathways, pathways A and B share a [4 + 2]- cycloaddition step. Hence, the investigation was initiated with the cycloaddition. The cycloaddition step gives us four possible isomers: endo and exo of I1 and I1*. However, the energy difference between endo and exo was typically within ~3 kcal/mol, hence only endo isomers (all intermediates and transition states) will be shown to simplify the figures and discussion. In the calculations modelling 1,4-dioxane solution, the cycloaddition between isoxazole and enamine followed a concerted mechanism to form a [2.2.1]-oxazabicyclic intermediate. The activation energy for the formation of I1 is 14 kcal/mol lower than I1* (Figure 2.3), and this is consistent with the experimental data. In the case of TS1, nucleophilic attack of the 7-carbon of the enamine builds up negative charge stabilized by electronegative nitrogen. However, the negative charge is developed on the carbon in TS1*, and cannot be as stabilized. Therefore, the final product derived from I1 is the only one observed experimentally. 26 55 50 45 40 35 30 25 20 15 10 5 0 -5 ) l o m / l a c k ( G Δ O N NH2 O N NH2 TS1* +54.97 TS1 +41.9 O N [M] TS1A_M +16.41 + O N [M] SM 0 + [M] N O H2N H2N O N NH2 O N NH2 I1* +34.2 I1 +31.3 I1_M +17.3 [M] O N NH2 [M] O N NH2 TS1B_M +18.1 NH2 O N [M] I1A_M +16.2 NH2 Reaction Coordinate Figure 2.6 Free energy profile for cycloaddition between isoxazole and enamine in 1,4-dioxane with (blue) and without TiCl4 (black).12 [M] = TiCl4. The dotted line represents the pathway of cycloaddition leading to the regioisomer that is not experimentally observed. Although the cycloaddition step occurs via a more or less concerted mechanism, the transition states were asynchronous, and the symmetry of the transition states are changed when incorporating solvent models into the calculations (vide infra). (The transition states for the cycloaddition step are “synchronous” when two equal bonds are being made between isoxazole and enamine, and “asynchronous” when different amounts of bond making occurs in the two new bonds between isoxazole and enamine.) To quantify the trend in the symmetry of the transition state (TS), we used bond length ratios τ (Eq 2.3). The ratio τ can serve as a means of distinguishing the symmetry character of the transition state. Subjectively, when τ ≤ 0.7, the transition state looks asynchronous, and, when τ > 0.7, the transition state looks synchronous. Based on the calculations, the τ values are lower and the transition states become slightly less synchronous when the dielectric constant of solvent is higher in the case of TS1-endo. However, the τ values of TS1*-endo remains 27 relatively consistent across different solvents. The τ values and energy barriers for other pathways are available in the Computation Details. 9 = (()( "!+, -.+/01 2+ 34)/(()( "!+, -.+/01 2+ 7&!,%80) (()9 "!+, -.+/01 2+ 34)/(()9 "!+, -.+/01 2+ 7&!,%80) (Eq 2.3) TS1-endo TS1*-endo 1 0.9 0.8 0.7 0.6 0.5 τ 0 10 20 30 50 40 Dielectric constant (k) 60 70 80 Gas Phase Heptane 1,4- Dioxane THF DCM Ethanol H2O k 0 1.92 2.21 7.52 8.93 24.6 78.5 TS1-endo 0.693 0.678 0.676 0.682 0.684 0.692 0.695 TS1*-endo 0.909 0.896 0.893 0.882 0.878 0.885 0.845 Figure 2.7 The τ value for cycloaddition in different solvents with their dielectric constant (k). Lastly, the effect of Lewis acid was investigated by including TiCl4 in the calculations. The reaction of the enamine with the isoxazole was found to occur in a stepwise fashion (C–C bond formation followed by C–N bond formation) in the presence of TiCl4 (Figure 2.3). Moreover, the activation energy for this stepwise mechanism is ~24 kcal/mol lower when TiCl4 is included. The cycloaddition product is also substantially stabilized by TiCl4 and is ~14 kcal/mol lower in free energy. 28 2.3.2 Two pathway: Ring opening and Amine loss Two possible pathways from the [2.2.1]-oxazabicyclic intermediate (I1 or I1_M) were investigated (Reaction pathways from I1* are not considered any longer after cycloaddition.) Pathway A is initial amine loss followed by ring opening, and Pathway B is ring opening followed by amine loss. Energy diagram for Pathway A and B are shown in Figure 2.5 and Figure 2.6, respectively. O N H H2N TS2_α 63.8 TS2_M_α 62.0 [M] O N H H2N Oδ– N δ+ TS3_α 59.8 TS3_M_α 41.2 [M] δ+ Oδ– N O N I2_α 26.8 I2_M_α 19.0 [M] O N 70 60 50 40 30 20 ) l o m / l a c k ( G Δ 10 0 -30 -60 O N NH2 I1 0 I1_M 0 [M] O N NH2 N O I3 –40.5 N O I3_M –56.0 [M] Figure 2.8 Free energy profile for pathway A in 1,4-dioxane with (blue) and without TiCl4 (black). [M] = TiCl4. The transition states and intermediate are marked with : in pathway A.12 Reaction Coordinate The first step of Pathway A was found to be very high energy. The amine loss step and the ring opening step require ~60 kcal/mol and ~33 kcal/mol as activation energy, respectively. In fact, the transition state for amine loss was stabilized by ~19 kcal/mol in the presence of TiCl4. However, the Lewis acid effect is insignificant for the amine loss step. In addition, the ring opening step was endergonic, and the intermediate is 27 kcal/mol higher in energy than the cycloaddition product. Consequently, Pathway A cannot be considered as a reasonable reaction mechanism due to its energetically demanding transition states and intermediate. In contrast, Pathway B is found to be more reasonable. Ring opening barriers (35.9 and 27.3 kcal/mol with and without TiCl4) are close to the ones in Pathway A. In addition, when 29 pyrrolidine is employed instead of NH2 in the calculations, the ring opening barrier dropped to ~20 kcal/mol in the presence of TiCl4 in Pathway B. The amine loss barrier without TiCl4 is ~27 kcal/mol and is far more reasonable than amine loss in Pathway A (63.8 and 62.0 kcal/mol without and with TiCl4). Amine loss may be easier because of aromatization of the pyridine once the ring is open. Unfortunately, the transition state for amine loss after ring opening in the presence of TiCl4 (TS2_M_7) was not located. However, the energy difference between the intermediates with and without the metal are only ~13 kcal/mol. Therefore, it is also reasonable to consider that amine loss could occur after decoordination of TiCl4. δ+ Oδ– N H2N TS3_β +35.9 TS3_M_β 27.3 [M] δ+ –Oδ N H2N O N NH2 I1 0 [M] I1_M 0 O N NH2 40 30 20 10 0 -10 -20 -30 -40 -50 -60 ) l o m / l a c k ( G Δ N O H N H2 TS2_β +7.95 TS2_M_β NF N O H NH2 I2_β –19.4 I2_M_β –27.3.0 H NH2 N O [M] Reaction Coordinate N O I3 –40.5 N O I3_M –56.0 [M] Figure 2.9 Free energy profile for pathway B in 1,4-dioxane with (blue) and without TiCl4 (black). [M] = TiCl4. The cycloaddition product and intermediate are marked with 7 in pathway B.12 The calculations suggest that the reaction mechanism can be changed and has lower energy barriers due to the Lewis acidic effect of TiCl4. Especially, the energy barriers for cycloaddition dropped significantly with the stepwise mechanism with TiCl4. Based on the calculations, a reasonable pathway after cycloaddition is ring opening followed by amine loss. 2.4 Conclusions By re-visiting the inverse-electron demand hetero-Diels–Alder reaction between isoxazoles and enamines, the reaction was successfully re-optimized with TiCl4(THF)2 and titanium powder in 1,4-dioxane to give a single observable regioisomer for the product with good 30 to excellent yields. The reaction tolerates many common functional groups, but requires isoxazoles without substitution in the 5-position. In this reaction, the nucleophilicity of enamine plays a crucial role, and more nucleophilic enamines give much better reactivity. The mechanism was investigated using DFT (B3LYPD3, aug-cc-PVDZ, SMD-1,4- dioxane). The mechanistic study showed that cycloaddition between isoxazole and enamine has a stepwise mechanism with energetically accessible barriers in the presence of TiCl4 (~18 kcal/mol). In contrast, cycloaddition between isoxazole and enamine has an energy demanding concerted mechanism without TiCl4 (~40 kcal/mol). In addition, the reasonable reaction pathway after cycloaddition is ring-opening followed by amine loss. Unfortunately, it is difficult to find the moment of reduction in the reaction. The absence of any observation of pyridine-N-oxide could imply two potential explanations. First, the reduction of pyridine-N-oxide may be faster than its production. Second, the intermediate imine-N-oxide (I2_M_β, Figure 2.6) could be reduced before amine loss, resulting in the absence of pyridine-N-oxide. C-C bond forming O N + NR2 C-N bond forming O N [M] NH2 [M] O N NH2 Ring opening (C-O cleavage) NR2 N O [M] Amine loss Reduction N O N Scheme 2.6 The reaction mechanism based on DFT results. Overall, the inverse-electron demand hetero-Diels–Alder reaction between isoxazoles and enamine is a fascinating reaction to produce substituted pyridines, with additional substitution possibly being added in the process. The reaction is highly regioselective and tolerates many common functional groups. In addition, the reaction mechanism was elucidated, except for the reduction, using DFT calculations. 31 2.5 Experimental Details General Considerations Syntheses and handling of materials were carried out under an inert nitrogen atmosphere, either in a MBraun glovebox or by standard Schlenk techniques, except as noted and for column chromatography and preparation of GC samples. The 1H and 13C{1H} NMR spectra were recorded on Agilent DDR2 500 MHz NMR spectrometer equipped with a 5 mm PFG OneProbe operating at 499.84 MHz (1H) and 125.73 MHz (13C), respectively. The chemical shifts (δ) for 1H and 13C NMR spectra are given in ppm relative to residual protio signals of the solvent (CDCl3: δH = 7.26 ppm 1H NMR, δC = 77.16 ppm 13C NMR and C6D6: δH = 7.16 ppm 1H NMR, δC = 128.06 ppm 13C NMR). GCMS data was collected on an Agilent 5973 MSD with a 6890N series GC. GCFID data were collected on a Hewlett Packard 6890 series GC system and standardized against dodecane as an internal standard. 5,6,7,8-Tetrahydroquinoline was used for reaction optimization, and the yield was quantified in situ utilizing GCFID standardized calibration curves. Pyrrolidine, cyclohexanone, and TiCl4 were purchased from Acros Organics and used as received. 5,6,7,8- Tetrahydroquinoline, isoxazole (1a), 3-aminoisoxazole, 4-bromoisoxazole (1c), 3- methylisoxazole (1e), 3-bromo-5-methylpyridine (3u), 3-bromo-6-methylpyridine (3v) were purchased from Fisher Scientific and used as received. Zinc and titanium powder were purchased and stored under N2 from Alfa Aesar and used as received. All materials were purchased commercially, dried prior to use, and stored under N2. 1,4-Dioxane was dried over Na/benzophenone and distilled under N2. CDCl3 and C6D6 were purchased commercially and dried over P2O5 and CaH2, respectively, and distilled under N2. All the glassware was dried in the oven at 140 °C overnight before use. TiCl4(THF)2,27 4-(p-tolyl)-isoxazole (1b),28 3-(N- acetylamino)isoxazole (1d),29 other isoxazoles (1f and 1g),30 enamines (2a-c, 2g, 2f),31 and diarylenamines (2d, 2e)32 were prepared according to the literature procedures. Procedure for GC-FID calibration (n-dodecane vs substituted pyridines) Pyridine solution (0.4 M) in dioxane and n-dodecane solution (1.6 M) in dioxane were prepared in two 5 mL volumetric flasks separately (0.266 g of 5,6,7,8-tetrahydroquinoline (3a), 0.3441 g for 3-bromo-5-methylpyridine (3u), 0.3441 g of 3-bromo-6-methylpyridine (3v), and 1.36 g of dodecane). Then, 0.2, 0.4, 0.6, 0.8 mL of the pyridine solution was transferred into 4 different GC vials, and 0.2 mL of the n-dodecane solution was transferred to each vial. The solution in every vial was diluted to 1 mL with dioxane. All samples were analyzed by GC-FID. Ethyl acetate and 32 DCM were used as wash solvents to prevent any contamination between samples. The integrations of peaks were calculated and inserted into the equation to plot the graph. 0.35 0.3 0.25 0.2 0.15 0.1 0.05 ) M ( ] Q [ 0 0 y = 0.4712x - 0.0012 R² = 0.9999 0.1 0.2 0.3 0.4 Q/D (integration) 0.5 0.6 0.7 0.8 Figure 2.10 GC-FID calibration curve: n-dodecane vs. 5,6,7,8-tetrahydroquinoline. 0.35 0.3 0.25 0.2 0.15 0.1 0.05 ) M ( ] Q [ 0 0 0.05 0.1 0.15 y = 0.6916x + 0.0012 R² = 0.9999 0.2 0.25 Q/D (intergration) 0.3 0.35 0.4 0.45 0.5 Figure 2.11 GC-FID calibration curve: n-dodecane vs. 3-bromo-5-methylpyridine. 33 0.35 0.3 0.25 ) M ( ] Q [ 0.2 0.15 0.1 0.05 0 0 0.05 0.1 0.15 y = 0.696x + 0.001 R² = 0.9999 0.2 0.25 Q/D (intergration) 0.3 0.35 0.4 0.45 0.5 Figure 2.12 GC-FID calibration curve: n-dodecane vs. 3-bromo-6-methylpyridine. Reactions of 4-bromoisoxazoles with terminal and intermal enamines Br Br O N 2c O N 2c N 2g N 2h TiCl4(THF)2 Ti powder Br dioxane, 100 °C N 3u (50%) TiCl4(THF)2 Ti powder Br dioxane, 100 °C N 3v No product observed by GCMS Scheme 2.7 Reactions of 4-bromoisoxazoles (2c) with enamines 2g and 2h. A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. In 15 mL pressure tube, 4-bromoisoxazole (1c, 0.069 g, 1 mmol), dodecane (0.170 g), and corresponding enamine (2g or 2h, 0.45 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure 34 tube was cooled to room temperature for 10 min. 0.3~0.35 mL) of reaction mixture was taken into a GC vial and diluted to 1 mL. Yield was calculated based on the GC-FID calibration curves above. The diluted reaction mixtures were analyzed by GCMS and GCFID. The top reaction between 4-bromoisoxazole (1c) and 1-methyl-1-(1-pyrroldinyl)ethene (2g) results in 50% GC yield of 3-bromo-5-methylpyridine (3u). However, the bottom reaction between 4-bromoisoxazole (1c) and 2-methyl-1-(1-pyrroldinyl)ethene (2h) did not give the corresponding pyridine (3v). As we mentioned in the paper, terminal enamines are less reactive and less nucleophilic. Reactions of isoxazole with 1-(1-cyclohexenyl)pyrrolidine in benzene O N 1a TiCl4 N benzene, 100 °C 2a (4 equiv) N 3a (31%) Scheme 2.8 The reaction of isoxazole with 1-(1-cyclohexenyl)pyrrolidine in benzene. A 15 mL pressure tube was charged with TiCl4 (0.190 g, 1 mmol, 1 equiv) and benzene (1.5 mL). To the reaction mixture, isoxazole (1a, 0.069 g, 1 mmol), dodecane (0.170 g), and 1-(1- cyclohexenyl)pyrrolidine (2a, 0.605 g, 4 mmol, 4 equiv) in benzene (1 mL) were added. The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature for 10 min. 0.3~0.35 mL) of reaction mixture was taken into a GC vial and diluted to 1 mL. Yield was calculated based on the GC-FID calibration curves above. Reactions of isoxazole with 1-(1-cyclohexenyl)pyrrolidine in benzene O N 1a (4 equiv) N 2a TiCl4 benzene, 100 °C N N O 3a observed by GCMS not observed by GCMS Scheme 2.9 The reaction of isoxazole with 1-(1-cyclohexenyl)pyrrolidine in benzene. A 15 mL pressure tube was charged with TiCl4 (0.190 g, 1 mmol, 1 equiv) and benzene (1.5 mL). To the reaction mixture, isoxazole (1a, 0.276 g, 4 mmol), dodecane (0.170 g), and 1-(1- 35 cyclohexenyl)pyrrolidine (2a, 0.151 g, 1 mmol, 0.25 equiv) in benzene (1 mL) were added. The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature for 10 min. 0.3~0.35 mL) of reaction mixture was taken into a GC vial and diluted to 1 mL. The sample was analyzed by GCMS. Synthesis of Pyridine Derivatives Synthesis of 5,6,7,8-tetrahydroquinoline N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. Isoxazole (1a, 0.069 g, 1 mmol) and 1-(1-cyclohexenyl)pyrrolidine (2a, 0.605 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature for 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by silica gel auto-column chromatography, eluted with hexane to get a colorless oil (101 mg, 76%). 1H NMR (CDCl3, 500 MHz): δ 8.34 (d, J = 4.0 Hz, 1H), 7.33 (d, J = 3.0 Hz, 1H), 7.01 (dd, J = 4.0 Hz, 3.0 Hz, 1H), 2.92 (t, J = 6.5 Hz, 2H), 2.76 (t, J = 6.5 Hz, 2H), 1.94-1.85 (m, 2H), 1.84-1.75 (m, 2H). 13C{1H} NMR (CDCl3, 126 MHz): δ 157.496, 146.886, 136.878, 132.392, 120.981, 32.622, 28.880, 23.187, 22.797. MS (EI): m/z 133 (M+). The 1H and 13C{1H} NMR spectroscopy of the compound matches that in the literature.33 Synthesis of 3-(4-tolyl)-5,6,7,8-tetrahydroquinoline N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which 36 solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-Tolylisoxazole (1b, 0.160 g, 1 mmol) and 1-(1-cyclohexenyl)pyrrolidine (2a, 0.605 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (8:2) to get a colorless solid (92 mg, 41%). Mp = 58-60 °C. 1H NMR (CDCl3, 500 MHz): δ 8.57 (s, 1H), 7.53 (s, 1H), 7.46 (d, J = 8.5 Hz, 2H), 7.26 (d, J = 8.5 Hz, 2H), 2.96 (t, J = 6.0 Hz, 4H), 2.83 (t, J = 6.0 Hz, 4H), 2.40 (s, 3H), 1.96-1.91 (m, 4H), 1.90- 1.82 (m, 4H). 13C{1H} NMR (CDCl3, 126 MHz): δ 156.077, 145.154, 137.682, 135.308, 135.128, 134.024, 132.206, 129.820, 126.935, 32.307, 29.006, 23.278, 22.880, 21.282. MS (EI): m/z 223 (M+). Synthesis of 3-bromo-5,6,7,8-tetrahydroquinoline Br N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-Bromoisoxazole (1c, 0.148 g, 1 mmol) and 1-(1-cyclohexenyl) pyrrolidine (0.605 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (9:1) to get a colorless oil (150 mg, 70%). 1H NMR (CDCl3, 500 MHz): δ 8.39 (s, 1H), 7.49 (s, 1H), 2.85 (t, J = 6.5 Hz, 4H), 2.75 (t, J = 6.5 Hz, 4H), 1.92-1.82 37 (m, 4H), 1.81-1.73 (m, 4H). 13C{1H} NMR (CDCl3, 126 MHz): δ 156.097, 147.707, 139.047, 134.312, 117.332, 32.103, 28.753, 22.920, 22.388. MS (EI): m/z 211 (M+). The 1H and 13C{1H} NMR spectroscopy of the compound matches that in the literature.34 Synthesis of 2-(N-acetoamino)-5,6,7,8-tetrahydroquinoline O N H N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 3-(N-acetoamino)isoxazole (1d, 0.126 g, 1 mmol) and 1-(1- cyclohexenyl)pyrrolidine (2a, 0.605 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (6:4) to get an amber solid (40 mg, 21%). m.p. = 127-129 °C. 1H NMR (DMSO, 500 MHz): δ 10.35 (s, 1H), δ 7.80 (d, J = 8.5 Hz, 1H), 7.7.41 (d, J = 8.5 Hz, 1H), 2.71 (t, J = 6.5 Hz, 4H), 2.66 (t, J = 6.5 Hz, 4H), 2.04 (s, 3H), 1.84-1.75 (m, 4H), 1.75-1.66 (m, 4H). 13C{1H} NMR (DMSO, 126 MHz): δ 154.603, 149.499, 138.633, 126.907, 110.851, 31.509, 27.380, 23.810, 22.590, 22.371. MS (EI): m/z 190 (M+). Synthesis of 2-methyl-5,6,7,8-tetrahydroquinoline N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 3-Methylisoxazole (1e, 0.083 g, 1 mmol) and 1-(1-cyclohexenyl)pyrrolidine (2a, 0.605 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was 38 sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane to get a yellow oil (108 mg, 73%). 1H NMR (CDCl3, 500 MHz): δ 7.23 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 2.87 (t, J = 6.5 Hz, 4H), 2.71 (t, J = 6.5 Hz, 4H), 2.48 (s, 3H), 1.91-1.84 (m, 4H), 1.82-1.74 (m, 4H). 13C{1H} NMR (CDCl3, 126 MHz): δ 156.548, 155.159, 137.592, 129.057, 120.575, 32.690, 28.516, 24.292, 23.332, 22.933. MS (EI): m/z 147 (M+). The 1H and 13C{1H} NMR spectroscopy of the compound matches that in the literature.35 Synthesis of 3-ethyl-2-(thiopheny-2-yl)-5,6,7,8-tetrahydroquinoline N S A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-Ethyl-3-(thiopheny-2-yl)-isoxazole (1f, 0.180 g, 1 mmol) and 1-(1- cyclohexenyl)pyrrolidine (2a, 0.605 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (8:2) to get an amber oil (176 mg, 72%). 1H NMR (CDCl3, 500 MHz): δ 7.36 (d, J = 3.5 Hz, 1H), 7.35 (d, J = 3.5 Hz, 1H), 7.25 (s, 1H), 7.08 (dd, J = 5.0 Hz, 4.0 Hz, 1H), 2.92 (t, J = 6.5 Hz, 4H), 2.81 (q, J = 6.0 Hz, 4H), 2.77 (t, J = 6.5 Hz, 4H), 2.17 (s, 1H), 1.93-1.86 (m, 4H), 1.85-1.77 (m, 4H), 1.25 (t, 6.0 Hz). 39 13C{1H} NMR (CDCl3, 126 MHz): δ 154.574, 148.344, 137.987, 133.565, 131.122, 127.383, 126.582, 126.253, 32.274, 28.581, 25.890, 23.381, 22.949, 14.960. MS (EI): m/z 243 (M+). Synthesis of 3-methyl-2-(4-tolyl)-5,6,7,8-tetrahydroquinoline. N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-methyl-3-(4-tolyl)-isoxazole (1g, 0.187 g, 1 mmol) and 1-(1- cyclohexenyl)pyrrolidine (2a, 0.605 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (8:2) to get an amber oil (194 mg, 82%). 1H NMR (CDCl3, 500 MHz): δ 7.37 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.23 (d, J = 3.0 Hz, 2H), 2.93 (t, J = 7.0 Hz, 4H), 2.77 (t, J = 7.0 Hz, 4H), 2.39 (s, 3H), 2.26 (s, 3H), 1.94- 1.86 (m, 4H), 1.85-1.77 (m, 4H). 13C{1H} NMR (CDCl3, 126 MHz): δ 155.970, 154.424, 139.233, 137.327, 130.520, 129.002, 128.922, 127.756, 32.389, 28.517, 23.482, 22.980, 21.400, 19.701. MS (EI): m/z 237 (M+). Synthesis of 2,3-dimethyl-5,6,7,8-tetrahydroquinoxaline. N N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 3,4-dimethyl-1,2,5-oxadiazole (1h, 0.98 g, 1 mmol) and 1-(1- cyclohexenyl)pyrrolidine (2a, 0.605 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C 40 aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (8:2) to get a colorless oil (31 mg, 19%). 1H NMR (CDCl3, 500 MHz): δ 2.61 (t, J = 6.0 Hz, 4H), 2.51 (t, J = 6.0 Hz, 4H), 2.36 (s, 3H), 1.85-1.79 (m, 4H), 1.78-1.71 (m, 4H). 13C{1H} NMR (CDCl3, 126 MHz): δ 116.106, 25.135, 23.551, 23.035, 22.940, 22.796. MS (EI): m/z 162 (M+). Synthesis of 3-phenylpyridine N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. Isoxazole (1a, 0.069 g, 1 mmol) and 1-pyrrolidinyl-2-phenylethene (2b, 0.693 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (9:1) to get a yellow oil (131 mg, 84%). 1H NMR (CDCl3, 500 MHz): δ 8.85 (s, 1H), δ 8.59 (d, J = 5.0 Hz, 1H), 7.88 (d, J = 5.0 Hz, 1H), 7.59 (d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.41 (t, J = 7.5 Hz, 2H), 7.37 (dd, J = 8.0 Hz, 4.5 Hz). 13C{1H} NMR (CDCl3, 126 MHz): δ 148.605, 148.472, 137.988, 136.769, 134.505, 129.216, 128.233, 127.292, 123.694. MS (EI): m/z 155 (M+). The 1H and 13C{1H} NMR spectroscopy of the compound matches that in the literature.36 41 Synthesis of 3-bromo-5-phenylpyridine Br N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-Bromoisoxazole (1c, 0.148 g, 1 mmol) and 1-pyrrolidinyl-2-phenylethene (2b, 0.693 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (9:1) to get white solid (133 mg, 86%). m.p. = 47-49 °C, 1H NMR (CDCl3, 500 MHz): δ 8.76 (s, 1H), 8.66 (s, 1H), 8.03 (s, 1H), 7.57 (d, J = 7.0 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.44 (t, J = 7.5 Hz, 1H). 13C{1H} NMR (CDCl3, 126 MHz): δ 148.001, 145.823, 140.878, 139.599, 138.077, 129.015, 128.962, 128.434, 119.083. MS (EI): m/z 211 (M+). The 1H and 13C{1H} NMR spectroscopy of the compound matches that in the literature37 Synthesis of 3-(4-tolyl)-5-phenylpyridine N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-Tolyl)isoxazole (1b, 0.159 g, 1 mmol) and 1-pyrrolidinyl-2-phenylethene (2b, 0.693 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. 42 After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (9:1) to get white solid (197 mg, 80%). m.p. = 128-130 °C. 1H NMR (CDCl3, 500 MHz): δ 8.81 (d, 2.0 Hz, 1H), 8.80 (d, 2.0 Hz, 1H), 8.07 (s, 1H), 7.65 (d, J = 7.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 7.51 (t, 8.0 Hz, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.32 (d, J = 7.0 Hz, 2H), 2.43 (s, 3H). 13C{1H} NMR (CDCl3, 126 MHz): δ 145.154, 137.682, 135.308, 135.128, 134.024, 132.206, 129.820, 126.935, 32.307, 29.006, 22.278, 22.879, 21.282. MS (EI): m/z 245 (M+). Synthesis of 3-methyl-2-phenylpyridine N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. Isoxazole (1a, 0.069 g, 1 mmol) and 1-(1-phenylprop-1-en-1-yl)pyrrolidine (2c, 0.750 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (9:1) to get a colorless oil (113 mg, 67%). 1H NMR (CDCl3, 500 MHz): δ 8.53 (d, J = 4.5 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1 Hz), 7.53 (d, J = 7.0 Hz, 2H), 7.45 (t, J = 7.0 Hz, 2H), 7.39(t, J = 7.0 Hz, 2H), 2.36 (s, 3H). 13C{1H} NMR (CDCl3, 126 MHz): δ 158.794, 147.082, 140.695, 138.662, 130.973, 129.067, 128.286, 128.058, 122.210, 20.211. MS (EI): m/z 169 (M+). The 1H and 13C{1H} NMR spectroscopy of the compound matches that in the literature.38 43 Synthesis of 3-bromo-5-methyl-6-phenylpyridine Br N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-Bromoisoxazole (1c, 0.148 g, 1 mmol) and 1-(1-phenylprop-1-en-1- yl)pyrrolidine (2c, 0.750 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (8:2) to get a colorless oil (208 mg, 84%). 1H NMR (CDCl3, 500 MHz): δ 8.58 (s, 1H), δ 7.74 (s, 1H), 7.50 (s, J = 7.0 Hz, 2H), 7.45 (t, J = 7.0 Hz, 2H), 7.41 (t, J = 7.0 Hz, 1H), 2.35 (s, 3H). 13C{1H} NMR (CDCl3, 126 MHz): δ 147.847, 145.669, 140.766, 137.962, 132.781, 128.880, 128.827, 128.303, 128.283, 118.949, 19.982. MS (EI): m/z 247 (M+). The 1H and 13C{1H} NMR spectroscopy of the compound matches that in the literature.39 Synthesis of 3-methyl-2-phenyl-5-(4-tolyl)pyridine N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. (4-Tolyl)isoxazole (1b, 0.159 g, 1 mmol) and 1-(1-phenylprop-1-en-1- yl)pyrrolidine (2c, 0.750 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. 44 The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (8:2) to get a white solid (200 mg, 77%). m.p. = 80-81 °C. 1H NMR (CDCl3, 500 MHz): δ 8.76 (s, 1H), δ 8.66 (s, 1H), 8.03 (s, 1H), 7.57 (d, J = 7.0 Hz, 2H), 7.49 (t, J = 7.0 Hz, 2H), (t, J = 7.0 Hz, 2H). 13C{1H} NMR (CDCl3, 126 MHz): δ 159.562, 147.642, 139.605, 137.960, 135.045, 134.966, 134.358, 129.907, 129.278, 128.787, 126.988, 126.587, 123.133, 44.429, 21.294 . MS (EI): m/z 259 (M+). Synthesis of 2-(N-acetoamino)-5-methyl-6-phenylpyridine O N H N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 3-(N-Acetoamino)isoxazole (1d, 0.126 g, 1 mmol) and 1-(1-phenylprop-1-en-1- yl)pyrrolidine (2c, 0.750 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (7:3) to get an amber solid (147 mg, 65%). m.p. = 159 °C, 1H NMR (CDCl3, 500 MHz): δ 7.99 (s br, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.29 (m, 4H), 7.20 (t, J = 7.0 Hz, 1H), 2.10 (s, 3H), 1.90 (s, 3H). 13C{1H} NMR (CDCl3, 126 MHz): δ 168.761, 156.566, 148.985, 141.148, 140.033, 128.870, 128.410, 128.263, 128.806, 112.552, 24.690, 19.325. MS (EI): m/z 226 (M+). 45 Synthesis of 2,3-diphenylpyridine N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. Isoxazole (1a, 0.069 g, 1 mmol) and 1-(1,2-diphenylvinyl)pyrrolidine (2d, 1 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (9:1) to get white solid (207 mg, 90%). m.p. = 56-58 °C, 1H NMR (CDCl3, 500 MHz): δ 8.71 (dd, J = 5.0 Hz, 2.0 Hz, 1H), 7.74 (dd, J = 5.0 Hz, 2.0 Hz, 1H), 7.39-7.32 (m, 2H), 7.31-7.23 (m, 6H), 7.21-7.17 (m, 2H). 13C{1H} NMR (CDCl3, 126 MHz): δ 157.227, 148.372, 140.107, 139.956, 138.791, 136.271, 130.016, 129.684, 128.462, 128.036, 127.960, 127.376, 122.248. MS (EI): m/z 231 (M+). The 1H and 13C{1H} NMR spectroscopy of the compound matches that in the literature.40 Synthesis of 3-bromo-5,6-diphenylpyridine Br N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-Bromoisoxazole (1c, 0.148 g, 1 mmol) and 1-(1,2-diphenylvinyl)pyrrolidine (2d, 1 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed 46 and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and dichloromethane (9:1 to 4:6) to get white solid (273 mg, 88%). m.p. = 103- 105 °C. 1H NMR (CDCl3, 500 MHz): δ 8.74 (s, 1H), 7.88 (s, 1H), 7.34-7.20 (m, 8H), 7.19-7.13 (m, 2H). 13C{1H} NMR (CDCl3, 126 MHz): δ 155.631, 149.103, 140.831, 138.905, 138.512, 137.616, 129.745, 129.423, 128.509, 128.180, 128.029, 127.801, 119.043. MS (EI): m/z 310 (M+). Synthesis of 3-methyl-5,6-diphenyl-2-(4-tolyl)pyridine N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-Methyl-3-(4-tolyl)isoxazole (0.174 g, 1 mmol) and 1-(1,2- diphenylvinyl)pyrrolidine (2d, 1 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto- column chromatography, eluted with hexane and dichloromethane (9:1 to 4:6) to get white solid (306 mg, 91%). m.p. = 119-122 °C. 1H NMR (CDCl3, 500 MHz): δ 8.76 (s, 1H), δ 8.66 (s, 1H), 8.03 (s, 1H), 7.57 (d, J = 7.0 Hz, 2H), 7.49 (t, J = 7.0 Hz, 2H), (t, J = 7.0 Hz, 2H). 13C{1H} NMR (CDCl3, 126 MHz): δ 148.001, 145.823, 140.878, 139.599, 138.077, 129.015, 128.962, 128.434, 119.083. MS (EI): m/z 334 (M+). 47 Synthesis of 2,3-di-(4-tolyl)pyridine N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. Isoxazole (1a, 0.069 g, 1 mmol) and 1-(1,2-di(4-tolyl)vinyl)pyrrolidine (2e, 1 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and ethyl acetate (9:1) to get a colorless oil (174 mg, 67%). 1H NMR (CDCl3, 500 MHz): δ 8.73 (d, J = 5.0 Hz, 1H), δ 7.76 (d, J = 8.0 Hz, 1H), 7.40-7.30 (m, 3H), 7.20-7.10 (m, 6H), 2.42 (s, 3H), 2.19 (s, 3H). 13C{1H} NMR (CDCl3, 126 MHz): δ 157.209, 148.179, 138.696, 137.608, 137.474, 137.271, 137.001, 136.002, 129.862, 129.485, 129.182, 128.741, 121.935, 21.393, 21.312. MS (EI): m/z 259 (M+). The 1H and 13C{1H} NMR spectroscopy of the compound matches that in the literature.41 Synthesis of 3-bromo-5,6-di-(4-tolyl)pyridine Br N A 15 mL pressure tube was charged with TiCl4(THF)2 (0.334 g, 1 mmol, 1 equiv), titanium powder (0.056 g, 1.0 mmol, 1.0 equiv), and dioxane (0.5 mL). The solution was stirred for 1 h over which solids form, and then 1 mL dioxane was added to the solution and stirring was continued for an additional 1 h. 4-Bromoisoxazole (1c, 0.148 g, 1 mmol) and 1-(1,2-di(4-tolyl)vinyl)pyrrolidine (2e, 1 g, 4 mmol, 4 equiv) were added to the solution in dioxane (1 mL). The pressure tube was sealed 48 and transferred from the glovebox to a preheated 100 °C aluminum block. The reaction was heated with stirring for 12 h. After heating, the pressure tube was cooled to room temperature over 10 min. Then, 2 mL of 20% aqueous K2CO3 was added, and the mixture was stirred for 5 min. After stirring, solids were removed by vacuum filtration and were washed with CH2Cl2 (~10 mL). The filtrate was dried with Na2SO4 and filtered through a piece of cotton. The solvent was removed under reduced pressure. The product was purified by a silica gel auto-column chromatography, eluted with hexane and dichloromethane (9:1 to 4:6) to get white solid (285 mg, 84%). m.p. = 93- 95 °C. 1H NMR (CDCl3, 500 MHz): δ 8.69 (s, 1H), δ 7.83 (s, 1H), 7.22 (d, J = 7.5 Hz, 2H), 7.09 (t, J = 8.0 Hz, 2H), 7.07-7.02 (m, 5H), 2.34 (s, 3H), 2.31 (s, 3H). 13C{1H} NMR (CDCl3, 126 MHz): δ155.763, 148.995, 140.830, 138.069, 137.671, 137.523, 136.477, 135.949, 129.731, 129.366, 129.353, 128.871, 118.815, 21.417, 21.345. MS (EI): m/z 337 (M+). 49 Spectral Data for Pyridine Derivatives 1H NMR and 13C{1H} NMR of 5,6,7,8-tetrahydroquinoline l 3 C D C 0 6 2 7 . 9 1 1 . 7 4 0 1 . 7 3 0 8 6 . 3 9 7 6 . 8 8 7 6 . 8 7 7 6 . 9 3 7 2 . 6 2 7 2 . 3 1 7 2 . 4 5 5 2 . 1 4 5 2 . 8 2 5 2 . 4 8 6 . 1 2 0 6 . 1 SJL_THQ_PROTON_01 2 5 1 . 8 2 4 1 . 8 9 8 10 N 7 4 3 5 2 6 1 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 . 1 8 2 . 1 3 2 . 1 5 5 3 . 2 6 3 . 5 5 3 . 6 5 3 . SJL_A1_CARBON_01 8 5 4 7 5 1 . 0 6 8 6 4 1 . 6 1 8 6 3 1 . 7 3 3 2 3 1 . 6 3 9 0 2 1 . 9 8 10 N 7 4 3 5 2 6 1 l 3 c d c 6 1 4 7 7 . l 3 C D C 0 6 1 . 7 7 l 3 c d c 1 6 1 . 7 7 l 3 c d c 7 0 9 6 7 . 5 9 5 2 3 . 3 4 8 8 2 . 9 5 1 . 3 2 6 6 7 2 2 . 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 50 1H NMR and 13C{1H} NMR of 3-(4-tolyl)-5,6,7,8-tetrahydroquinoline l 3 c d c 0 7 2 7 . SJL_D1_PROTON_01 0 8 5 8 . 6 7 5 8 . 5 4 5 7 . 3 4 5 7 . 1 4 5 7 . 6 7 4 7 . 9 5 4 7 . 0 8 2 7 . CH3 17 14 15 13 16 12 11 9 8 10 N 7 4 3 5 2 6 1 5 6 2 7 . 4 8 9 2 . 1 7 9 2 . 8 5 9 2 . 4 5 8 2 . 1 4 8 2 . 0 3 8 2 . 8 2 8 2 . 9 0 4 2 . 2 4 9 . 1 5 6 8 . 1 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 9 8 0 . 3 0 . 1 3 0 2 . 7 5 2 . 0 2 2 . 8 1 . 2 9 1 . 3 SJL_D1_CARBON_01 6 7 0 6 5 1 . 4 5 1 . 5 4 1 2 8 6 7 3 1 . 8 0 3 5 3 1 . 8 2 1 . 5 3 1 4 2 0 4 3 1 . 6 0 2 2 3 1 . 0 2 8 9 2 1 . 5 3 9 6 2 1 . CH3 17 14 15 13 16 12 11 9 8 10 N 7 4 3 5 2 6 1 l 3 c d c 4 1 4 7 7 . l 3 C D C 0 6 1 . 7 7 l 3 c d c 0 6 1 . 7 7 l 3 c d c 6 0 9 6 7 . 0 9 4 . 2 1 0 -1 -2 7 0 3 2 3 . 5 0 0 9 2 . 8 7 2 3 2 . 9 7 8 2 2 . 2 8 2 . 1 2 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 51 1H NMR and 13C{1H} NMR of 3-bromo-5,6,7,8-tetrahydroquinoline l 3 C D C 0 6 2 7 . SJL_B1_PROTON_01 6 8 3 8 . 1 9 4 7 . Br 11 9 8 10 N 7 4 3 5 2 6 1 4 6 8 2 . 1 5 8 2 . 8 3 8 2 . 0 6 7 2 . 7 4 7 2 . 4 3 7 2 . 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 . 1 4 0 . 1 4 8 4 . 3 9 4 . SJL_B1_CARBON_01 7 9 0 6 5 1 . 7 0 7 7 4 1 . 7 4 0 9 3 1 . . 2 1 3 4 3 1 2 3 3 7 1 1 . l 3 C D C 0 6 1 . 7 7 3 0 1 . 2 3 3 5 7 8 2 . 0 2 9 2 2 . 8 8 3 2 2 . Br 11 9 8 10 N 7 4 3 5 2 6 1 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 52 1H NMR and 13C{1H} NMR of 2-(N-acetylamino)-5,6,7,8-tetrahydroquinoline SJL_C1_PROTON_01 13 O 12 CH3 14 NH 11 9 8 10 N 7 4 3 5 2 6 1 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 . 1 7 9 0 . 2 0 . 1 1 0 2 . 0 1 . 2 0 2 3 . 1 1 . 2 8 9 . 1 SJL_C1_DMSO_CARBON_01 3 0 6 4 5 1 . 9 9 4 9 4 1 . 3 3 6 8 3 1 . 7 0 9 6 2 1 . 1 5 8 0 1 1 . 6 d - O S M D 0 2 5 9 3 . o s m d 0 2 0 0 4 . o s m d 3 5 8 9 3 . o s m d 6 8 6 9 3 . o s m d 9 7 6 9 3 . o s m d 9 1 5 9 3 . o s m d 2 5 3 9 3 . o s m d 6 8 1 . 9 3 o s m d 8 1 0 9 3 . 9 0 5 . 1 3 0 8 3 7 2 . 0 1 8 3 2 . 0 9 5 2 2 . 1 7 3 2 2 . 13 O 12 CH3 14 NH 11 9 8 10 N 7 4 3 5 2 6 1 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 53 1H NMR and 13C{1H} NMR of 2-methyl-5,6,7,8-tetrahydroquinoline SJL_2Me_THQ_PROTON_01 l 3 C D C 0 6 2 7 . 3 2 4 N 1 5 10 6 9 7 8 CH3 11 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 SJL_2Me_THQ_CARBON_01 6 1 4 6 5 1 . 8 2 0 5 5 1 . 8 3 1 . 7 3 1 7 3 1 . 7 3 1 7 2 9 8 2 1 . 4 4 4 0 2 1 . 5 8 2 7 7 . 0 3 0 7 7 . 6 7 7 6 7 . 9 5 5 2 3 . 5 8 3 8 2 . 2 6 1 . 4 2 6 8 1 . 3 2 2 0 8 2 2 . 0 0 . 1 7 9 0 . 8 4 2 . 6 8 2 . 1 7 3 . 0 9 2 . 7 9 2 . 3 2 4 N 1 5 10 6 9 7 8 CH3 11 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 54 1H NMR and 13C{1H} NMR of 3-ethyl-2-(thiopheny-2-yl)-5,6,7,8-tetrahydroquinoline 3 5 2 7 . 1 9 0 7 . 3 8 0 7 . 1 8 0 7 . 3 7 0 7 . 3 3 9 2 . 0 2 9 2 . 7 0 9 2 . 5 3 8 2 . 0 2 8 2 . 4 0 8 2 . 9 8 7 2 . 2 8 7 2 . 0 7 7 2 . 7 5 7 2 . 3 6 2 . 1 8 4 2 . 1 3 3 2 . 1 l 3 C D C 0 6 2 7 . SJL_F1_PROTON_01 2 6 3 7 . 9 5 3 7 . 1 5 3 7 . 9 4 3 7 . 3 2 3 7 . 6 1 3 7 . 13 CH3 8 7 5 4 9 10 11 S 12 6 17 2 1 16 15 N 3 14 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 . 1 8 0 . 1 6 0 . 1 7 0 . 1 9 5 2 . 5 1 . 2 0 9 2 . 5 4 5 . 0 0 4 . l 3 c d c 0 8 2 7 7 . l 3 c d c 5 2 0 7 7 . l 3 c d c 1 7 7 6 7 . 9 3 1 . 2 3 6 4 4 8 2 . 5 5 7 5 2 . 6 4 2 3 2 . 4 1 8 2 2 . 2 2 2 8 1 . 5 2 8 4 1 . SJL_F1_CARBON_01 9 3 4 4 5 1 . 9 0 2 8 4 1 . 2 5 8 7 3 1 . 0 3 4 3 3 1 . 7 8 9 0 3 1 . 9 4 2 7 2 1 . 8 4 4 6 2 1 . 8 1 1 . 6 2 1 13 CH3 8 7 5 4 9 10 11 S 12 6 17 2 1 16 15 N 3 14 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 55 1H NMR and 13C{1H} NMR of 3-methyl-2-(4-tolyl)-5,6,7,8-tetrahydroquinoline 6 3 2 7 . 3 3 2 7 . 0 2 2 7 . 6 1 2 7 . 4 4 9 2 . 2 3 9 2 . 8 1 9 2 . 5 8 7 2 . 2 7 7 2 . 0 6 7 2 . 6 8 3 2 . 1 6 2 2 . l 3 C D C 0 6 2 7 . SJL_E1_PROTON_01 5 8 3 7 . 9 6 3 7 . 7 6 8 N 5 3 2 4 1 18 17 CH3 10 9 15 12 13 11 14 CH3 16 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 SJL_E1_CARBON_01 0 7 9 5 5 1 . 4 2 4 4 5 1 . 3 3 2 9 3 1 . 7 2 3 7 3 1 . 0 2 5 0 3 1 . 2 0 0 9 2 1 . 2 2 9 8 2 1 . 6 5 7 7 2 1 . l 3 C D C 0 6 1 . 7 7 9 8 3 2 3 . 7 1 5 8 2 . 2 8 4 3 2 . 0 8 9 2 2 . 0 0 4 . 1 2 1 0 7 9 1 . 1 9 . 1 2 0 3 . 6 0 5 . 0 6 3 . 4 6 3 . 6 4 5 . 7 6 8 N 5 3 2 4 1 18 17 CH3 10 9 15 12 13 11 14 CH3 16 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 56 1H NMR and 13C{1H} NMR of 2,3-dimethyl-5,6,7,8-tetrahydroquinoxaline SJL_2_3-DiMeTHQuinoxaline_PROTON_01 l 3 C D C 0 6 2 7 . CH3 12 CH3 11 3 2 4 N N 1 5 10 6 9 7 8 0 8 . 1 0 0 2 . 6 5 2 . 5 8 4 . 5 4 3 2 1 0 -1 -2 l 3 c d c 3 1 4 7 7 . l 3 C D C 0 6 1 . 7 7 l 3 c d c 0 6 1 . 7 7 l 3 c d c 6 0 9 6 7 . 5 3 1 . 5 2 1 5 5 3 2 . 5 3 0 3 2 . 0 4 9 2 2 . 6 9 7 2 2 . 14 13 12 11 10 9 8 7 SJL_THQuinoxaline_CARBON_01 6 f1 (ppm) 6 0 1 . 6 1 1 CH3 11 10 N 9 8 CH3 12 N 7 4 3 5 2 6 1 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 57 1H NMR and 13C{1H} NMR of 3-phenylpyridine SJL_A2_PROTON_01 5 5 8 8 . 1 5 8 8 . 8 9 5 8 . 8 8 5 8 . 5 8 8 7 . 9 6 8 7 . 5 9 5 7 . 0 8 5 7 . 1 0 5 7 . 6 8 4 7 . 1 7 4 7 . 6 2 4 7 . 2 1 4 7 . 0 8 3 7 . 1 7 3 7 . 4 6 3 7 . 5 5 3 7 . l 3 C D C 0 6 2 7 . 0 6 2 7 . 4 3 5 8 6 7 11 10 12 N 9 2 1 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 . 1 2 0 . 1 4 1 . 1 9 1 . 2 6 0 2 . 5 2 2 . SJL_A2_CARBON_01 5 0 6 8 4 1 . 2 7 4 8 4 1 . 8 6 9 7 3 1 . 9 6 7 6 3 1 . 5 0 5 4 3 1 . 6 1 2 9 2 1 . 3 3 2 8 2 1 . 2 9 2 7 2 1 . 4 8 6 3 2 1 . 4 3 5 8 6 7 11 10 12 N 9 2 1 l 3 C D C 0 6 1 . 7 7 l 3 c d c 1 6 1 . 7 7 l 3 c d c 5 1 4 7 7 . l 3 c d c 7 0 9 6 7 . 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 58 1H NMR and 13C{1H} NMR of 3-bromo-5-phenylpyridine l 3 C D C 0 6 2 7 . SJL_3Br_5Ph_Py_PROTON_01 3 4 8 8 . 8 5 7 8 . 6 5 6 8 . 1 3 0 8 . 2 7 5 7 . 1 6 5 7 . 8 5 5 7 . 6 5 5 7 . 6 9 4 7 . 1 8 4 7 . 4 5 4 7 . 9 3 4 7 . 4 3 5 8 6 7 Br 13 11 10 12 N 9 2 1 14 13 12 11 10 9 SJL_3Br_5Ph_Py_CARBON_01 0 0 . 1 2 0 . 1 8 0 2 . 4 1 . 2 1 2 . 1 6 0 . 1 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 4 3 9 4 1 . 0 0 4 6 4 1 . 4 4 2 7 3 1 . 6 3 4 9 2 1 . 0 0 4 9 2 1 . 6 1 9 8 2 1 . 7 5 3 7 2 1 . l 3 C D C 0 6 1 . 7 7 4 3 5 8 6 7 Br 13 11 10 12 N 9 2 1 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 59 1H NMR and 13C{1H} NMR of 3-(4-tolyl)-5-phenylpyridine 2 3 4 2 . l 3 C D C 0 6 2 7 . SJL_D2_PROTON_01 5 1 8 8 . 1 1 8 8 . 3 0 8 8 . 9 9 7 8 . 0 7 0 8 . 6 6 0 8 . 1 6 0 8 . 3 5 6 7 . 9 3 6 7 . 8 5 5 7 . 2 4 5 7 . 3 1 5 7 . 7 9 4 7 . 5 5 4 7 . 0 4 4 7 . 1 3 3 7 . 9 2 3 7 . 3 1 3 7 . CH3 19 16 17 15 18 14 13 4 3 5 8 6 7 11 10 12 N 9 2 1 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 2 9 0 . 8 8 0 . 0 0 . 1 2 1 . 2 6 9 . 1 8 0 2 . 0 0 . 1 2 9 . 1 4 2 3 . SJL_D2_CARBON_01 6 8 6 6 4 1 . 5 3 5 6 4 1 . 3 5 2 8 3 1 . 0 8 7 7 3 1 . 5 6 6 6 3 1 . 8 4 7 4 3 1 . 6 3 8 2 3 1 . 0 7 8 9 2 1 . 7 2 1 . 9 2 1 7 2 2 8 2 1 . 8 6 2 7 2 1 . 1 8 0 7 2 1 . CH3 19 11 12 10 13 9 7 18 8 17 14 16 15 3 2 4 N 1 5 6 l 3 c d c 3 6 2 7 7 . l 3 c d c 9 0 0 7 7 . l 3 c d c 5 5 7 6 7 . 2 9 1 . 1 2 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 60 1H NMR and 13C{1H} NMR of 3-methyl-2-phenylpyridine l 3 C D C 0 6 2 7 . 5 9 1 . 7 9 8 1 . 7 5 8 1 . 7 0 8 1 . 7 3 7 1 . 7 0 7 1 . 7 SJL_A3_PROTON_01 7 3 5 8 . 8 2 5 8 . 4 9 5 7 . 9 7 5 7 . 4 3 5 7 . 1 3 5 7 . 9 1 5 7 . 7 1 5 7 . 5 1 5 7 . 4 5 4 7 . 1 5 4 7 . 6 0 4 7 . 3 9 3 7 . 7 6 8 N 5 3 2 CH3 4 1 9 13 10 12 11 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 . 1 2 0 . 1 4 9 . 1 4 0 2 . 0 2 . 1 7 0 . 1 7 4 3 . SJL_A3_CARBON_01 4 9 7 8 5 1 . 2 8 0 7 4 1 . 5 9 6 0 4 1 . 2 6 6 8 3 1 . 3 7 9 0 3 1 . 7 6 0 9 2 1 . 6 8 2 8 2 1 . 8 5 0 8 2 1 . 0 1 2 2 2 1 . l 3 C D C 0 6 1 . 7 7 1 1 2 0 2 . 7 6 8 N 5 3 2 CH3 4 1 9 13 10 12 11 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 61 1H NMR and 13C{1H} NMR of 3-bromo-5-methyl-6-phenylpyridine SJL_3Br5Me6PhPy_PROTON_01 Br 14 7 6 8 N 5 3 2 CH3 4 1 9 13 10 12 11 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 . 1 6 1 . 1 6 8 7 . 3 9 4 . SJL_B3_CARBON_01 7 4 8 7 4 1 . 9 6 6 5 4 1 . 6 6 7 0 4 1 . 2 6 9 7 3 1 . . 1 8 7 2 3 1 0 8 8 8 2 1 . 7 2 8 8 2 1 . 3 0 3 8 2 1 . 3 8 2 8 2 1 . 9 4 9 8 1 1 . Br 14 7 6 8 N 5 3 2 CH3 4 1 9 13 10 12 11 l 3 c d c 9 7 2 7 7 . 8 2 2 7 7 . l 3 c d c 5 2 0 7 7 . l 3 c d c 1 7 7 6 7 . 2 8 9 9 1 . 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 62 1H NMR and 13C{1H} NMR of 3-methyl-2-phenyl-5-(4-tolyl)pyridine l 3 C D C 0 6 2 7 . SJL_D3_PROTON_01 CH3 20 17 18 16 19 15 8 6 5 7 N 4 2 1 CH3 3 9 10 14 11 13 12 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 . 1 9 0 . 1 4 2 2 . 7 9 3 . 4 9 2 . 9 9 0 . 0 1 . 1 5 3 2 . 7 5 3 . 2 4 6 7 4 1 . 5 0 6 9 3 1 . 0 6 9 7 3 1 . 5 4 0 5 3 1 . 6 6 9 4 3 1 . 8 5 3 4 3 1 . 7 0 9 9 2 1 . 8 7 2 9 2 1 . 7 8 7 8 2 1 . 8 8 9 6 2 1 . 7 8 5 6 2 1 . 3 3 1 . 3 2 1 l 3 C D C 0 6 1 . 7 7 9 2 4 4 4 . 4 9 2 . 1 2 SJL_D3_CARBON_02 2 6 5 9 5 1 . 13 12 CH3 20 17 18 16 19 15 8 6 5 7 N 4 2 1 CH3 3 9 10 14 11 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 63 1H NMR and 13C{1H} NMR of 2-(N-acetoamino)-5-methyl-6-phenylpyridine 8 5 2 7 . 6 4 2 7 . 2 4 2 7 . 2 1 2 7 . 8 9 1 . 7 4 8 1 . 7 3 0 1 . 2 6 9 8 . 1 l 3 C D C 0 6 2 7 . SJL_C2_PROTON_01 9 8 9 7 . 7 7 8 7 . 0 6 8 7 . 5 1 4 7 . 9 9 3 7 . 5 6 2 7 . 2 6 2 7 . 17 O 15 CH3 16 NH 7 8 6 9 N 5 1 2 CH3 4 3 10 14 11 13 12 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 3 0 . 1 0 0 . 1 3 1 . 1 5 1 . 1 5 8 3 . 1 9 3 . l 3 c d c 3 1 4 7 7 . l 3 C D C 0 6 1 . 7 7 l 3 c d c 0 6 1 . 7 7 l 3 c d c 4 0 9 6 7 . 6 3 8 9 2 . 0 9 6 4 2 . 5 2 3 9 1 . SJL_C2_CARBON_01 . 1 6 7 8 6 1 6 6 5 6 5 1 . 5 8 9 8 4 1 . 8 4 1 . 1 4 1 3 3 0 0 4 1 . 0 7 8 8 2 1 . 0 1 4 8 2 1 . 3 6 2 8 2 1 . 6 0 8 6 2 1 . 2 5 5 2 1 1 . 17 O 15 CH3 16 NH 7 8 6 9 N 5 1 2 CH3 4 3 10 14 11 13 12 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 64 1H NMR and 13C{1H} NMR of 2,3-diphenylpyridine SJL_A4_PROTON_01 11 10 12 N 9 2 1 4 3 13 14 5 8 18 15 6 7 17 16 0 0 . 1 5 2 . 1 6 8 2 . 4 0 6 . 3 1 . 2 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 2 7 3 8 4 1 . 7 0 1 . 0 4 1 6 5 9 9 3 1 . . 1 9 7 8 3 1 . 1 7 2 6 3 1 6 1 0 0 3 1 . 4 8 6 9 2 1 . 2 6 4 8 2 1 . 6 3 0 8 2 1 . 0 6 9 7 2 1 . 6 7 3 7 2 1 . 8 4 2 2 2 1 . l 3 C D C 0 6 1 . 7 7 l 3 c d c 1 6 1 . 7 7 l 3 c d c 5 1 4 7 7 . l 3 c d c 7 0 9 6 7 . 14 13 12 11 10 SJL_A4_CARBON_01 11 10 12 N 9 2 1 9 7 2 2 7 5 1 . 4 3 13 14 5 8 18 15 6 7 17 16 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 65 1H NMR and 13C{1H} NMR of 3-bromo-5,6-diphenylpyridine l 3 C D C 0 6 2 7 . SJL_B4_real_pure_PROTON_01 0 4 7 8 . 5 3 7 8 . 3 8 8 7 . 9 7 8 7 . Br 7 2 1 3 N 6 4 5 19 8 9 10 18 15 14 11 17 16 13 12 14 13 12 11 10 9 0 0 . 1 4 0 . 1 8 5 0 6 1 . 5 3 2 . 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 SJL_B4_pure.10.fid 1 3 6 5 5 1 . 3 0 1 . 9 4 1 1 3 8 0 4 1 . 5 0 9 8 3 1 . 2 1 5 8 3 1 . 6 1 6 7 3 1 . 5 4 7 9 2 1 . 3 2 4 9 2 1 . 9 0 5 8 2 1 . 0 8 1 . 8 2 1 9 2 0 8 2 1 . 1 0 8 7 2 1 . 3 4 0 9 1 1 . Br 7 2 1 3 N 6 4 5 19 8 9 10 18 15 14 11 17 16 13 12 210 200 190 180 170 160 150 140 130 120 110 100 f1 (ppm) 90 80 70 60 50 40 30 20 10 0 -10 66 1H NMR and 13C{1H} NMR of 3-methyl-5,6-diphenyl-2-(4-tolyl)pyridine SJL_E4_PROTON_01 7 6 8 N 5 3 2 CH3 20 19 25 22 23 21 24 CH3 26 18 4 1 9 17 14 13 10 16 15 12 11 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 -2 0 0 . 1 3 4 2 . 6 4 2 . 0 5 6 . 9 7 . 1 1 4 4 . 4 3 3 . 6 6 3 . SJL_E4_CARBON_01 2 1 0 7 5 1 . 3 0 1 . 4 5 1 9 6 9 9 3 1 . 5 2 7 7 3 1 . 6 7 1 . 1 4 1 6 0 1 . 4 3 1 9 0 1 . 0 3 1 3 8 5 9 2 1 . 5 1 2 9 2 1 . 5 0 8 8 2 1 . 5 6 2 8 2 1 . 9 3 7 7 2 1 . 0 6 4 7 2 1 . 2 3 0 7 2 1 . 7 6 8 N 5 3 2 CH3 20 19 25 22 23 21 24 CH3 26 18 4 1 9 17 14 13 10 16 15 12 11 l 3 c d c 0 8 2 7 7 . l 3 c d c 6 2 0 7 7 . 9 2 2 7 7 . l 3 c d c 1 7 7 6 7 . 0 3 3 . 1 2 2 6 8 9 1 . 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 67 1H NMR and 13C{1H} NMR of 2,3-di-(4-tolyl)pyridine SJL_A5_PROTON_01 0 4 7 8 . 6 3 7 8 . 7 2 7 8 . 2 7 7 7 . 9 6 7 7 . 3 5 7 7 . 6 D 6 C 0 6 1 . 7 0 2 4 2 . 2 9 3 2 . 11 10 12 N 9 2 1 4 3 13 14 5 8 18 15 6 7 17 16 CH3 19 CH3 20 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 4 3 2 1 0 -1 0 0 . 1 0 2 . 1 2 5 3 . 8 3 6 . 8 1 . 3 2 2 3 . l 3 c d c 5 0 9 6 7 . l 3 c d c 3 1 4 7 7 . l 3 C D C 0 6 1 . 7 7 l 3 c d c 9 5 1 . 7 7 SJL_A5_CARBON_01 9 0 2 7 5 1 . 9 7 1 . 8 4 1 6 9 6 8 3 1 . 8 0 6 7 3 1 . 4 7 4 7 3 1 . 1 7 2 7 3 1 . 1 0 0 7 3 1 . 2 0 0 6 3 1 . 2 6 8 9 2 1 . 5 8 4 9 2 1 . 2 8 1 . 9 2 1 . 1 4 7 8 2 1 5 3 9 . 1 2 1 11 10 12 N 9 2 1 4 3 13 14 5 8 18 15 6 7 17 16 CH3 19 CH3 20 3 9 3 . 1 2 2 1 3 . 1 2 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 68 1H NMR and 13C{1H} NMR of 3-bromo-5,6-di-4-tolylpyridine SJL_B5_PROTON_01 3 9 6 8 . 8 8 6 8 . 6 2 8 7 . l 3 C D C 0 6 2 7 . 0 3 2 7 . 6 2 2 7 . 8 1 2 7 . 4 1 2 7 . 4 0 1 . 7 8 8 0 7 . 3 4 3 2 . 1 1 3 2 . Br 19 7 6 8 N 5 3 2 18 4 1 9 17 14 13 10 16 15 12 11 CH3 20 CH3 21 0 0 . 1 5 1 . 1 0 6 2 . 5 5 2 . 5 3 5 . 1 9 3 . 0 2 4 . 3 2 1 0 -1 -2 7 1 4 . 1 2 5 4 3 . 1 2 l 3 c d c 6 0 9 6 7 . 4 l 3 C D C 0 6 1 . 7 7 l 3 c d c 0 6 1 . 7 7 l 3 c d c 3 1 4 7 7 . 14 13 12 11 10 9 8 7 6 f1 (ppm) 5 SJL_B5_CARBON_01 3 6 7 5 5 1 . 5 9 9 8 4 1 . 0 3 8 0 4 1 . 9 6 0 8 3 1 . 1 7 6 7 3 1 . 3 2 5 7 3 1 . 7 7 4 6 3 1 . 9 4 9 5 3 1 . . 1 3 7 9 2 1 6 6 3 9 2 1 . 3 5 3 9 2 1 . 1 7 8 8 2 1 . 5 1 8 8 1 1 . Br 19 7 6 8 N 5 3 2 18 4 1 9 17 14 13 10 16 15 12 11 CH3 20 CH3 21 230 220 210 200 190 180 170 160 150 140 130 120 110 f1 (ppm) 100 90 80 70 60 50 40 30 20 10 0 -10 69 REFERENCES 1. Hilf, J. A.; Holzwarth, M. S.; Rychnovsky, S. D. Route to Highly Substituted Pyridines. J. Org. Chem. 2016, 81 (21), 10376–10382. 2. Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. 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Regioselective Conversion of Alkynes to 4-Substituted and 3,4-Disubstituted Isoxazoles Using Titanium-Catalyzed Multicomponent Coupling Reactions. Tetrahedron 2012, 68 (3), 807–812. 26. Odom, A. L.; McDaniel, T. J. Titanium-Catalyzed Multicomponent Couplings: Efficient One-Pot Syntheses of Nitrogen Heterocycles. Acc. Chem. Res. 2015, 48 (11), 2822–2833. 27. Görl, C.; Betthausen, E.; Alt, H. G. Di- and Trinuclear Iron/titanium and Iron/zirconium Complexes with Heterocyclic Ligands as Catalysts for Ethylene Polymerization. Polyhedron 2016, 118, 37–51. 28. Pei, Z.; Mendonca, R.; Gazzard, L.; Pastor, R.; Goon, L.; Gustafson, A.; VanderPorten, E.; Hatzivassiliou, G.; Dement, K.; Cass, R.; Yuen, P.-W.; Zhang, Y.; Wu, G.; Lin, X.; Liu, Y.; Sellers, B. D. Aminoisoxazoles as Potent Inhibitors of Tryptophan 2,3-Dioxygenase 2 (TDO2). ACS Med. Chem. Lett. 2018, 9 (5), 417–421. 29. Tóth, B. L.; Kovács, S.; Sályi, G.; Novák, Z. Mild and Efficient Palladium-Catalyzed Direct Trifluoroethylation of Aromatic Systems by C-H Activation. Angew. Chem. Int. Ed Engl. 2016, 55 (6), 1988–1992. 30. Jia, Q.-F.; Benjamin, P. M. S.; Huang, J.; Du, Z.; Zheng, X.; Zhang, K.; Conney, A. H.; Wang, J. letterSynthesis of 3, 4-Disubsituted Isoxazoles via Enamine [3+2] Cycloaddition. Advanced online publication: 2012, 10, 12. 71 31. Liu, Y.-P.; Zhu, C.-J.; Yu, C.-C.; Wang, A.-E.; Huang, P.-Q. Tf2O-Mediated Intermolecular Coupling of Secondary Amides with Enamines or Ketones: A Versatile and Direct Access to β-Enaminones. European J. Org. Chem. 2019, 2019 (42), 7169–7174. 32. Timofeeva, D. S.; Mayer, R. J.; Mayer, P.; Ofial, A. R.; Mayr, H. Which Factors Control the Nucleophilic Reactivities of Enamines? Chemistry 2018, 24 (22), 5901–5910. 33. Anderson, E. D.; Boger, D. L. Inverse Electron Demand Diels-Alder Reactions of 1,2,3- Triazines: Pronounced Substituent Effects on Reactivity and Cycloaddition Scope. J. Am. Chem. 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The 1,3-Diaminobenzene-Derived Aminophosphine Palladium Pincer Complex C6H3[NHP(piperidinyl)2]2Pd(cl) - A Highly Active Suzuki-Miyaura Catalyst with Excellent Functional Group Tolerance. Adv. Synth. Catal. 2010, 352 (6), 1075– 1080. 39. Zhou, Q.; Zhang, B.; Su, L.; Jiang, T.; Chen, R.; Du, T.; Ye, Y.; Shen, J.; Dai, G.; Han, D.; Jiang, H. Palladium-Catalyzed Highly Regioselective 2-Arylation of 2,x-Dibromopyridines and Its Application in the Efficient Synthesis of a 17β-HSD1 Inhibitor. Tetrahedron 2013, 69 (51), 10996–11003. 40. Jin, Z.; Li, Y.-J.; Ma, Y.-Q.; Qiu, L.-L.; Fang, J.-X. Biphenyl-Based Diaminophosphine Oxides as Air-Stable Preligands for the Nickel-Catalyzed Kumada-Tamao-Corriu Coupling of Deactivated Aryl Chlorides, Fluorides, and Tosylates. Chemistry - A European Journal. 2012, pp 446–450. 41. Yang, Z.-Y.; Luo, H.; Zhang, M.; Wang, X.-C. Borane-Catalyzed Reduction of Pyridines via a Hydroboration/Hydrogenation Cascade. ACS Catal. 2021, 11 (17), 10824–10829. 72 Chapter 3. Investigation of Asymmetric Ancillary Ligand Effect for Titanium-Catalyzed Hydroamination 3.1 Introduction Catalysis affects all fields of chemical synthesis, such as food production, transportation, pharmaceuticals, etc.1 Although attention to organocatalysis has been rapidly growing,2 transition metal catalysis has been the major pillar of the field of catalysis. Numerous innovative chemical reactions have been developed with transition metal catalysis, such as coupling reactions3, olefin metathesis4, and C–H activation5, and these chemistries are currently being used widely in various fields. In the field of transition metal catalysis, understanding ancillary ligand effects is one of the most critical aspects to study and design catalysts. To understand ligand effects in depth, methods for quantification of ligand properties, such as electronic and steric effects, are needed. Moreover, high valent transition metals, such as titanium(IV), play a critical role in chemical industry. For example, polyolefins are produced on a massive scale from Zeigler-Natta polymerization.6 Polyolefins are widely used materials, accounting for more than 50% in weight of the produced polymers. In 2015, approximately 178 million tons of polyolefins were produced.7,8 Consequently, parameterization methods of ligand properties for high valent transition metals are necessary and are drawing interests from researchers. Optimization and design of new catalysts with high valent transition metals would be more rational if the relationship between ligand properties and reaction outcomes, such as yields, rates, and selectivity, is unveiled using these parameterization methods. 3.1.1 Electronic Parameterization for Low Valent Transition Metals Phosphine ligands are widely used in palladium and other low valent transition metal catalysts, such as Suzuki-Miyaura coupling or Buchwald-Hartwig coupling reactions. Especially, Suzuki-Miyaura coupling and other palladium-catalyzed cross coupling reactions are frequently used reactions in the area of medicinal chemistry.9 Naturally, phosphines became the most important ligands for late transition metal catalysts. Parameterization tools for phosphine ligands were developed by Chadwick Tolman in 1970s to measure the electronic donation from phosphine ligands to low valent, late transition metals.10 Electronic effects of phosphines were experimentally measured using Ni(CO)3(PR3) complexes with various phosphines (PR3), and the CO stretching frequencies in the nickel complexes were used as parameters for the donor properties of phosphines. A more electron-donating phosphine ligand results in a weaker CO bond due to a higher electron occupation in the antibonding orbital of CO ligands, giving a lower CO stretching frequency. 73 Therefore, the donating effect of various phosphine ligands can be directly compared by measuring CO stretching frequencies of Ni(CO)3(PR3) complexes. Table 3.1 CO Stretching Frequencies (v, cm-1).11 Ni(CO)4 + PR3 − CO PR3 OC Ni CO CO Cone Angle, 𝚹 R 2.28 Å R R P Ni(CO)3 Phosphine ligands CO v, cm-1 Cone angle, deg P(o-Tol)3 PMe3 PEt3 P(iPr)3 P(tBu)3 2066.6 2064.1 2061.7 2059.2 2056.1 194±6 118±4 132±4 160±10 182±2 Tolman’s cone angle was introduced to explain steric effect of phosphine ligands.11 The cone angle is the apex angle of a cylindrical cone, centered at 2.28 Å from the ligand center P atom, and this was used as steric parameter. < = = + >(?) + @(A) (Eq 3.1) These steric and electronic parameters can be used together in an equation (Eq 3.1), where a, b, and c are coefficients and Z can be an experimental outcome being investigated, such as reaction rate. However, these methods were not applicable for high oxidation state transition metal catalysts with various types of ligands. For example, titanium(IV) has many common ancillary ligands, such as halide, pyrrolide, indolide, and alkoxide. But it is very difficult to rank these ligands by electron donating ability. In addition, the use of early transition metal catalysis is a recent trend due to the potential benefits from studying catalysts with the earth abundant metals, such as global accessibility and biocompatibility.12 Various catalysts with earth abundant metals have been investigated in parallel with the better known precious metal catalysis in organic 74 synthesis.12 As a result, electronic parameterization methods for high valent transition metal catalysts are needed to understand the donor abilities of these ligands. 3.1.2 Electronic Parameterization for High Valent Transition Metals Although Tolman successfully described the ligand donation to low valent metal centers, electronic parametrization methods are not available for high valent transition metals with a very different group of ancillary ligands in high oxidation state metal catalysts. pKa values or Hammett parameters are often considered as quantification methods for the electronic donation from organic ligands. However, these methods do not measure accurate electronic interactions between high oxidation metals and ligands. For example, B-donation is not considered when comparing pKa values. Figure 3.1 Chromium system for the measurement of LDP of ligand X.13 In 2012, the Odom group developed an experimentally-defined parameter for the electron donation of ancillary ligands towards a high valent metal center to provide a better approach to investigate electronic effects of anionic ligands.14 A chromium(VI) complex, NCr(NiPr2)2X, with various mono-anionic ligands, X, was synthesized for measuring electronic donation from X to a high valent metal center (Figure 3.1). In this system, the electron donation competition between the amido ligand and the X ligand is utilized to study the donating effect of X ligands. The electron donation competition between the amide lone pair and the X ligand affects the Cr-NiPr2 bond's single or double bond character. 75 Figure 3.2 Ligand Donor Parameters (kcal/mol) for various ligands measured with NCr(NiPr2)2X.15 If X is a good donor ligand, the amide ligand lone pair donates less electron density to the metal center, and the Cr-N bond will have more single bond character. If X is a poor donor ligand, more electron donation comes from the amide ligand lone pair to the metal center, and the Cr-N bond will have more double bond character. In short, the rotation barrier of the Cr-N bond can be utilized as a parameter for the donor ability of the X ligand towards the metal center. Using 1H NMR spectroscopy the rotation rate of the Cr-N bond can be measured, and these rate values are inserted into the Eyring equation to obtain the free energy for rotation. With an assumption that ΔS‡ = –9 cal/mol•K for a temperature independent measurement (This value was obtained from experiments using NCr(NiPr2)2I over a wide range of temperatures), the enthalpic barrier (Ligand Donor Paramter, LDP) can be obtained. A poor donor ligand will give high LDP values. Using LDP, the donor ability of various ligands toward high valent transition metal center can be directly compared. LDP values from some of the ligands we have explored are shown in Figure 3.2.15 76 3.1.3 Percent Buried Volume (%Vbur) For a metric of ligand steric effects, a structurally-based system (Percent Buried Volume, %Vbur) developed by Cavallo and coworkers16 is used instead of cone angle from Tolman’s work. In this system, the coordination sphere occupied by the ligand within 3.5 Å radius from the metal center can be measured from crystal structure data of chromium(VI) complexes with X ligands. This system demonstrates a strong correlation with Tolman's cone angle. Using this tool, the steric effect is considered by using this measured volume (percent buried volume or %Vbur). The %Vbur and LDP can be used together in a simple model (Eq. 3.1). For our study, the sterics (%Vbur) and electronics (LDP) were measured with chromium complexes, NCr(NiPr2)2X, with mono-anionic ligands X. These data sets have a potential use for other high valent metal catalysts. Figure 3.3 Percent Buried Volume (%Vbur) is defined as the percent of the coordination sphere occupied by X ligand within 3.5 Å radius (R) from the metal center. The bond length between metal and ligand (d) is determined from the X-ray crystallography.16 77 3.1.4 Investigation of Symmetric Ligand Effects in Titanium Catalysis The Odom group has been interested in C-N and C-C bond forming reactions. Titanium- catalyzed hydroamination and iminoamination have been incorporated into various nitrogen- containing heterocycles but also biologically-active compounds.17 For example, the exploration of NRF2 inhibitors was started from titanium-catalyzed iminoamination.18 The LDP and %Vbur system are employed to understand ligand effects in titanium catalysis. In the previous study, the Odom group designed a model to correlate the electronic and steric parameters of the symmetrical bidentate ligands with reaction rate of titanium-catalyzed hydroamination (Eq. 3.2).13 This model not only allows the prediction of catalyst performance but also guides future catalytic studies. CD=@EFGH I=ED = = + -./(DJD@EIGHF@ K=I=LDEDI) + %5"%&(MEDIF@ K=I=LDEDI) (Eq 3.2) As mentioned above, LDP and %Vbur of the ligands were measured on the same chromium complex. Only one half of the bidentate ligand can be measured for the LDP system, and the linkers between the fragments are ignored due to a small influence on catalysis. NH2 10 mol % Ti cat toluene-d8, 75 °C N (Eq. 3.3) 10 equiv (5 M) (0.5 M) With a set of ligands (Figure 3.4), LDP and %Vbur were measured, and the reaction rates of titanium-catalyzed hydroamination were obtained using the catalysts with various bidentate ligands. For the kinetic study of titanium-catalyzed intermolecular hydroamination, pseudo-first order kinetics was measured using 10-fold of aniline to give pseudo-first order kinetics. (Eq 3.3). The concentration of alkyne was monitored over time and fit into an exponential decay. Eq. 3.4 was obtained from modeling the rate constant with the electronic and steric parameters of the ligands with scaled coefficients.13 Based on the model, electron-deficient and small ligands provide faster reaction rates than those with electron-rich and sterically bulky ligands. "!"#(× 104) = 1.34 + 1.61(-./) − 2.25(%5"%&) (Eq. 3.4) 78 Figure 3.4 Titanium-catalyzed hydroamination reaction and a set of catalysts with symmetric bidentate ligands used for studying ligand effects.13 Catalysts with various ligands fit the model very well, and a prediction of reaction rates can be made prior to the catalyst synthesis using this model. However, this study only considered symmetric ligands, and it has been shown that unsymmetrical ligands can perform faster catalysis than symmetrical ligands in the preliminary studies. In this chapter, the investigation of bidentate ligands in titanium-catalyzed hydroamination reactions is expanded to unsymmetrical ligands using a 5-parameter model. In addition, 3-unsubstituted indoles as a part of the ligand are proposed to go through a unique hydroamination mechanism where the indole fragments are involved in proton transfer resulting in faster catalysis. 3.1.5 Asymmetrical Ligand Environments The ancillary ligand effect toward a high-valent metal was studied by Schrock and coworkers for olefin metathesis using d0 molybdenum catalysts (Mo(=NR)(=CHR’)(X)(Y), X and Y are mono-anionic ligands, such as pyrrolide, alkoxide). From these studies, Schrock and coworkers discovered that the reactivity increases when the Lewis acidity of their d0 molybdenum catalysts increased when X and Y are same or very similar.19 However, the reactivity can be even higher when X and Y are very different ligands, in particular a weak σ-donor, such as an alkoxide or siloxide, and a strong σ-donor, such as alkyl or pyrrolide.20 79 N N iPr N Mo O O Mo-1 50 mol % 80 °C, 48 h < 5% conv. catalyst benzene, 22 °C, 1 h N N iPr N Mo iPr Ph iPr Ph F3C F3C F3C O O CF3 Mo-2 20 mol % 22°C, 2 h > 98% conv. 59% yield iPr N Mo N F3C O CF3 iPr Ph Mo-3 1 mol % 22°C, 1 h > 98% conv. 79% yield Figure 3.5 Examples of the molybdenum catalysts used for ring closing metathesis.20 Theoretical studies from Eisenstein and Copéret also supported the results.21,22 Based on the proposed mechanism, the strong σ-donor ligand would minimize the unfavorable trans-effect, and olefin approaches more readily to the vacant site. In addition, the metal center is Lewis acidic enough due to the weak σ-donor ligand so that the olefin can coordinate to the metal center easily. Lastly, the donor ligand is trans to the new olefin after cycloreversion, and this leads to the disassociation of the new olefin. In short, electronic dissymmetry from two different ligands can facilitate olefin coordination and metallacyclobutane collapse. Ar N Mo R1 D A N Mo R2 Ar D A R2 R Ar N D Mo R1 A R2 N Ar D R2 Mo A R1 Ar N D Mo R1 A R2 Ar N D Mo R2 A R1 Figure 3.6 Proposed mechanism of molybdenum-catalyzed ring closing metathesis. D is a strong σ-donor and A is a weak σ-donor.20 80 R1 L2 (or L1) L1 (or L2) N Ti R3 R1HN A R2 R3 N R1 NHR1 Ti L1 (or L2) L2 (or L1) B The protonolysis from a five-coordinated titanium complex is believed to be the rate determining step for the titanium-catalyzed hydroamination of alkynes shown below in Figure 3.7. Two scenarios can be considered for a five-coordinated titanium complex. A bidentate ligand is on the same plane with Ti-C bond (A in Figure 3.7), and asymmetric ligands are not making a significant difference in the reaction rate since effects from both sides would be averaged out. However, electronic dissymmetry from asymmetric ligands can be effective since each side of the ligands can be in a different environment (B). R2 R3 N Ti R1 X X R3 R2 H2NR1 R2 TiX2(NMe2)2 H2NR1 − 2 HNMe2 N Ti R1 X X R2 R3 H R1 N H Dimerization X X Ti N N Ti R1 R2 R3 R1HN R1 X N Ti X R1 X X R1 X X R2 N Ti R3 R1H2N R ate D etermining Step Figure 3.7 Proposed mechanism of titanium-catalyzed hydroamination of alkynes. A and B are possible geometries for five-coordinated titanium complex in the catalytic cycle. 3.1.6 Model Considerations In the new model for asymmetric ligands, LDP and %Vbur are measured separately for each side of the chelating ligand, using the chromium(VI) system. For example, ligand A has pyrrole and indole as each side of the chelate (Figure 3.8). With this strategy, we can utilize each LDP and %Vbur for various combination of two mono-anionic ligands. "!"#(× 104) = = + >(NOPQ) + @(NOPR) + S(%T:; 0.7, the transition state looks symmetric. 9 = (()( "!+, -.+/01 2+ 34)/(()( "!+, -.+/01 2+ 7&!,%80) (()9 "!+, -.+/01 2+ 34)/(()9 "!+, -.+/01 2+ 7&!,%80) (Eq 4.1) 121 Table 4.1 The τ value for cycloaddition in different solvents with their dielectric constant (k). See Figure 4.1 for structures. No solvent Heptane 1,4- Dioxane THF DCM EtOH H2O k 0 1.92 TS1-1-endo 0.693 0.678 TS1-1-exo 0.745 0.708 TS1-2-endo 0.909 0.896 TS1-2-exo 0.873 0.865 2.21 0.676 0.699 0.893 0.864 7.52 0.682 0.649 0.882 0.857 8.93 0.684 0.649 0.878 0.854 24.6 0.692 0.591 0.885 0.844 78.5 0.695 0.588 0.845 0.823 After the cycloaddition step, this reaction mechanism divaricates into two pathways. In Path A, I1 (cycloaddition products, endo and exo) eliminates ammonia and forms a double bond within the pyridine ring to make I2_α (Figure 4.2). Then, C–O bond cleavage of norbornadiene- like I2_α leads to pyridine-N-oxide (I3). In Path B, C–O bond cleavage in I1 leads to dihydropyridine-N-oxide I2_β, and, losing ammonia, the pyridine ring aromatizes to give pyridine- N-oxide (I3). In Path A, norbornadiene-like I2_α (plus ammonia) is roughly 26 kcal/mol higher in energy than the initial cycloaddition products (I1), and the transition state energy is 61.5 kcal/mol (TS2_α). The activation energy for the formation of the pyridine-N-oxide (TS3_α) is 60 kcal/mol, and this is an exergonic by 100 kcal/mol. Gas phase - exo O N H NH2 TS2_𝛂 61.5 Pathway A O N NH2 TS2_𝛃 38.7 I1 exo 0 O N NH2 Pathway B O N TS3_𝛂 60.0 TS3_𝛃 29.3 H NH2 N O O N I2_𝛂 25.8 NH2 N O I2_𝛃 - 21.7 △G (kcal/mol) 70 60 50 40 30 20 10 0 -10 -20 -30 -40 Gas phase - endo O N H H2N TS2_𝛂 NF Pathway A O N NH2 I1 endo 0 TS2_𝛃 36.8 O N NH2 Pathway B △G (kcal/mol) 70 60 50 40 30 20 10 0 -10 -20 -30 -40 TS3_𝛂 60.0 O N TS3_𝛃 29.3 O N H NH2 O N I2_𝛂 25.8 N O NH2 I2_𝛃 -19.2 N O I3 - 40.8 N O I3 - 40.8 Reaction coordinate Reaction coordinate Figure 4.2 Energy diagram for two pathway mechanism for exo (right) and endo (left). Energy values for I1 in each energy diagram are set to 0; however, I1-1 endo is ~1.5 kcal/mol higher in energy than I1-1 exo. 122 In Path B, cyclohexadiene-like I2_β is 21.7 kcal/mol lower in energy than the initial cycloaddition product I1, and the activation energy is 38.7 kcal/mol. Elimination of the amine to make the pyridine-N-oxide (Step 2 in Path B) is also exergonic with an activation barrier of 29.3 kcal/mol. Effects on Solvent on the Mechanistic Pathway To get more realistic data we added a solvent model and reoptimized the pathway. It was noticed that TS1-1 (Figure 4.1), both exo and endo, are asymmetric when a solvent model is used; whereas, TS1-2 endo/exo were both symmetric. The asymmetric transition states for TS1-1 endo/exo show more C–N bond formation than C–C bond. While the nature of the transition state is different with the inclusion of the solvent model, the energy of the transition state is similar to the gas phase calculation. 1 0.9 0.8 t 0.7 0.6 0.5 0 20 40 60 dielectric constant (k) TS1-1 Exo 80 100 Figure 4.3 Correlation between 9 (Eq. 4.1) and dielectric constant (U) of different solvents. The dielectric constants for the solvents are (left to right) represented by the vertical lines: gas phase (0), heptane, dioxane, THF, dichloromethane, EtOH, and water. To investigate the effect of solvent polarity on the energies and structures, the compounds and transition states were reoptimized in different solvents using the SMD model. The energies were recalculated in heptane, dioxane, THF, DCM, ethanol (EtOH), and H2O. Figure 4 shows variation of τ value (Eq. 4.1) in different solvents. The only transition state structure showing structural changes (by this metric) as a function of solvent polarity is TS1-1 exo, which gets more asymmetric as the polarity is increased. The other isomers of the transition state showed little energy change with solvent polarity. 123 It was observed that I1-1 endo/exo are energetically favored products irrespective of the solvent polarity (Figure 4.4). In low polarity solvents, I1-1 exo is slightly less kinetically favored than endo isomer but in high polarity solvents, I1-1 exo is both kinetically and thermodynamically favored product. 124 ∆G‡ (kcal/mol) Gas Phase Heptane Dioxane THF DCM EtOH H2O Reactants 0.00 TS1-1-endo 41.93 TS1-1-exo 42.89 TS1-2-endo 54.46 TS1-2-exo I1-1-endo I1-1-exo I1-2-endo I1-2-exo 55.25 31.27 27.94 34.44 32.86 0.00 40.69 42.12 54.97 55.92 30.70 27.66 34.23 32.82 0.00 39.51 40.90 54.10 55.13 29.70 26.70 33.18 31.84 0.00 0.00 0.00 0.00 39.42 39.52 37.13 36.17 40.64 40.83 36.56 35.22 55.45 55.81 54.50 54.02 56.67 56.94 55.67 54.86 31.10 31.24 29.01 26.94 28.36 28.55 26.57 24.57 34.40 34.59 32.45 30.35 33.28 33.46 31.31 28.95 Figure 4.4 Energy barrier ∆G‡ (kcal/mol) of cycloaddition transition states in different solvents (top), free energy for cycloaddition products ∆Grxn (kcal/mol) (middle), and the table of the transition state energy barrier (∆G‡) and free energy of cycloaddition products (∆Grxn) in different solvents. See Figure 4.1 for structures. 125 Input Files for Calculated Structures Gas phase Enamine Zero-point correction= 0.068536 (Hartree/Particle) Thermal correction to Energy= 0.072490 Thermal correction to Enthalpy= 0.073434 Thermal correction to Gibbs Free Energy= 0.043867 Sum of electronic and zero-point Energies= -133.904049 Sum of electronic and thermal Energies= -133.900095 Sum of electronic and thermal Enthalpies= -133.899151 Sum of electronic and thermal Free Energies= -133.928718 %chk=eneamine.chk # opt=calcall freq b3lyp/aug-cc-pvdz scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.34782233 H 0.94716921 0.00000000 1.89365212 H 0.94164247 -0.01044363 -0.54625521 H -0.92722554 -0.00229978 -0.57737189 N -1.11429162 -0.06923289 2.17241399 H -1.00796633 0.32196915 3.10013323 H -2.00660723 0.15987070 1.74775490 1 2 2.0 4 1.0 5 1.0 2 3 1.0 6 1.0 3 126 4 5 6 7 1.0 8 1.0 7 8 Isoxazole Zero-point correction= 0.057503 (Hartree/Particle) Thermal correction to Energy= 0.061104 Thermal correction to Enthalpy= 0.062049 Thermal correction to Gibbs Free Energy= 0.031287 Sum of electronic and zero-point Energies= -246.014287 Sum of electronic and thermal Energies= -246.010685 Sum of electronic and thermal Enthalpies= -246.009741 Sum of electronic and thermal Free Energies= -246.040503 %chk=isoxazole.chk # opt=calcall freq b3lyp/aug-cc-pvdz scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.18714946 C 0.86473601 0.00000000 1.13365854 O -1.27343458 -0.00000000 1.74883784 N -1.26839185 0.00000000 0.34354479 H 0.26067470 -0.00000000 -1.05610309 H 1.94848522 0.00000000 1.15545321 H 0.13761140 0.00000000 3.26453969 127 1 3 1.0 5 2.0 6 1.0 2 3 2.0 4 1.0 8 1.0 3 7 1.0 4 5 1.0 5 6 7 8 TS1-1-endo Zero-point correction= 0.128669 (Hartree/Particle) Thermal correction to Energy= 0.135481 Thermal correction to Enthalpy= 0.136425 Thermal correction to Gibbs Free Energy= 0.098057 Sum of electronic and zero-point Energies= -379.871783 Sum of electronic and thermal Energies= -379.864971 Sum of electronic and thermal Enthalpies= -379.864027 Sum of electronic and thermal Free Energies= -379.902395 %chk=TS1.chk # opt=(calcall,qst3) freq b3lyp/aug-cc-pvdz scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.17083335 C 0.86208892 0.00000000 1.12772671 C 0.83299138 0.06712128 9.30152225 C 0.12414789 0.07990156 8.16657357 128 O -1.26057329 0.00000000 1.73185536 N -1.25671581 0.00000000 0.35042800 H 1.91944912 0.06764409 9.26378999 H -0.96235871 0.07655710 8.16912213 H 0.25453484 0.00000000 -1.05053483 H 1.93889331 0.00000000 1.15088209 H 0.13147162 -0.00000000 3.24213867 N 0.32406562 -0.01120616 10.58495978 H 0.90537030 0.37225981 11.31452717 H -0.65232227 0.22474995 10.69447636 H 0.63144567 0.08187087 7.20992462 1 3 1.0 7 2.0 10 1.0 2 3 2.0 6 1.0 12 1.0 3 11 1.0 4 5 2.0 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 8 9 10 11 12 13 14 1.0 15 1.0 14 15 16 Title Card Required 129 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.25005113 C 0.87597857 0.00000000 1.00969615 C -1.67287559 -1.29803818 1.15498189 C -0.66257787 -1.40410048 2.33189052 O -1.12070685 0.80114217 1.78706748 N -1.36131191 0.07732914 0.53719546 H -2.69329284 -1.18613166 1.54131607 H 0.06282010 -2.21548468 2.19974948 H 0.14419158 -0.09140943 -1.07177776 H 1.95824101 -0.08852023 0.97375506 H 0.40549714 0.41210285 3.17781246 N -1.54551196 -2.33695332 0.15399493 H -1.32130528 -3.23099568 0.58066030 H -2.40900181 -2.45390652 -0.37037842 H -1.18490639 -1.53794048 3.28573349 1 3 2.0 7 1.0 10 1.0 2 3 1.0 5 1.0 6 1.0 12 1.0 3 11 1.0 4 5 1.0 7 1.0 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 8 9 10 11 12 13 14 1.0 15 1.0 130 14 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.25005113 C 0.87597857 0.00000000 1.00969615 C -1.73973760 -1.59319396 1.28755974 C -0.79693292 -1.68881869 2.34848560 O -1.12070685 0.80114217 1.78706748 N -1.36131191 0.07732914 0.53719546 H -2.76015484 -1.48128744 1.67389392 H -0.07153494 -2.50020289 2.21634456 H 0.14419158 -0.09140943 -1.07177776 H 1.95824101 -0.08852023 0.97375506 H 0.40549714 0.41210285 3.17781246 N -1.61237396 -2.63210910 0.28657278 H -1.38816729 -3.52615147 0.71323815 H -2.47586382 -2.74906231 -0.23780058 H -1.31926144 -1.82265869 3.30232858 1 3 1.5 7 1.5 10 1.0 2 3 1.5 5 0.5 6 1.0 12 1.0 3 11 1.0 4 5 1.5 7 0.5 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 131 8 9 10 11 12 13 14 1.0 15 1.0 14 15 16 TS1-1-exo Zero-point correction= 0.128590 (Hartree/Particle) Thermal correction to Energy= 0.135560 Thermal correction to Enthalpy= 0.136504 Thermal correction to Gibbs Free Energy= 0.097707 Sum of electronic and zero-point Energies= -379.869986 Sum of electronic and thermal Energies= -379.863017 Sum of electronic and thermal Enthalpies= -379.862072 Sum of electronic and thermal Free Energies= -379.900869 %chk=TS2.chk # opt=(calcall,qst3) freq b3lyp/aug-cc-pvdz scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -1.53442125 -0.52845528 -0.02008667 C -1.53442125 -0.52845528 2.15074668 C -0.67233234 -0.52845528 1.10764004 C -0.70142987 -0.46133399 9.28143558 C -1.41027336 -0.44855372 8.14648690 132 O -2.79499454 -0.52845528 1.71176868 N -2.79113706 -0.52845528 0.33034132 H 0.38502787 -0.46081118 9.24370332 H -2.49677996 -0.45189818 8.14903546 H -1.27988641 -0.52845528 -1.07062151 H 0.40447206 -0.52845528 1.13079542 H -1.40294963 -0.52845528 3.22205199 N -1.21035563 -0.53966144 10.56487310 H -0.62905095 -0.15619547 11.29444049 H -2.18674353 -0.30370533 10.67438968 H -0.90297559 -0.44658441 7.18983795 1 3 1.0 7 2.0 10 1.0 2 3 2.0 6 1.0 12 1.0 3 11 1.0 4 5 2.0 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 8 9 10 11 12 13 14 1.0 15 1.0 14 15 16 Title Card Required 133 0 1 C -1.62894017 -0.53610502 -0.06400123 C -1.32499850 1.60206454 0.57437368 C -2.27109380 0.63411760 -0.12517340 C 0.56609432 0.40615780 -0.27247620 C -0.10735634 1.80872008 -0.36079817 O -0.74065483 0.73251531 1.57664249 N -0.37412702 -0.36730550 0.67550333 H 0.56449882 -0.13784978 -1.22277384 H -0.39110999 2.08947351 -1.38032504 H -1.85391390 -1.50489926 -0.50234163 H -3.20090980 0.87876531 -0.63090002 H -1.74578841 2.49481929 1.04473155 N 1.91519152 0.48601038 0.22838947 H 1.92669717 0.95119741 1.13499602 H 2.29854309 -0.44775776 0.36482588 H 0.56421000 2.57374417 0.04548253 1 3 2.0 7 1.0 10 1.0 2 3 1.0 5 1.0 6 1.0 12 1.0 3 11 1.0 4 5 1.0 7 1.0 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 8 9 10 11 12 13 14 1.0 15 1.0 134 14 15 16 Title Card Required 0 1 C -2.15240728 0.22975930 -0.11280289 C -1.84846561 2.36792886 0.52557202 C -2.79456092 1.39998192 -0.17397505 C 0.24186483 1.33592287 -0.52215947 C -0.37864535 2.61738351 -0.60327730 O -1.26412195 1.49837963 1.52784083 N -0.89759413 0.39855882 0.62670168 H 0.24026932 0.79191529 -1.47245711 H -0.66239900 2.89813694 -1.62280417 H -2.37738102 -0.73903494 -0.55114328 H -3.72437691 1.64462963 -0.67970168 H -2.26925552 3.26068361 0.99592989 N 1.59096203 1.41577545 -0.02129380 H 1.60246767 1.88096248 0.88531276 H 1.97431359 0.48200731 0.11514261 H 0.29292099 3.38240760 -0.19699660 1 3 1.5 7 1.5 10 1.0 2 3 1.5 5 0.5 6 1.0 12 1.0 3 11 1.0 4 5 1.5 7 0.5 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 135 8 9 10 11 12 13 14 1.0 15 1.0 14 15 16 TS1-2-endo Zero-point correction= 0.128284 (Hartree/Particle) Thermal correction to Energy= 0.135222 Thermal correction to Enthalpy= 0.136166 Thermal correction to Gibbs Free Energy= 0.097476 Sum of electronic and zero-point Energies= -379.851627 Sum of electronic and thermal Energies= -379.844690 Sum of electronic and thermal Enthalpies= -379.843746 Sum of electronic and thermal Free Energies= -379.882435 %chk=TS3.chk # opt=(calcall,qst3) freq b3lyp/aug-cc-pvdz scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.88414629 -0.32520325 0.00000000 C -0.88414629 -0.32520325 2.17083335 C -0.02205738 -0.32520325 1.12772671 C -0.75999840 -0.24530169 8.16657357 136 C -0.05115491 -0.25808196 9.30152225 O -2.14471958 -0.32520325 1.73185535 N -2.14086210 -0.32520325 0.35042799 H -0.62961145 -0.32520325 -1.05053484 H 1.05474702 -0.32520325 1.15088209 H -0.75267467 -0.32520325 3.24213866 H 1.03530283 -0.25755915 9.26378999 H -0.25270063 -0.24333238 7.20992462 H -1.84650500 -0.24864615 8.16912213 N -0.56008067 -0.33640941 10.58495977 H -1.53646857 -0.10045330 10.69447635 H 0.02122401 0.04705656 11.31452716 1 3 1.0 7 2.0 8 1.0 2 3 2.0 6 1.0 10 1.0 3 9 1.0 4 5 2.0 13 1.0 12 1.0 5 11 1.0 14 1.0 6 7 1.0 7 8 9 10 11 12 13 14 16 1.0 15 1.0 15 16 Title Card Required 137 0 1 C -1.63019696 0.68927789 0.00000000 C -0.40308053 0.82517287 1.87779991 C -0.95519878 1.60659441 0.69813412 C -0.14538786 -1.09507136 0.50100458 C 0.72167729 -0.12097967 1.34927757 O -1.45647374 -0.14427631 2.08809974 N -1.56761874 -0.60171704 0.69319836 H -2.12110331 0.73748644 -0.96850074 H -0.75920679 2.64348381 0.44424786 H -0.18677583 1.36246632 2.80546961 H 1.12866334 -0.66199714 2.21751639 H -0.09297319 -2.12270732 0.87367392 H 0.10515156 -1.07475018 -0.56582340 N 1.75455748 0.56831093 0.57045212 H 2.34145744 1.12507853 1.19104997 H 2.37673479 -0.11637795 0.14392389 1 3 2.0 7 1.0 8 1.0 2 3 1.0 5 1.0 6 1.0 10 1.0 3 9 1.0 4 5 1.0 7 1.0 12 1.0 13 1.0 5 11 1.0 14 1.0 6 7 1.0 7 8 9 10 11 12 138 13 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C -2.94310726 -0.33916849 0.00000000 C -1.71599083 -0.20327351 1.87779991 C -2.26810908 0.57814804 0.69813412 C -1.12803148 -2.23808317 0.45637385 C -0.36938814 -1.33604319 1.24503293 O -2.76938404 -1.17272269 2.08809974 N -2.88052904 -1.63016341 0.69319836 H -3.43401361 -0.29095993 -0.96850074 H -2.07211709 1.61503743 0.44424786 H -1.49968613 0.33401994 2.80546961 H 0.03759792 -1.87706065 2.11327175 H -1.07561680 -3.26571912 0.82904318 H -0.87749206 -2.21776198 -0.61045413 N 0.66349205 -0.64675258 0.46620748 H 1.25039201 -0.08998499 1.08680533 H 1.28566936 -1.33144146 0.03967925 1 3 1.5 7 1.5 8 1.0 2 3 1.5 5 0.5 6 1.0 10 1.0 3 9 1.0 4 5 1.5 7 0.5 12 1.0 13 1.0 5 11 1.0 14 1.0 6 7 1.0 139 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 TS1-2-exo Zero-point correction= 0.128257 (Hartree/Particle) Thermal correction to Energy= 0.135190 Thermal correction to Enthalpy= 0.136134 Thermal correction to Gibbs Free Energy= 0.097515 Sum of electronic and zero-point Energies= -379.850431 Sum of electronic and thermal Energies= -379.843498 Sum of electronic and thermal Enthalpies= -379.842553 Sum of electronic and thermal Free Energies= -379.881172 %chk=TS4.chk # opt=(calcall,qst3) freq b3lyp/aug-cc-pvdz scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.57926826 -0.32520325 0.00000000 C -0.57926826 -0.32520325 2.17083335 C 0.28282065 -0.32520325 1.12772671 C -0.45512037 -0.24530169 8.16657357 140 C 0.25372312 -0.25808196 9.30152225 O -1.83984155 -0.32520325 1.73185535 N -1.83598407 -0.32520325 0.35042799 H -0.32473342 -0.32520325 -1.05053484 H 1.35962505 -0.32520325 1.15088209 H -0.44779664 -0.32520325 3.24213866 H 1.34018086 -0.25755915 9.26378999 H 0.05217740 -0.24333238 7.20992462 H -1.54162697 -0.24864615 8.16912213 N -0.25520264 -0.33640941 10.58495977 H -1.23159054 -0.10045330 10.69447635 H 0.32610204 0.04705656 11.31452716 1 3 1.0 7 2.0 8 1.0 2 3 2.0 6 1.0 10 1.0 3 9 1.0 4 5 2.0 13 1.0 12 1.0 5 11 1.0 14 1.0 6 7 1.0 7 8 9 10 11 12 13 14 16 1.0 15 1.0 15 16 Title Card Required 141 0 1 C -2.17724292 -0.18599562 0.00000000 C -3.97323550 -1.39692251 0.61253180 C -2.65162670 -1.42679591 -0.13777443 C -4.30500935 0.85668057 -0.04968782 C -4.97584218 -0.55246442 -0.22060038 O -3.66049867 -0.45912457 1.67759310 N -3.10116106 0.60242098 0.82971730 H -1.30739374 0.30685105 -0.42623111 H -2.24817746 -2.25164485 -0.71794040 H -4.36892272 -2.32865994 1.02436892 H -4.99766727 -0.87557991 -1.26704418 H -4.97812988 1.53748420 0.48305472 H -3.97794301 1.32162675 -0.98611972 N -6.32988799 -0.67689614 0.32547044 H -6.34217976 -0.34117478 1.28866742 H -6.96985420 -0.07516021 -0.19070513 1 3 2.0 7 1.0 8 1.0 2 3 1.0 5 1.0 6 1.0 10 1.0 3 9 1.0 4 5 1.0 7 1.0 12 1.0 13 1.0 5 11 1.0 14 1.0 6 7 1.0 7 8 9 10 11 12 142 13 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C -2.78993439 0.40481400 0.00000000 C -4.58592698 -0.80611289 0.61253180 C -3.26431818 -0.83598629 -0.13777443 C -5.20237830 1.50761568 -0.25764329 C -5.79302919 0.21058413 -0.39052923 O -4.27319015 0.13168505 1.67759310 N -3.71385253 1.19323060 0.82971730 H -1.92008522 0.89766067 -0.42623111 H -2.86086893 -1.66083523 -0.71794040 H -4.98161419 -1.73785033 1.02436892 H -5.81485428 -0.11253136 -1.43697303 H -5.87549883 2.18841931 0.27509926 H -4.87531196 1.97256187 -1.19407518 N -7.14707499 0.08615241 0.15554159 H -7.15936676 0.42187377 1.11873857 H -7.78704120 0.68788834 -0.36063398 1 3 1.5 7 1.5 8 1.0 2 3 1.5 5 0.5 6 1.0 10 1.0 3 9 1.0 4 5 1.5 7 0.5 12 1.0 13 1.0 5 11 1.0 14 1.0 6 7 1.0 143 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 I1-1 endo Zero-point correction= 0.132540 (Hartree/Particle) Thermal correction to Energy= 0.138743 Thermal correction to Enthalpy= 0.139687 Thermal correction to Gibbs Free Energy= 0.102681 Sum of electronic and zero-point Energies= -379.892455 Sum of electronic and thermal Energies= -379.886253 Sum of electronic and thermal Enthalpies= -379.885309 Sum of electronic and thermal Free Energies= -379.922314 %chk=I1N.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.17544496 -1.27014475 -0.63381447 C -1.06900567 -0.42073047 0.31597016 C 0.44198878 1.41836854 -0.08311413 C 1.26486459 0.72403180 -0.87641270 144 C 1.22195026 -0.68130375 -0.29319254 H -1.43226714 -1.02748483 1.15052695 H -0.44964201 -1.15071188 -1.68826158 H 0.10115958 2.44782549 -0.13928463 H 1.78726156 1.04982393 -1.77129236 H -0.22746992 -2.33281058 -0.37317295 N -0.06014925 0.55052329 0.98224831 O 1.05468826 -0.38559222 1.11387635 N -2.19232531 0.20104180 -0.32879690 H -1.91102817 0.77953972 -1.11606194 H -2.73209797 0.76832119 0.31942214 H 2.08778190 -1.33204911 -0.44366422 1 2 1.0 5 1.0 7 1.0 10 1.0 2 6 1.0 11 1.0 13 1.0 3 4 2.0 8 1.0 11 1.0 4 5 1.0 9 1.0 5 12 1.0 16 1.0 6 7 8 9 10 11 12 1.0 12 13 14 1.0 15 1.0 14 15 16 I1-1 exo Zero-point correction= 0.132491 (Hartree/Particle) 145 Thermal correction to Energy= 0.138703 Thermal correction to Enthalpy= 0.139647 Thermal correction to Gibbs Free Energy= 0.102598 Sum of electronic and zero-point Energies= -379.894804 Sum of electronic and thermal Energies= -379.888592 Sum of electronic and thermal Enthalpies= -379.887647 Sum of electronic and thermal Free Energies= -379.924697 %chk=I1X.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.99183102 -0.21223765 -0.54478675 C 0.32162386 1.19287018 -0.63269700 C -0.89185609 0.98256591 0.31086586 C -1.84864286 0.02386368 -0.39169185 C -1.20788537 -1.14701772 -0.34025413 N 0.04904560 -0.98910691 0.39444583 O -0.30656627 0.10707191 1.30001022 H -1.30666766 1.87242526 0.79271075 H -2.78513631 0.27043804 -0.88282256 H -1.44542083 -2.11430553 -0.77388607 H 0.99909880 -0.74687074 -1.50196088 H 0.03640908 1.47403932 -1.65195968 H 1.00016488 1.95449979 -0.23267147 N 2.33782539 -0.13247161 -0.04005880 H 2.33432659 0.31100371 0.87701952 H 2.72123535 -1.06702183 0.08416262 146 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 I2_α Zero-point correction= 0.126331 (Hartree/Particle) Thermal correction to Energy= 0.135225 Thermal correction to Enthalpy= 0.136169 Thermal correction to Gibbs Free Energy= 0.091625 Sum of electronic and zero-point Energies= -379.846568 Sum of electronic and thermal Energies= -379.837674 Sum of electronic and thermal Enthalpies= -379.836730 Sum of electronic and thermal Free Energies= -379.881273 %chk=I2-1_NH3.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 147 0 1 C -2.02660273 -0.18781117 -0.32158089 C 0.01225212 -0.75247566 0.48761132 C -1.50101750 -1.06957762 0.52858847 H -3.04753819 0.03233497 -0.61512705 H -1.99282417 -1.82188505 1.13632153 C -0.39578158 1.46082558 0.22721327 H -0.57740048 2.53031741 0.21511404 C 0.20453974 0.65470939 1.10168925 H 0.70293877 0.88823363 2.03608712 H 0.72982580 -1.52668843 0.76504397 O 0.12934760 -0.40609691 -0.91120099 N -0.92128145 0.63334887 -0.90472042 N 3.15725008 -0.26460810 -0.12062838 H 2.38801188 -0.14900195 -0.78069973 H 3.96450333 -0.58746236 -0.65012043 H 3.38558148 0.66771850 0.21930153 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 1.0 14 0.5 12 148 13 14 1.0 15 1.0 16 1.0 14 15 16 I2__β endo Zero-point correction= 0.131584 (Hartree/Particle) Thermal correction to Energy= 0.138804 Thermal correction to Enthalpy= 0.139748 Thermal correction to Gibbs Free Energy= 0.100161 Sum of electronic and zero-point Energies= -379.921427 Sum of electronic and thermal Energies= -379.914207 Sum of electronic and thermal Enthalpies= -379.913263 Sum of electronic and thermal Free Energies= -379.952850 %chk=I2-2N.chk # opt=(calcall,tight) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.58789118 -0.65054582 0.35647587 C 0.59945383 -1.42989753 -0.20948513 C 1.90469365 -0.72065960 0.01959088 C 1.90846092 0.62728527 0.05140207 C 0.68541651 1.39115819 -0.08022122 N -0.50025212 0.82621494 0.00618942 O -1.60394996 1.46074412 -0.05325409 H 2.83132088 -1.29047744 0.08245895 H 2.83531337 1.19254688 0.15014129 H 0.67537405 2.46979246 -0.21781782 H 0.42799744 -1.57401938 -1.29065230 149 H 0.59586177 -2.43056920 0.24415444 H -0.53379024 -0.63629895 1.46333416 N -1.84053948 -1.15410635 -0.16836815 H -2.12075610 -1.98799485 0.34034028 H -2.55498262 -0.43773562 -0.03725001 1 2 1.0 6 1.0 13 1.0 14 1.0 2 3 1.0 11 1.0 12 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 I2_β_exo Zero-point correction= 0.132350 (Hartree/Particle) Thermal correction to Energy= 0.139362 Thermal correction to Enthalpy= 0.140306 Thermal correction to Gibbs Free Energy= 0.101391 Sum of electronic and zero-point Energies= -379.926003 Sum of electronic and thermal Energies= -379.918992 Sum of electronic and thermal Enthalpies= -379.918048 Sum of electronic and thermal Free Energies= -379.956962 150 %chk=I2-2X.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.39182318 0.92498171 -0.30534961 C -1.06649386 0.95351854 -0.76808140 C -1.91281117 -0.05119911 -0.03307431 C -1.34309165 -1.19939004 0.38814619 C 0.06789577 -1.46516302 0.19564312 N 0.89602553 -0.51563850 -0.19078883 O 2.15054838 -0.66306470 -0.35478030 H -2.97876514 0.13225575 0.09638443 H -1.93183114 -1.97997097 0.87038857 H 0.51709496 -2.43868648 0.37985773 H 1.06043815 1.35522339 -1.05669583 H -1.10630977 0.73336278 -1.84892831 H -1.43746860 1.97792065 -0.63593162 N 0.57797998 1.62224698 0.94103923 H -0.01624830 1.23911759 1.67320059 H 1.54673057 1.56254703 1.24451018 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 151 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 I3 Zero-point correction= 0.129145 (Hartree/Particle) Thermal correction to Energy= 0.138027 Thermal correction to Enthalpy= 0.138971 Thermal correction to Gibbs Free Energy= 0.094571 Sum of electronic and zero-point Energies= -379.952773 Sum of electronic and thermal Energies= -379.943891 Sum of electronic and thermal Enthalpies= -379.942947 Sum of electronic and thermal Free Energies= -379.987346 %chk=I3_NH3.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -1.14897497 -1.23136829 -0.00000000 C -2.30146874 -0.46065540 0.00000001 C -2.21698402 0.93451520 0.00000000 C -0.94281412 1.50901391 -0.00000000 C 0.19469473 0.71489612 -0.00000002 N 0.09247187 -0.65267506 -0.00000002 152 H -3.11352814 1.55196830 0.00000002 H -1.12994742 -2.31729095 -0.00000000 H -3.26487398 -0.96936850 0.00000002 H -0.81224314 2.59061595 0.00000000 H 1.21633189 1.09200139 -0.00000003 O 1.14653989 -1.39491133 -0.00000003 N 3.51153736 0.59039990 -0.00000006 H 2.95919126 -0.27150414 -0.00000005 H 4.11898369 0.56019245 0.81634820 H 4.11898490 0.56019300 -0.81634744 1 2 1.5 6 1.5 8 1.0 2 3 1.5 9 1.0 3 4 1.5 7 1.0 4 5 1.5 10 1.0 5 6 1.5 11 1.0 6 12 1.0 7 8 9 10 11 12 14 0.5 13 14 1.0 15 1.0 16 1.0 14 15 16 I2-1 (without NH3) Zero-point correction= 0.090279 (Hartree/Particle) Thermal correction to Energy= 0.095032 Thermal correction to Enthalpy= 0.095976 153 Thermal correction to Gibbs Free Energy= 0.062247 Sum of electronic and zero-point Energies= -323.304118 Sum of electronic and thermal Energies= -323.299365 Sum of electronic and thermal Enthalpies= -323.298421 Sum of electronic and thermal Free Energies= -323.332151 %chk=I2-1.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.48448483 -0.67888251 1.19056230 C 0.33783302 1.06105591 -0.00000000 C -0.48448483 0.65239965 1.24744321 H -0.95587102 -1.44078893 1.80241687 H -0.95797396 1.31584415 1.96365615 C -0.48448483 -0.67888251 -1.19056230 H -0.95587102 -1.44078893 -1.80241687 C -0.48448483 0.65239965 -1.24744321 H -0.95797396 1.31584415 -1.96365615 H 0.82736026 2.03860915 -0.00000000 O 1.30130728 -0.01032896 -0.00000000 N 0.31292990 -1.10780415 0.00000000 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 154 7 8 9 1.0 9 10 11 12 1.0 12 I3 (without NH3) Zero-point correction= 0.092635 (Hartree/Particle) Thermal correction to Energy= 0.097707 Thermal correction to Enthalpy= 0.098651 Thermal correction to Gibbs Free Energy= 0.064572 Sum of electronic and zero-point Energies= -323.407838 Sum of electronic and thermal Energies= -323.402765 Sum of electronic and thermal Enthalpies= -323.401821 Sum of electronic and thermal Free Energies= -323.435900 %chk=I3.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.00000000 -1.18114406 0.28568423 C -0.00000000 -1.19627916 -1.10057461 C -0.00000000 0.00000000 -1.82412224 C 0.00000000 1.19627916 -1.10057461 C 0.00000000 1.18114406 0.28568423 N 0.00000000 0.00000000 0.98512743 H -0.00000000 -0.00000000 -2.91248950 H -0.00000000 -2.06580882 0.91575002 H -0.00000000 -2.16134098 -1.60642677 155 H 0.00000000 2.16134098 -1.60642677 H 0.00000000 2.06580882 0.91575002 O 0.00000000 -0.00000000 2.26517112 1 2 1.5 6 1.5 8 1.0 2 3 1.5 9 1.0 3 4 1.5 7 1.0 4 5 1.5 10 1.0 5 6 1.5 11 1.0 6 12 1.0 7 8 9 10 11 12 Biradical Zero-point correction= 0.087296 (Hartree/Particle) Thermal correction to Energy= 0.092978 Thermal correction to Enthalpy= 0.093922 Thermal correction to Gibbs Free Energy= 0.056845 Sum of electronic and zero-point Energies= -323.332751 Sum of electronic and thermal Energies= -323.327069 Sum of electronic and thermal Enthalpies= -323.326125 Sum of electronic and thermal Free Energies= -323.363202 %chk=BR.chk # opt=(calcall,tight,maxcycle=500) freq ub3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 156 0 3 C 1.12186144 -1.16171475 0.05130517 C -1.05535375 0.00000106 -0.32246401 C -0.22836885 -1.24564691 -0.17890003 H 1.70823354 -2.07535483 0.17375176 H -0.74016426 -2.20670851 -0.22655216 C 1.12186295 1.16171386 0.05130555 H 1.70823617 2.07535299 0.17375349 C -0.22836712 1.24564750 -0.17890039 H -0.74016102 2.20670996 -0.22655212 H -1.52505980 0.00000007 -1.35029000 O -2.19557473 0.00000032 0.47230680 N 1.82338646 -0.00000098 0.16333670 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 TS2_α_exo (amine loss from I1-1 Exo) Zero-point correction= 0.128601 (Hartree/Particle) Thermal correction to Energy= 0.135067 Thermal correction to Enthalpy= 0.136011 Thermal correction to Gibbs Free Energy= 0.098481 157 Sum of electronic and zero-point Energies= -379.794247 Sum of electronic and thermal Energies= -379.787782 Sum of electronic and thermal Enthalpies= -379.786838 Sum of electronic and thermal Free Energies= -379.824367 %mem=4GB %Nprocs=1 %chk=TS1X.chk # opt=(calcall,tight,qst3,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.55924133 C 1.52620463 0.00000000 1.83811661 C 2.06017478 -1.36835255 1.42504870 C 1.98750898 -1.34008105 0.09159477 N 1.50087697 -0.03060650 -0.34779198 O 1.99333162 0.81694265 0.74182411 H 1.85715601 0.42226036 2.79114337 H 2.34794956 -2.18722934 2.07747078 H 2.17772355 -2.10736005 -0.65352713 H -0.44512933 -0.90455313 -0.43094197 H -0.52132014 -0.86003451 1.99267615 H -0.46513994 0.91960919 1.93137246 N -0.67136281 1.15573737 -0.53512294 H -0.22656476 2.00294710 -0.18568704 H -0.58535715 1.17248963 -1.54909559 158 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.33226020 C 1.50445488 0.00000000 1.69399426 C 2.08909620 -1.35496647 1.23087643 C 1.99793623 -1.29518150 -0.09752692 N 1.41836051 0.02942814 -0.47909202 O 1.99493286 0.83319428 0.61901328 H 1.78948967 0.40194519 2.66789442 H 2.45548288 -2.15676797 1.86337534 H 2.23129758 -2.00568341 -0.88344829 H -0.79501056 -0.04334300 -0.73690174 159 H -0.83101661 -0.01364103 2.02886615 H 1.08472007 3.98659347 2.62825746 N 0.72065798 3.05979286 2.41670622 H 1.18460311 2.73835041 1.56687326 H -0.26207046 3.18007018 2.17859146 1 11 1.0 2 2.0 6 1.0 2 3 1.0 12 1.0 3 4 1.0 8 1.0 7 1.0 4 5 2.0 9 1.0 5 10 1.0 6 1.0 6 7 1.0 7 15 0.5 8 9 10 11 12 13 14 1.0 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C 0.82177355 -0.09009585 -0.72034797 C 0.26621281 1.23539663 -0.65019319 C -0.83905803 1.00069895 0.39754924 C -1.89578427 0.09356631 -0.25035232 C -1.30311097 -1.10568361 -0.34725241 160 N 0.03876803 -1.00684670 0.22959162 O -0.20178619 0.01884389 1.26741729 H -1.19328611 1.84528197 0.99630696 H -2.86864374 0.39582054 -0.62918036 H -1.59820691 -2.02958427 -0.83420011 H 1.05425714 -0.58337035 -1.67061585 H -0.01325016 1.71082786 -1.59114403 H 2.89010347 0.56945379 -0.33856397 N 2.28652037 -0.13556432 0.08351758 H 2.02069127 0.18814942 1.01971496 H 2.74540714 -1.05374754 0.14015955 1 2 1.5 6 1.0 11 1.0 14 0.5 2 3 1.0 12 1.0 13 0.5 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 13 0.5 15 0.5 8 9 10 11 12 13 14 0.5 14 15 1.0 16 1.0 15 16 TS3_α (ring opening from I2-2) Zero-point correction= 0.129228 (Hartree/Particle) 161 Thermal correction to Energy= 0.135722 Thermal correction to Enthalpy= 0.136666 Thermal correction to Gibbs Free Energy= 0.098972 Sum of electronic and zero-point Energies= -379.833384 Sum of electronic and thermal Energies= -379.826890 Sum of electronic and thermal Enthalpies= -379.825946 Sum of electronic and thermal Free Energies= -379.863640 %mem=4GB %Nprocs=4 %chk=TS3.chk # opt=(calcall,tight,qst3) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.33200977 C 1.50631533 0.00000000 1.69340004 C 2.08948054 -1.35908818 1.23349720 C 1.99866229 -1.29795388 -0.09432913 N 1.42345053 0.02990814 -0.47045308 O 1.99869839 0.83280604 0.62372576 H 1.80598906 0.38774641 2.67058924 H 2.44787029 -2.16393754 1.86672210 H 2.22041540 -2.01092067 -0.88116212 H -0.77882040 -0.04742856 -0.75384631 H -0.83540647 -0.02601213 2.02377754 H 0.80576048 0.54418068 -2.62970601 N 0.00473195 0.52697760 -3.26359083 H 0.34822833 0.24282384 -4.17883647 162 H -0.31008664 1.49079580 -3.36086777 1 11 1.0 2 2.0 6 1.0 2 3 1.0 12 1.0 3 4 1.0 8 1.0 7 1.0 4 5 2.0 9 1.0 5 10 1.0 6 1.0 6 7 1.0 7 13 0.5 8 9 10 11 12 13 14 1.0 14 16 1.0 15 1.0 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.38644869 C 1.20670795 0.00000000 2.09178147 C 2.39256150 0.00000000 1.35197828 C 2.36477607 0.00000000 -0.03502465 N 1.17114986 0.00000000 -0.71027026 O 1.14010734 -0.00000000 -1.99907211 H 1.22158965 0.00000000 3.18027495 H 3.36423262 0.00000000 1.84469201 163 H 3.24616479 0.00000000 -0.67463753 H -0.89210235 0.00000000 -0.61947017 H -0.95841796 0.00000000 1.90449648 H 3.08158069 0.00000000 -2.88135851 N 4.10508708 0.00000000 -2.86137572 H 4.41765135 0.81634732 -3.38311177 H 4.41765021 -0.81634821 -3.38311106 1 2 1.5 6 1.5 11 1.0 2 3 1.5 12 1.0 3 4 1.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 13 0.5 8 9 10 11 12 13 14 1.0 14 16 1.0 15 1.0 15 16 Title Card Required 0 1 C 1.24814029 -1.18630544 -0.52132968 C 2.12089546 -0.35279221 0.07646749 C 1.45926861 0.82482064 0.63915938 164 C 0.55555788 1.50276758 -0.28465633 C -0.30407420 0.64616026 -0.87429960 N -0.11584018 -0.71167496 -0.39619887 O -0.29406076 -0.60305446 0.97617161 H 1.87085280 1.34044183 1.50626779 H 0.48182195 2.58548877 -0.35490712 H -1.22317999 0.87810762 -1.40306824 H 1.42199540 -2.20213347 -0.86389012 H 3.17361148 -0.57380722 0.23779456 H -3.53271280 -0.93269765 -0.26833083 N -3.28066854 -0.00880880 0.07830559 H -2.48229328 -0.14609588 0.70103041 H -4.06077675 0.31061287 0.64893605 1 2 2.0 6 1.0 11 1.0 2 3 1.0 12 1.0 3 4 1.0 7 0.5 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 13 0.5 8 9 10 11 12 13 14 1.0 14 15 1.0 16 1.0 15 16 165 TS3_β_endo (ring opening from I1-1 endo) Zero-point correction= 0.129370 (Hartree/Particle) Thermal correction to Energy= 0.135841 Thermal correction to Enthalpy= 0.136785 Thermal correction to Gibbs Free Energy= 0.099147 Sum of electronic and zero-point Energies= -379.833455 Sum of electronic and thermal Energies= -379.826984 Sum of electronic and thermal Enthalpies= -379.826040 Sum of electronic and thermal Free Energies= -379.863678 %mem=4GB %Nprocs=4 %chk=TS2N.chk # opt=(calcall,qst3) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.55629234 C 1.53000171 0.00000000 1.82935800 C 2.04918838 -1.37769929 1.44290625 C 1.97983124 -1.37600992 0.10734000 N 1.50735077 -0.07178616 -0.35747976 O 2.00350188 0.79074382 0.71321005 H 1.86834128 0.43580033 2.77348718 H 2.33320177 -2.18554650 2.11116355 H 2.18132363 -2.16046275 -0.61594118 166 H -0.31047778 0.97500808 -0.38672650 H -0.46826433 0.90978031 1.94735169 H -0.51433586 -0.87155700 1.97718875 N -0.82475875 -1.01728225 -0.59083152 H -0.77393716 -1.00081551 -1.60596413 H -0.57869007 -1.94819603 -0.26460499 1 2 1.0 11 1.0 6 1.0 14 1.0 2 3 1.0 13 1.0 12 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 10 1.0 6 1.0 6 7 1.0 7 8 9 10 11 12 13 14 16 1.0 15 1.0 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.52888511 C 1.39186542 0.00000000 2.09620954 C 2.37116786 -0.61202886 1.40024341 167 C 2.11781380 -1.21795110 0.10976481 N 1.00326171 -0.99830658 -0.55504052 O 0.75402649 -1.46724688 -1.71361184 H 1.57858815 0.42262571 3.08302522 H 3.38357682 -0.69715511 1.79534744 H 2.84189990 -1.85155470 -0.39692190 H 0.39302350 0.96601510 -0.37497925 H -0.57693941 0.87127003 1.86825845 H -0.55097122 -0.89417834 1.86942420 N -1.30496255 -0.35057793 -0.52185480 H -1.91665765 0.46068320 -0.50289977 H -1.19350302 -0.65124963 -1.49035179 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 13 1.0 12 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 Title Card Required 168 0 1 C 1.08633558 0.03717126 0.39558703 C 0.31024060 1.42046110 0.36110345 C -1.09672612 1.16898801 -0.01488234 C -1.33671180 0.18912278 -1.03195442 C -0.73707334 -1.02102778 -0.81410256 N 0.05487933 -1.01301253 0.37462562 O -0.77605336 -0.81091170 1.39722861 H -1.88514906 1.86073180 0.27797545 H -2.14259601 0.28589285 -1.75909377 H -1.07269679 -1.96806855 -1.22804262 H 1.56754536 -0.06063712 1.37496699 H 0.39696197 1.98031773 1.29891870 H 0.81455111 1.99851468 -0.42942053 N 2.07856258 -0.05111932 -0.64934591 H 2.58683556 -0.93017568 -0.59217866 H 1.65249188 0.00134864 -1.57241928 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.5 7 0.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 8 9 10 11 12 169 13 14 15 1.0 16 1.0 15 16 TS3_β_exo (Ring opening from I1-1 exo) Zero-point correction= 0.129228 (Hartree/Particle) Thermal correction to Energy= 0.135722 Thermal correction to Enthalpy= 0.136666 Thermal correction to Gibbs Free Energy= 0.098972 Sum of electronic and zero-point Energies= -379.833384 Sum of electronic and thermal Energies= -379.826890 Sum of electronic and thermal Enthalpies= -379.825946 Sum of electronic and thermal Free Energies= -379.863640 %mem=4GB %Nprocs=4 %chk=TS2X.chk # opt=(calcall,qst3) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.55924133 C 1.52620463 0.00000000 1.83811661 C 2.06017478 -1.36835255 1.42504870 C 1.98750898 -1.34008105 0.09159477 N 1.50087697 -0.03060650 -0.34779198 O 1.99333162 0.81694265 0.74182411 170 H 1.85715601 0.42226036 2.79114337 H 2.34794956 -2.18722934 2.07747078 H 2.17772355 -2.10736005 -0.65352713 H -0.44512933 -0.90455313 -0.43094197 H -0.52132014 -0.86003451 1.99267615 H -0.46513994 0.91960919 1.93137246 N -0.67136281 1.15573737 -0.53512294 H -0.58535715 1.17248963 -1.54909559 H -0.22656476 2.00294710 -0.18568704 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 16 1.0 15 1.0 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 171 C 0.00000000 0.00000000 1.53010891 C 1.39143916 0.00000000 2.10039877 C 2.38629713 -0.59293416 1.41030685 C 2.14258596 -1.20097416 0.11605766 N 1.02056572 -1.00384919 -0.53343854 O 0.74972935 -1.50350074 -1.69302237 H 1.56604508 0.43008306 3.08589732 H 3.39763783 -0.66506280 1.80869035 H 2.87921568 -1.83217830 -0.37728053 H -0.94804655 -0.37486185 -0.39553219 H -0.53400449 -0.89363680 1.89430647 H -0.57602384 0.87105852 1.86604874 N 0.25100415 1.31238923 -0.54301603 H 0.28324850 1.28570635 -1.55919916 H 1.13473468 1.69078292 -0.20717727 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 16 1.0 15 1.0 15 172 16 Title Card Required 0 1 C 0.93973558 0.08934461 -0.58175770 C 0.28528108 1.41444414 -0.02993143 C -1.09200947 1.12528545 0.41719588 C -1.86053307 0.19506882 -0.35776468 C -1.23346576 -0.99806614 -0.58412083 N 0.09848009 -1.02135636 -0.07459242 O -0.00116984 -0.90124216 1.25822839 H -1.58369133 1.76147525 1.15251240 H -2.93832296 0.29031583 -0.48542912 H -1.74151921 -1.93914088 -0.77972665 H 0.89344983 0.04864835 -1.67687746 H 0.26505879 2.10518913 -0.88975747 H 0.89209155 1.87771050 0.75579397 N 2.31412904 0.02140897 -0.15704698 H 2.76363415 -0.79803491 -0.55869295 H 2.33634386 -0.09305554 0.85609854 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.5 7 0.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 8 9 173 10 11 12 13 14 15 1.0 16 1.0 15 16 TS2_β_endo (amine loss from I2_β endo) Zero-point correction= 0.129256 (Hartree/Particle) Thermal correction to Energy= 0.135918 Thermal correction to Enthalpy= 0.136862 Thermal correction to Gibbs Free Energy= 0.098915 Sum of electronic and zero-point Energies= -379.845307 Sum of electronic and thermal Energies= -379.838645 Sum of electronic and thermal Enthalpies= -379.837701 Sum of electronic and thermal Free Energies= -379.875648 %mem=4GB %Nprocs=1 %chk=TS4N_TS.chk # opt=(calcall,tight,ts,verytight,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.45442619 C 1.31312532 0.00000000 1.99392573 C 2.43373664 0.23575411 1.18512099 C 2.23079243 0.77278621 -0.10892224 174 N 1.01260091 0.76146819 -0.67411958 O 0.70702202 1.30633044 -1.82399504 H 1.44516407 -0.06348227 3.07637914 H 3.44532458 0.21343849 1.58622530 H 3.00961647 1.24982870 -0.69691177 H -0.93906693 0.10630263 -0.53990988 H -0.64671895 0.65661773 2.04108449 H 1.52546215 -1.51785156 0.00028303 N 0.58915124 -1.59591631 -0.42257213 H 0.65703039 -1.71665291 -1.43216400 H 0.05099333 -2.33632602 0.02338804 1 2 1.3 6 1.2 11 0.5 13 0.5 14 0.5 2 3 1.2 11 0.5 12 1.0 13 0.2 3 4 1.8 8 1.0 4 5 1.3 9 1.0 5 6 1.8 10 1.0 6 7 1.0 7 13 0.3 8 9 10 11 12 13 14 0.5 14 15 1.0 16 1.0 15 16 175 TS2_β_exo (amine loss from I2_β_exo) Zero-point correction= 0.129256 (Hartree/Particle) Thermal correction to Energy= 0.135917 Thermal correction to Enthalpy= 0.136862 Thermal correction to Gibbs Free Energy= 0.098915 Sum of electronic and zero-point Energies= -379.845307 Sum of electronic and thermal Energies= -379.838645 Sum of electronic and thermal Enthalpies= -379.837701 Sum of electronic and thermal Free Energies= -379.875648 %mem=4GB %Nprocs=4 %chk=TS4X.chk # opt=(calcall,tight,qst3,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.53023647 C 1.39502894 0.00000000 2.09578067 C 2.37869871 -0.61176277 1.40405129 C 2.13622792 -1.22170308 0.11263388 N 1.01176171 -1.01256635 -0.54201330 O 0.73615095 -1.48894184 -1.69073449 H 1.58044566 0.43776773 3.07590983 H 3.38969543 -0.68801694 1.80473750 H 2.86540534 -1.85401004 -0.38931342 176 H -0.94840116 -0.36828461 -0.40196604 H -0.53297725 -0.89673293 1.89091530 H -0.57797215 0.87164007 1.86291843 N 0.26102181 1.30888387 -0.54130302 H 1.14628712 1.68061261 -0.20354765 H 0.28812843 1.27821779 -1.55740402 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.38728131 C 1.20043305 0.00000000 2.10318505 C 2.39277213 0.00000000 1.37382493 177 C 2.36500338 0.00000000 -0.01234575 N 1.17986258 0.00000000 -0.69901698 O 1.18508586 0.00000000 -1.98818213 H 1.20735543 0.00000000 3.19175833 H 3.36137373 -0.00000000 1.87257298 H 3.24451967 0.00000000 -0.64955935 H -0.89402259 -0.00000000 -0.62183156 H -0.96160787 0.00000000 1.89935754 H -0.77366922 0.00000000 -2.83140645 N -1.79657014 0.00000000 -2.79092817 H -2.11952028 0.81634826 -3.30629865 H -2.11952144 -0.81634738 -3.30629934 1 2 1.5 6 1.5 11 1.0 2 3 1.5 12 1.0 3 4 1.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 13 0.5 8 9 10 11 12 13 14 1.0 14 15 1.0 16 1.0 15 16 Title Card Required 178 0 1 C 0.08475011 -1.00929196 0.38954841 C -1.03334505 -0.39755404 1.11786218 C -1.50282233 0.78163624 0.56991502 C -0.78451914 1.39611823 -0.49819111 C 0.55780489 1.03731588 -0.68656572 N 1.09947327 -0.06074571 -0.07056262 O 2.22552684 0.17316458 0.59692908 H -2.39375548 1.26802277 0.96856885 H -1.18092115 2.26997372 -1.01172136 H 1.29849218 1.70421075 -1.12202320 H 0.56751730 -1.88715923 0.82335053 H -1.38084264 -0.81403875 2.06018509 H -1.00216117 -0.49731520 -1.31629757 N -0.58863569 -1.43046866 -1.05156803 H 0.10117255 -1.71131578 -1.75201932 H -1.32079027 -2.12854031 -0.92597377 1 2 1.5 6 1.0 11 1.0 13 0.5 14 0.5 2 3 1.0 12 1.0 13 0.5 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 13 0.5 8 9 10 11 12 179 13 14 0.5 14 15 1.0 16 1.0 15 16 TS3_α (ring opening from I2-2, without NH3) Zero-point correction= 0.087360 (Hartree/Particle) Thermal correction to Energy= 0.092346 Thermal correction to Enthalpy= 0.093290 Thermal correction to Gibbs Free Energy= 0.059064 Sum of electronic and zero-point Energies= -323.248926 Sum of electronic and thermal Energies= -323.243940 Sum of electronic and thermal Enthalpies= -323.242996 Sum of electronic and thermal Free Energies= -323.277223 %mem=4GB %Nprocs=4 %chk=TS3_wo_NH3.chk # opt=(calcall,tight,qst3) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.33249554 C 1.50771074 0.00000000 1.68753518 C 2.08931749 -1.35940299 1.22601466 C 1.99406791 -1.29742983 -0.10162649 N 1.41654044 0.02960666 -0.47933886 O 1.99486766 0.83257371 0.61712942 H 1.80964668 0.38755450 2.66420691 180 H 2.45465935 -2.16192498 1.85830925 H 2.22217588 -2.00818076 -0.88894383 H -0.79673413 -0.04394323 -0.73508651 H -0.83425505 -0.02201169 2.02592678 1 11 1.0 2 2.0 6 1.0 2 3 1.0 12 1.0 3 4 1.0 8 1.0 7 1.0 4 5 2.0 9 1.0 5 10 1.0 6 1.0 6 7 1.0 7 8 9 10 11 12 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.38634146 C 1.20410705 0.00000000 2.09678585 C 2.39241573 0.00000000 1.36022120 C 2.36214735 0.00000000 -0.02578979 N 1.17343765 0.00000000 -0.71229641 O 1.15946304 -0.00000000 -1.99226382 H 1.21598907 0.00000000 3.18508825 H 3.36294258 0.00000000 1.85550735 H 3.23988077 0.00000000 -0.66547617 181 H -0.89149064 0.00000000 -0.62037009 H -0.95948178 0.00000000 1.90269933 1 2 1.5 6 1.5 11 1.0 2 3 1.5 12 1.0 3 4 1.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 8 9 10 11 12 Title Card Required 0 1 C -0.45409171 -0.59515511 -1.21375208 C -0.45409171 0.75262425 -1.22661036 C 0.10524498 1.32011474 0.00000000 C -0.45409171 0.75262425 1.22661036 C -0.45409171 -0.59515511 1.21375208 N 0.15407509 -1.10902668 0.00000000 O 1.41382126 -0.56402896 0.00000000 H 0.58402487 2.29864788 0.00000000 H -0.71901960 1.35744118 2.09110446 H -0.63417508 -1.27421497 2.04171916 H -0.63417508 -1.27421497 -2.04171916 H -0.71901960 1.35744118 -2.09110446 182 1 2 2.0 6 1.0 11 1.0 2 3 1.0 12 1.0 3 4 1.0 7 0.5 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 8 9 10 11 12 TS_Biradical (N-O cleavage from I2_α) Zero-point correction= 0.087093 (Hartree/Particle) Thermal correction to Energy= 0.092091 Thermal correction to Enthalpy= 0.093035 Thermal correction to Gibbs Free Energy= 0.058755 Sum of electronic and zero-point Energies= -323.260597 Sum of electronic and thermal Energies= -323.255599 Sum of electronic and thermal Enthalpies= -323.254655 Sum of electronic and thermal Free Energies= -323.288935 %mem=4GB %Nprocs=4 %chk=TSR.chk # opt=(calcall,qst3) freq b3lyp/aug-cc-pvdz geom=connectivity empiricaldispersion=gd3 Title Card Required 183 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.26295050 C 0.88780008 0.00000000 0.99365998 H 0.10435710 -0.04397503 -1.07900258 H 1.97192271 -0.02204696 0.95491092 C -1.55462742 -1.29751131 1.25273125 H -2.24921502 -2.00829547 0.81752470 C -0.74108519 -1.35948782 2.30622879 H -0.59216372 -2.16206527 3.02107233 H 0.42552905 0.38756596 3.19244783 O -1.07643582 0.83245900 1.78932004 N -1.37571255 0.02960157 0.58636418 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 1.0 12 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 184 C 0.00000000 0.00000000 2.49591517 C 0.71181387 0.00000000 1.17323294 H 0.53005411 0.02028883 -0.95508841 H 1.80104347 0.03720666 1.17949228 C -2.05640389 0.00457851 1.08142824 H -3.14362640 0.02846971 0.97683775 C -1.49316148 0.00490930 2.33279221 H -2.10515600 0.04590268 3.23369572 H 0.29430176 -0.93424965 3.05949621 O 0.46264714 0.97509246 3.37152891 N -1.35885761 -0.00526795 -0.08801713 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 Title Card Required 0 1 C -1.19630840 -0.86892763 -0.07591932 C -0.07096172 1.12166026 -0.15368977 C -1.35143899 0.38490956 -0.50328835 185 H -1.90212930 -1.69712202 -0.13891124 H -2.22448608 0.80438220 -0.99577589 C 1.14099205 -0.91060231 -0.27575134 H 2.02422185 -1.54525039 -0.20504869 C 1.13816570 0.38518483 -0.73551604 H 2.01665839 0.89550901 -1.12731975 H -0.10208588 2.19881349 -0.38690538 O 0.22445779 0.88468503 1.20457321 N 0.06135242 -1.20102298 0.52605203 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 0.5 12 In 1,4-dioxane Enamine Zero-point correction= 0.068466 (Hartree/Particle) Thermal correction to Energy= 0.072411 Thermal correction to Enthalpy= 0.073355 Thermal correction to Gibbs Free Energy= 0.043812 Sum of electronic and zero-point Energies= -133.905785 186 Sum of electronic and thermal Energies= -133.901841 Sum of electronic and thermal Enthalpies= -133.900896 Sum of electronic and thermal Free Energies= -133.930439 %chk=eneamine.chk # opt=calcall freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -1.25611076 -0.19663277 0.01314654 C -0.06575363 0.43013315 0.00049825 H -0.02436375 1.52229660 -0.00536861 H -2.17873080 0.38018942 0.00678221 H -1.33712187 -1.28560215 0.01436371 N 1.18442722 -0.17223587 -0.07946532 H 1.95741765 0.34791818 0.31466431 H 1.22299457 -1.16015320 0.14394687 1 2 2.0 4 1.0 5 1.0 2 3 1.0 6 1.0 3 4 5 6 7 1.0 8 1.0 7 8 Isoxazole Zero-point correction= 0.057630 (Hartree/Particle) Thermal correction to Energy= 0.061228 187 Thermal correction to Enthalpy= 0.062172 Thermal correction to Gibbs Free Energy= 0.031415 Sum of electronic and zero-point Energies= -246.017103 Sum of electronic and thermal Energies= -246.013506 Sum of electronic and thermal Enthalpies= -246.012561 Sum of electronic and thermal Free Energies= -246.043318 %chk=isoxazole.chk # opt=calcall freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.61819600 -0.96588700 0.00000000 C 0.00000000 1.13010200 0.00000000 C 1.12822700 0.36593600 0.00000000 O -1.09589200 0.34942900 0.00000000 N -0.69473100 -0.99523300 0.00000000 H 1.16481300 -1.90602500 0.00000000 H 2.16098400 0.69439800 0.00000000 H -0.17408900 2.20192000 0.00000000 1 3 1.5 5 2.0 6 1.0 2 3 2.0 4 1.0 8 1.0 3 7 1.0 4 5 1.0 5 6 7 8 188 TS1-I-endo Zero-point correction= 0.128697 (Hartree/Particle) Thermal correction to Energy= 0.135453 Thermal correction to Enthalpy= 0.136397 Thermal correction to Gibbs Free Energy= 0.098170 Sum of electronic and zero-point Energies= -379.880260 Sum of electronic and thermal Energies= -379.873504 Sum of electronic and thermal Enthalpies= -379.872560 Sum of electronic and thermal Free Energies= -379.910787 %chk=TS1.chk # opt=(calcall,qst3) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.18525469 C 0.86596214 0.00000000 1.13313420 C -7.57957227 -0.00049825 3.27682996 C -8.89861311 -0.01314654 3.01241200 O -1.27197387 0.00000000 1.74649261 N -1.26759683 0.00000000 0.34327262 H -7.23090629 0.00536861 4.31267075 H -9.28437825 -0.01436371 1.99084341 H 0.25832848 0.00000000 -1.05636953 H 1.94945173 0.00000000 1.15601841 H 0.13623331 0.00000000 3.26253828 N -6.55086670 0.07946532 2.34539801 189 H -6.79335098 -0.14394687 1.38692555 H -5.66230347 -0.31466431 2.62562974 H -9.62036541 -0.00678221 3.82667558 1 3 1.0 7 2.0 10 1.0 2 3 2.0 6 1.0 12 1.0 3 11 1.0 4 5 2.0 8 1.0 13 1.0 5 16 1.0 9 1.0 6 7 1.0 7 8 9 10 11 12 13 15 1.0 14 1.0 14 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.24779242 C 0.87703471 0.00000000 1.00780718 C -1.67499509 -1.28990241 1.15103613 C -0.66470981 -1.40495607 2.32807991 O -1.11792567 0.80141511 1.78817359 N -1.35961742 0.08103159 0.53719980 190 H -2.69478086 -1.17492089 1.53963222 H 0.05882252 -2.21773918 2.19218908 H 0.14188693 -0.09427391 -1.07132598 H 1.95905643 -0.08717643 0.96965668 H 0.40537368 0.41026923 3.17674791 N -1.54527989 -2.32508906 0.14586634 H -1.37304913 -3.23187155 0.56823007 H -2.38552174 -2.40004623 -0.42145507 H -1.18657263 -1.54041536 3.28215798 1 3 2.0 7 1.0 10 1.0 2 3 1.0 5 1.0 6 1.0 12 1.0 3 11 1.0 4 5 1.0 7 1.0 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 8 9 10 11 12 13 14 1.0 15 1.0 14 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 191 C 0.00000000 0.00000000 2.24779242 C 0.87703471 0.00000000 1.00780718 C -1.74222093 -1.58213043 1.28188136 C -0.79525782 -1.68088734 2.34384826 O -1.11792567 0.80141511 1.78817359 N -1.35961742 0.08103159 0.53719980 H -2.76200670 -1.46714891 1.67047746 H -0.07172549 -2.49367045 2.20795742 H 0.14188693 -0.09427391 -1.07132598 H 1.95905643 -0.08717643 0.96965668 H 0.40537368 0.41026923 3.17674791 N -1.61250573 -2.61731708 0.27671158 H -1.44027497 -3.52409958 0.69907530 H -2.45274758 -2.69227426 -0.29060983 H -1.31712064 -1.81634663 3.29792633 1 3 1.5 7 1.5 10 1.0 2 3 1.5 5 0.5 6 1.0 12 1.0 3 11 1.0 4 5 1.5 7 0.5 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 8 9 10 11 12 13 14 1.0 15 1.0 14 15 192 16 TS1-I-exo Zero-point correction= 0.128283 (Hartree/Particle) Thermal correction to Energy= 0.135358 Thermal correction to Enthalpy= 0.136302 Thermal correction to Gibbs Free Energy= 0.097179 Sum of electronic and zero-point Energies= -379.877479 Sum of electronic and thermal Energies= -379.870404 Sum of electronic and thermal Enthalpies= -379.869460 Sum of electronic and thermal Free Energies= -379.908583 %chk=TS2BCDIOCARTESIAN.chk # opt=(calcall,qst3) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) scf=(qc,maxcycle=600) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.18525469 C 0.86596214 0.00000000 1.13313420 C -7.57957227 -0.00049825 3.27682996 C -8.89861311 -0.01314654 3.01241200 O -1.27197387 0.00000000 1.74649261 N -1.26759683 0.00000000 0.34327262 H -7.23090629 0.00536861 4.31267075 H -9.28437825 -0.01436371 1.99084341 H 0.25832848 0.00000000 -1.05636953 193 H 1.94945173 0.00000000 1.15601841 H 0.13623331 0.00000000 3.26253828 N -6.55086670 0.07946532 2.34539801 H -6.79335098 -0.14394687 1.38692555 H -5.66230347 -0.31466431 2.62562974 H -9.62036541 -0.00678221 3.82667558 1 3 1.0 7 2.0 10 1.0 2 3 2.0 6 1.0 12 1.0 3 11 1.0 4 5 2.0 8 1.0 13 1.0 5 16 1.0 9 1.0 6 7 1.0 7 8 9 10 11 12 13 15 1.0 14 1.0 14 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.25011467 C 0.87952098 0.00000000 1.00538892 C -1.63567114 -1.33909314 1.13291768 194 C -0.65882313 -1.39946626 2.34623038 O -1.12344683 0.78779498 1.78883988 N -1.36064838 0.05635140 0.53816868 H -1.39877773 -2.06647861 0.34883812 H 0.06154014 -2.22177550 2.28271130 H 0.13692335 -0.08347660 -1.07474634 H 1.96264691 -0.07123315 0.96696557 H 0.40465467 0.42235879 3.17410919 N -3.00687227 -1.50705730 1.53926665 H -3.25293061 -0.80344713 2.23364966 H -3.63015479 -1.37272761 0.74553911 H -1.22650156 -1.49815024 3.27849326 1 3 2.0 7 1.0 10 1.0 2 3 1.0 5 1.0 6 1.0 12 1.0 3 11 1.0 4 5 1.0 7 1.0 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 8 9 10 11 12 13 14 1.0 15 1.0 14 15 16 Title Card Required 195 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.22589609 C 0.89370120 0.00000000 1.04292516 C -1.38773444 -2.05032810 1.58674941 C -0.54472644 -1.77140942 2.66072335 O -1.17573323 0.63046051 1.76239591 N -1.29260430 0.18359733 0.38343723 H -1.02041679 -2.47568229 0.65719254 H 0.37095838 -2.36508427 2.73448231 H 0.19199420 -0.18454220 -1.05735123 H 1.95118798 -0.24272124 1.02585931 H 0.33899999 0.47034416 3.15489571 N -2.68337789 -2.21864404 1.84647802 H -3.08581727 -1.85416089 2.70213459 H -3.32911715 -2.46396682 1.10665084 H -1.04009733 -1.71679656 3.63807449 1 3 1.5 7 1.5 10 1.0 2 3 1.5 5 0.5 6 1.0 12 1.0 3 11 1.0 4 5 1.5 7 0.5 8 1.0 13 1.0 5 9 1.0 16 1.0 6 7 1.0 7 8 9 10 11 12 196 13 14 1.0 15 1.0 14 15 16 I1-I-endo Zero-point correction= 0.132481 (Hartree/Particle) Thermal correction to Energy= 0.138695 Thermal correction to Enthalpy= 0.139639 Thermal correction to Gibbs Free Energy= 0.102613 Sum of electronic and zero-point Energies= -379.899341 Sum of electronic and thermal Energies= -379.893127 Sum of electronic and thermal Enthalpies= -379.892183 Sum of electronic and thermal Free Energies= -379.929210 %chk=I1N.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.17093221 -1.27029869 -0.63360824 C -1.06961543 -0.42827312 0.31710169 C 0.43466408 1.42004686 -0.08021721 C 1.25841316 0.72937170 -0.87548373 C 1.22371006 -0.67641019 -0.29762587 H -1.43259597 -1.03596244 1.15022377 197 H -0.44539213 -1.15040440 -1.68783897 H 0.08498076 2.44666588 -0.13595152 H 1.77546356 1.05689869 -1.77297817 H -0.21559597 -2.33392935 -0.37545686 N -0.06255131 0.54763258 0.98365065 O 1.05958973 -0.38421764 1.11385312 N -2.18939329 0.19813415 -0.32878370 H -1.90430679 0.77332289 -1.11759492 H -2.72440074 0.77327079 0.31743045 H 2.09130364 -1.32310730 -0.45372726 1 2 1.0 5 1.0 7 1.0 10 1.0 2 6 1.0 11 1.0 13 1.0 3 4 2.0 8 1.0 11 1.0 4 5 1.0 9 1.0 5 12 1.0 16 1.0 6 7 8 9 10 11 12 1.0 12 13 14 1.0 15 1.0 14 15 16 I1-I-exo Zero-point correction= 0.132466 (Hartree/Particle) Thermal correction to Energy= 0.138681 Thermal correction to Enthalpy= 0.139625 198 Thermal correction to Gibbs Free Energy= 0.102574 Sum of electronic and zero-point Energies= -379.901311 Sum of electronic and thermal Energies= -379.895096 Sum of electronic and thermal Enthalpies= -379.894152 Sum of electronic and thermal Free Energies= -379.931204 %chk=I1X.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.99221062 -0.21248454 -0.54589937 C 0.32022071 1.19139044 -0.63288225 C -0.89457839 0.98330579 0.30667737 C -1.84648830 0.02057327 -0.39325196 C -1.20547675 -1.15005281 -0.33762513 N 0.05060262 -0.98742572 0.39723966 O -0.30959438 0.11072809 1.30265709 H -1.31202623 1.87494388 0.78271210 H -2.78086766 0.26610976 -0.88959368 H -1.43859403 -2.11849707 -0.77186860 H 0.99470783 -0.75190817 -1.49931715 H 0.03534363 1.47359650 -1.65188058 H 0.99594120 1.95472570 -0.23060669 N 2.33834865 -0.13253788 -0.04086391 H 2.34214814 0.32454365 0.86954408 H 2.72211591 -1.06598657 0.09301163 1 2 1.0 6 1.0 11 1.0 14 1.0 199 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 I2_α Zero-point correction= 0.125939 (Hartree/Particle) Thermal correction to Energy= 0.135039 Thermal correction to Enthalpy= 0.135983 Thermal correction to Gibbs Free Energy= 0.090137 Sum of electronic and zero-point Energies= -379.850682 Sum of electronic and thermal Energies= -379.841583 Sum of electronic and thermal Enthalpies= -379.840639 Sum of electronic and thermal Free Energies= -379.886485 %chk=I2-2_NH3.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 200 0 1 C 1.66719518 -0.99051379 0.21237444 C 0.76203196 0.90124588 -0.64088476 C 2.07914877 0.15277931 -0.33474379 H 2.19658509 -1.83455616 0.64257813 H 3.08737933 0.51461301 -0.50902963 C -0.22554518 0.05545987 1.21439430 H -0.68210155 -0.25446105 2.14795066 C 0.10044960 1.24630619 0.71369097 H -0.02765841 2.23610981 1.13972664 H 0.76946432 1.66442432 -1.42312452 O -0.05901872 -0.23094731 -1.01333716 N 0.17377790 -1.00051559 0.23204472 N -3.24860808 -0.22456935 -0.15116105 H -2.33978741 -0.36555770 -0.59196616 H -3.35197602 0.78155988 -0.02814120 H -3.95562628 -0.51062374 -0.82646929 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 1.0 14 0.5 12 201 13 14 1.0 15 1.0 16 1.0 14 15 16 I2_W_endo Zero-point correction= 0.131697 (Hartree/Particle) Thermal correction to Energy= 0.138888 Thermal correction to Enthalpy= 0.139832 Thermal correction to Gibbs Free Energy= 0.100384 Sum of electronic and zero-point Energies= -379.928812 Sum of electronic and thermal Energies= -379.921622 Sum of electronic and thermal Enthalpies= -379.920677 Sum of electronic and thermal Free Energies= -379.960126 %chk=I2-1N_1.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.59561068 -0.64095887 0.36004656 C 0.59327031 -1.43447604 -0.18339784 C 1.89940864 -0.72299396 0.02166009 C 1.91016426 0.62475157 0.03817776 C 0.68811141 1.39127157 -0.08746741 N -0.49691480 0.83127999 0.00632246 O -1.60267743 1.47487864 -0.04381468 H 2.82433877 -1.29665606 0.07884658 H 2.83975530 1.18828991 0.11991844 202 H 0.68592609 2.47010173 -0.22686124 H -0.56354222 -0.62217560 1.46641484 H 0.59291495 -2.42191418 0.29796429 H 0.42785345 -1.60834420 -1.26150136 N -1.83625518 -1.14685851 -0.18928684 H -2.02310386 -2.07339431 0.18652949 H -2.60259677 -0.53145233 0.07584211 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 I2_W_exo Zero-point correction= 0.132294 (Hartree/Particle) Thermal correction to Energy= 0.139302 Thermal correction to Enthalpy= 0.140247 Thermal correction to Gibbs Free Energy= 0.101354 Sum of electronic and zero-point Energies= -379.933814 203 Sum of electronic and thermal Energies= -379.926805 Sum of electronic and thermal Enthalpies= -379.925861 Sum of electronic and thermal Free Energies= -379.964753 %chk=I2-1X.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.39024790 0.92841555 -0.30623075 C -1.06839518 0.95034567 -0.76805658 C -1.91150562 -0.05793632 -0.03730583 C -1.34047768 -1.20271188 0.38981692 C 0.07242438 -1.46054086 0.19865049 N 0.89534893 -0.51084120 -0.18893036 O 2.15612742 -0.66244607 -0.35835110 H -2.97921699 0.12182787 0.08573956 H -1.92554184 -1.98668507 0.87100560 H 0.52065902 -2.43512745 0.38207004 H 1.05656479 1.36120856 -1.05701566 H -1.11003080 0.73334911 -1.84926650 H -1.44669180 1.97179987 -0.63382926 N 0.57086691 1.62280637 0.94334723 H -0.02090484 1.23267146 1.67438639 H 1.53886942 1.57133505 1.25155503 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 204 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 I3 Zero-point correction= 0.128942 (Hartree/Particle) Thermal correction to Energy= 0.137918 Thermal correction to Enthalpy= 0.138862 Thermal correction to Gibbs Free Energy= 0.093830 Sum of electronic and zero-point Energies= -379.958684 Sum of electronic and thermal Energies= -379.949707 Sum of electronic and thermal Enthalpies= -379.948763 Sum of electronic and thermal Free Energies= -379.993795 %chk=I3_NH3.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 205 C -1.13139946 -1.23830180 0.00001455 C -2.30209479 -0.49537926 0.00003896 C -2.24984242 0.90093798 0.00002146 C -0.99096730 1.50690851 -0.00002117 C 0.16307814 0.73728500 -0.00004463 N 0.09245537 -0.62917504 -0.00002638 H -3.16108601 1.49684771 0.00004037 H -1.09195831 -2.32387177 0.00002719 H -3.25283424 -1.02731723 0.00007104 H -0.88520619 2.59111950 -0.00003598 H 1.17275708 1.14180311 -0.00007332 O 1.17162772 -1.34755811 -0.00004534 N 3.56981602 0.58285335 0.00005740 H 2.93301551 -0.21945571 0.00004171 H 4.17192854 0.48838908 0.81629033 H 4.17181713 0.48849950 -0.81627081 1 2 1.5 6 1.5 8 1.0 2 3 1.5 9 1.0 3 4 1.5 7 1.0 4 5 1.5 10 1.0 5 6 1.5 11 1.0 6 12 1.0 7 8 9 10 11 12 14 0.5 13 14 1.0 15 1.0 16 1.0 14 206 15 16 I2_X (without NH3) Zero-point correction= 0.090351 (Hartree/Particle) Thermal correction to Energy= 0.095100 Thermal correction to Enthalpy= 0.096045 Thermal correction to Gibbs Free Energy= 0.062320 Sum of electronic and zero-point Energies= -323.309924 Sum of electronic and thermal Energies= -323.305175 Sum of electronic and thermal Enthalpies= -323.304231 Sum of electronic and thermal Free Energies= -323.337955 %chk=I2-2.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.48399108 -0.67951871 1.19081180 C 0.33558496 1.06268953 -0.00000000 C -0.48399108 0.65181256 1.24561710 H -0.95695339 -1.44215622 1.80099327 H -0.95898070 1.31683624 1.95963765 C -0.48399108 -0.67951871 -1.19081180 H -0.95695339 -1.44215622 -1.80099327 C -0.48399108 0.65181256 -1.24561710 H -0.95898070 1.31683624 -1.95963765 H 0.82156632 2.04161253 -0.00000000 O 1.30384581 -0.00967854 -0.00000000 207 N 0.31168737 -1.10817252 0.00000000 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 1.0 12 Biradical Zero-point correction= 0.087274 (Hartree/Particle) Thermal correction to Energy= 0.092966 Thermal correction to Enthalpy= 0.093911 Thermal correction to Gibbs Free Energy= 0.056795 Sum of electronic and zero-point Energies= -323.339605 Sum of electronic and thermal Energies= -323.333913 Sum of electronic and thermal Enthalpies= -323.332969 Sum of electronic and thermal Free Energies= -323.370084 %chk=Biradical_Triplet.chk # opt=(calcall,maxcycle=500) freq ub3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 208 0 3 C -1.12081734 -1.16285298 -0.05124530 C 1.05545353 -0.00015193 0.32091301 C 0.22900078 -1.24612771 0.17968015 H -1.70672539 -2.07694054 -0.17209259 H 0.73847430 -2.20824847 0.23309194 C -1.12058428 1.16298167 -0.05122245 H -1.70633263 2.07718621 -0.17196680 C 0.22925512 1.24605541 0.17967984 H 0.73887632 2.20809784 0.23316291 H 1.52139537 -0.00008786 1.35149535 O 2.19017509 -0.00005018 -0.47363658 N -1.82013365 0.00013821 -0.16448995 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 I3 (without NH3) Zero-point correction= 0.092713 (Hartree/Particle) Thermal correction to Energy= 0.097778 Thermal correction to Enthalpy= 0.098722 209 Thermal correction to Gibbs Free Energy= 0.064001 Sum of electronic and zero-point Energies= -323.415284 Sum of electronic and thermal Energies= -323.410219 Sum of electronic and thermal Enthalpies= -323.409275 Sum of electronic and thermal Free Energies= -323.443996 %chk=I3.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.00000000 0.28552634 1.18001547 C 0.00000000 -1.10080685 1.19648629 C 0.00000000 -1.82278125 0.00000000 C 0.00000000 -1.10080685 -1.19648629 C -0.00000000 0.28552634 -1.18001547 N -0.00000000 0.98068260 0.00000000 H 0.00000010 -2.91136714 0.00000000 H -0.00000000 0.91178829 2.06748546 H -0.00000003 -1.60610689 2.16161217 H -0.00000003 -1.60610689 -2.16161217 H -0.00000000 0.91178829 -2.06748546 O -0.00000000 2.26940998 -0.00000000 1 2 1.5 6 1.5 8 1.0 2 3 1.5 9 1.0 3 4 1.5 7 1.0 4 5 1.5 10 1.0 5 6 1.5 11 1.0 210 6 12 1.0 7 8 9 10 11 12 TS2_X_endo Zero-point correction= 0.128708 (Hartree/Particle) Thermal correction to Energy= 0.135259 Thermal correction to Enthalpy= 0.136204 Thermal correction to Gibbs Free Energy= 0.098488 Sum of electronic and zero-point Energies= -379.797289 Sum of electronic and thermal Energies= -379.790737 Sum of electronic and thermal Enthalpies= -379.789792 Sum of electronic and thermal Free Energies= -379.827508 %chk=TS1N_TS.chk # opt=(calcall,tight,ts,verytight,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -0.83328103 -0.72638177 0.31774671 C -0.03081477 -1.27535350 -0.73788146 C 1.26811193 -0.52453820 -0.50968356 C 1.04892535 0.94342752 -0.87213036 C 0.25319485 1.41455571 0.09158878 211 N 0.00078019 0.32499650 1.06495714 O 1.28194904 -0.36349027 0.98924219 H 2.19694123 -0.99510023 -0.84270075 H 1.40352292 1.44601749 -1.76820529 H -0.21978407 2.38188687 0.23538355 H -1.36968358 -1.37053733 1.01799489 H 0.04112015 -2.36378200 -0.76826756 H -2.86867285 -0.47272456 -0.56119980 N -2.17520007 0.20723751 -0.25256103 H -2.60646483 0.84715905 0.42258455 H -1.84845015 0.71910615 -1.07414051 1 2 1.5 6 1.0 11 1.0 14 0.5 2 3 1.0 12 1.0 13 0.5 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 13 0.3 8 9 10 11 12 13 14 0.5 14 15 1.0 16 1.0 15 16 TS2_X_exo Zero-point correction= 0.128351 (Hartree/Particle) 212 Thermal correction to Energy= 0.134973 Thermal correction to Enthalpy= 0.135918 Thermal correction to Gibbs Free Energy= 0.098043 Sum of electronic and zero-point Energies= -379.805584 Sum of electronic and thermal Energies= -379.798962 Sum of electronic and thermal Enthalpies= -379.798017 Sum of electronic and thermal Free Energies= -379.835892 %chk=TS1X_TS.chk # opt=(calcall,tight,ts,verytight,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.79919263 -0.06048530 -0.73236172 C 0.22266683 1.23431147 -0.65381274 C -0.87793321 0.99188291 0.39472313 C -1.92272874 0.05706997 -0.24066376 C -1.29627364 -1.12269216 -0.34389336 N 0.05242235 -0.98466391 0.22233501 O -0.21721064 0.02946666 1.26493944 H -1.24899551 1.83365872 0.98787050 H -2.91176424 0.33097697 -0.59967515 H -1.57047818 -2.05801742 -0.82221391 H 1.07183912 -0.55015797 -1.67025905 H -0.02247003 1.75380868 -1.58023316 H 2.99025600 0.53141024 -0.36211883 N 2.36641660 -0.13411026 0.09202333 H 2.14560634 0.21248401 1.02717667 213 H 2.80227579 -1.05899865 0.15547971 1 2 1.5 6 1.0 11 1.0 14 0.5 2 3 1.0 12 1.0 13 0.5 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 13 0.2 15 0.3 8 9 10 11 12 13 14 0.5 14 15 1.0 16 1.0 15 16 TS3_X Zero-point correction= 0.123688 (Hartree/Particle) Thermal correction to Energy= 0.132610 Thermal correction to Enthalpy= 0.133554 Thermal correction to Gibbs Free Energy= 0.089312 Sum of electronic and zero-point Energies= -379.792294 Sum of electronic and thermal Energies= -379.783373 Sum of electronic and thermal Enthalpies= -379.782429 Sum of electronic and thermal Free Energies= -379.826671 %mem=4GB %Nprocs=4 214 %chk=TS3.chk # opt=(calcall,qst3,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.33232546 C 1.50339939 0.00000000 1.69484882 C 2.09030710 -1.35315681 1.23308390 C 1.99877440 -1.29476068 -0.09521375 N 1.41820921 0.02735817 -0.47695663 O 1.99624562 0.83708833 0.62195934 H 1.80049606 0.38701675 2.67277881 H 2.45470462 -2.15381258 1.86868807 H 2.22751105 -2.00661951 -0.88177132 H -0.79258524 -0.02963267 -0.73956240 H -0.83458180 -0.02275882 2.02556737 H 0.84557932 2.67377652 -0.21477367 N 0.07929809 3.29369866 -0.47678763 H -0.50756202 3.38598287 0.35097654 H 0.48445372 4.21185307 -0.65167128 1 11 1.0 2 2.0 6 1.0 2 3 1.0 12 1.0 3 4 1.0 8 1.0 7 1.0 4 5 2.0 9 1.0 5 10 1.0 6 1.0 6 7 1.0 7 13 0.5 215 8 9 10 11 12 13 14 1.0 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.38713418 C 1.20260710 0.00000000 2.09826216 C 2.39328369 0.00000000 1.36701569 C 2.36183160 -0.00000000 -0.01915610 N 1.17602892 -0.00000000 -0.69939730 O 1.17494056 -0.00000000 -1.99581004 H 1.21241695 0.00000000 3.18701238 H 3.36333550 -0.00000000 1.86286142 H 3.24310339 -0.00000000 -0.65427638 H -0.89674450 0.00000454 -0.61557760 H -0.96070374 0.00000000 1.90069743 H -0.74087042 0.00014938 -2.83531600 N -1.76167848 0.00019299 -2.91996593 H -2.01713632 0.81644068 -3.47330144 H -2.01720903 -0.81612046 -3.47317133 1 2 1.5 6 1.5 11 1.0 216 2 3 1.5 12 1.0 3 4 1.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 13 0.5 8 9 10 11 12 13 14 1.0 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C -0.25676844 0.69927474 0.87719299 C 0.62971008 1.50901797 0.26397519 C 1.49216222 0.77806367 -0.65729073 C 2.10608742 -0.41900175 -0.08969181 C 1.20213733 -1.20351668 0.52910885 N -0.14192315 -0.67423354 0.42605532 O -0.33610412 -0.57699314 -0.95900712 H 1.90510428 1.25708062 -1.54478399 H 3.14242323 -0.69528943 -0.27223823 H 1.33624951 -2.22464560 0.87577155 H -1.14311522 0.98545993 1.43514832 H 0.61101315 2.59513757 0.32107574 217 H -2.47574234 -0.09811814 -0.67008450 N -3.31158344 0.01166390 -0.09194558 H -4.10145356 0.13654028 -0.72274341 H -3.45107172 -0.88526037 0.37137628 1 2 2.0 6 1.0 11 1.0 2 3 1.0 12 1.0 3 4 1.0 7 0.5 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 13 0.5 8 9 10 11 12 13 14 1.0 14 15 1.0 16 1.0 15 16 $END YZ[_]_endo Zero-point correction= 0.129192 (Hartree/Particle) Thermal correction to Energy= 0.135680 Thermal correction to Enthalpy= 0.136624 Thermal correction to Gibbs Free Energy= 0.098960 Sum of electronic and zero-point Energies= -379.841689 Sum of electronic and thermal Energies= -379.835201 218 Sum of electronic and thermal Enthalpies= -379.834257 Sum of electronic and thermal Free Energies= -379.871921 %mem=4GB %Nprocs=4 %chk=TS2N.chk # opt=(calcall,qst3,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.55579174 C 1.52736733 0.00000000 1.83465332 C 2.04933331 -1.37426567 1.44697805 C 1.98451146 -1.37343227 0.11137293 N 1.51023026 -0.07003704 -0.35377527 O 2.00527026 0.79493974 0.71918726 H 1.86095638 0.43366479 2.78120317 H 2.32908215 -2.18245071 2.11682046 H 2.18424147 -2.15822647 -0.61218588 H -0.31327816 0.97210287 -0.38987995 H -0.46915863 0.90889415 1.94789985 H -0.51272183 -0.87244354 1.97658138 N -0.81305056 -1.02612442 -0.59116322 H -0.75043258 -1.01904924 -1.60636605 H -0.56384044 -1.95334716 -0.25576520 1 2 1.0 11 1.0 6 1.0 14 1.0 2 3 1.0 13 1.0 12 1.0 219 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 10 1.0 6 1.0 6 7 1.0 7 8 9 10 11 12 13 14 16 1.0 15 1.0 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.52675812 C 1.38808481 0.00000000 2.10137937 C 2.38680565 -0.59047234 1.41518502 C 2.15880157 -1.20975933 0.12503729 N 1.04089967 -1.02244374 -0.53819998 O 0.78252796 -1.53239418 -1.68051185 H 1.55797035 0.42723775 3.08958784 H 3.39646682 -0.65368886 1.82183264 H 2.90032939 -1.84365575 -0.35786156 H 0.38988664 0.95231430 -0.38794890 H -0.57605518 0.87149142 1.86168127 H -0.54654735 -0.89223040 1.88747947 220 N -1.30410528 -0.23010923 -0.52746039 H -1.26774170 -0.31593029 -1.54034669 H -1.69588580 -1.09855979 -0.16734145 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C -1.08523753 -0.03809327 0.40009728 C -0.30554232 -1.41845948 0.36973314 C 1.09780199 -1.16600005 -0.00975776 C 1.33320417 -0.19525087 -1.03564333 C 0.73127518 1.01306809 -0.82085459 N -0.06173254 1.01947857 0.36661240 O 0.78378124 0.82349169 1.39320124 221 H 1.89165463 -1.84664086 0.29553166 H 2.13772261 -0.29559537 -1.76406954 H 1.05335044 1.95611589 -1.25562819 H -1.56294908 0.06154715 1.38043107 H -0.39045393 -1.97837315 1.30740736 H -0.80129717 -2.00237244 -0.42234116 N -2.07996105 0.04386712 -0.64379909 H -2.57740289 0.93060083 -0.60035292 H -1.65802814 -0.02822188 -1.56772986 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.5 7 0.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 $END YZ[_]_exo Zero-point correction= 0.129312 (Hartree/Particle) 222 Thermal correction to Energy= 0.135783 Thermal correction to Enthalpy= 0.136727 Thermal correction to Gibbs Free Energy= 0.099095 Sum of electronic and zero-point Energies= -379.841325 Sum of electronic and thermal Energies= -379.834854 Sum of electronic and thermal Enthalpies= -379.833909 Sum of electronic and thermal Free Energies= -379.871541 %mem=4GB %Nprocs=4 %chk=TS2X.chk # opt=(calcall,qst3,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.55884618 C 1.52356036 0.00000000 1.84269864 C 2.06021476 -1.36399623 1.42508182 C 1.99177152 -1.33294203 0.09140018 N 1.50245045 -0.02349091 -0.34461796 O 1.99425409 0.82346765 0.74911636 H 1.85001208 0.41790060 2.79908695 H 2.34421096 -2.18524568 2.07669792 H 2.18137692 -2.09856099 -0.65604397 H -0.43548086 -0.90679281 -0.43367359 H -0.52062504 -0.86017806 1.99266189 H -0.46458288 0.91956889 1.93255773 N -0.67285265 1.15455677 -0.53647725 223 H -0.24379535 2.00582861 -0.17727427 H -0.57996454 1.17910280 -1.55003323 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.53016459 C 1.39213642 0.00000000 2.09886543 C 2.38136795 -0.60399775 1.40920932 C 2.14021869 -1.21200509 0.11634943 N 1.01766423 -1.00785701 -0.53752228 O 0.74594425 -1.49598449 -1.69040980 H 1.57149307 0.43419302 3.08211032 224 H 3.39217141 -0.67969226 1.81046145 H 2.87376987 -1.84418957 -0.38026059 H -0.94672005 -0.36984305 -0.40237204 H -0.53341168 -0.89532582 1.89306896 H -0.57699052 0.87150647 1.86490683 N 0.26394261 1.30983438 -0.53936550 H 1.15060033 1.67928134 -0.20148335 H 0.29201553 1.28581964 -1.55588181 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C 0.93805394 0.09067171 -0.58278232 C 0.28553980 1.41205538 -0.02624424 225 C -1.09184304 1.12384715 0.41475217 C -1.85977480 0.19616078 -0.36196033 C -1.23001825 -0.99576416 -0.58336439 N 0.10274663 -1.02524941 -0.07713928 O -0.00684546 -0.90161265 1.26550934 H -1.58320643 1.75529407 1.15494678 H -2.93757316 0.29157521 -0.49052647 H -1.73785118 -1.93481450 -0.79239554 H 0.88793468 0.05120347 -1.67697408 H 0.26004202 2.10912238 -0.88106334 H 0.88822290 1.87433988 0.76328407 N 2.31451499 0.02295000 -0.16089715 H 2.34448243 -0.07483999 0.85372447 H 2.76013512 -0.80470866 -0.55122089 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.5 7 0.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 226 $END YZR_]_endo Zero-point correction= 0.130416 (Hartree/Particle) Thermal correction to Energy= 0.137238 Thermal correction to Enthalpy= 0.138182 Thermal correction to Gibbs Free Energy= 0.099880 Sum of electronic and zero-point Energies= -379.886008 Sum of electronic and thermal Energies= -379.879187 Sum of electronic and thermal Enthalpies= -379.878243 Sum of electronic and thermal Free Energies= -379.916545 %mem=4GB %Nprocs=1 %chk=TS4N_1.chk # opt=(calcall,qst3,verytight,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 scf=xqc Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.52919565 C 1.38761368 0.00000000 2.10259003 C 2.37918129 -0.58989346 1.40572138 C 2.14184987 -1.17479332 0.10252580 N 1.02753579 -0.96499226 -0.56152382 O 0.79516957 -1.41539725 -1.73735766 H 1.56079221 0.40614479 3.09903866 227 H 3.38941550 -0.67253675 1.80696124 H 2.88391224 -1.78350608 -0.40945288 H 0.35950915 0.97637320 -0.37799539 H -0.57642705 0.87072387 1.87024625 H -0.54663257 -0.89567731 1.87394927 N -1.29894725 -0.39087532 -0.50680660 H -1.24847943 -0.51312616 -1.51616546 H -1.97781492 0.33917074 -0.30484034 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 16 1.0 15 1.0 15 16 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.38713418 228 C 1.20260710 0.00000000 2.09826216 C 2.39328369 0.00000000 1.36701569 C 2.36183160 -0.00000000 -0.01915610 N 1.17602892 -0.00000000 -0.69939730 O 1.17494056 -0.00000000 -1.99581004 H 1.21241695 0.00000000 3.18701238 H 3.36333550 -0.00000000 1.86286142 H 3.24310339 -0.00000000 -0.65427638 H -0.89674450 0.00000454 -0.61557760 H -0.96070374 0.00000000 1.90069743 H -2.01720904 -0.81612047 -3.47317133 N -1.76167848 0.00019299 -2.91996593 H -2.01713632 0.81644068 -3.47330144 H -0.74087042 0.00014938 -2.83531600 1 2 1.5 6 1.5 11 1.0 2 3 1.5 12 1.0 3 4 1.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 16 0.5 8 9 10 11 12 13 14 1.0 14 15 1.0 16 1.0 15 16 229 Title Card Required 0 1 C -0.29475911 0.87507724 -0.42105897 C 1.05545198 0.69105575 -0.96820739 C 1.80335991 -0.31668535 -0.37383692 C 1.18235970 -1.22853528 0.50903810 C -0.22266241 -1.31465939 0.48869543 N -0.96740555 -0.36381626 -0.09921720 O -2.21596389 -0.53935448 -0.51707251 H 2.85112831 -0.45930301 -0.64574084 H 1.75166536 -1.98194811 1.04941789 H -0.77657361 -2.18591490 0.83243981 H -0.98299309 1.51281262 -0.97495939 H 1.33553421 1.16475919 -1.90661616 H 0.51889749 0.99301859 1.53882524 N -0.10634241 1.61656681 1.01400793 H 0.37258122 2.50986688 0.88312588 H -0.96879347 1.75477290 1.54877099 1 2 1.5 6 1.0 11 1.0 13 0.5 14 0.5 2 3 1.0 12 1.0 13 0.5 3 4 2.0 8 1.0 4 5 1.5 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 16 0.5 8 9 10 230 11 12 13 14 0.5 14 15 1.0 16 1.0 15 16 $END YZR_]_exo Zero-point correction= 0.130213 (Hartree/Particle) Thermal correction to Energy= 0.137110 Thermal correction to Enthalpy= 0.138055 Thermal correction to Gibbs Free Energy= 0.099557 Sum of electronic and zero-point Energies= -379.885931 Sum of electronic and thermal Energies= -379.879034 Sum of electronic and thermal Enthalpies= -379.878090 Sum of electronic and thermal Free Energies= -379.916588 %mem=4GB %Nprocs=1 %chk=TS4X_2.chk # opt=(calcall,qst3,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.53016459 C 1.39213642 0.00000000 2.09886543 231 C 2.38136795 -0.60399775 1.40920932 C 2.14021869 -1.21200509 0.11634943 N 1.01766423 -1.00785701 -0.53752228 O 0.74594425 -1.49598449 -1.69040980 H 1.57149307 0.43419302 3.08211032 H 3.39217141 -0.67969226 1.81046145 H 2.87376987 -1.84418957 -0.38026059 H -0.94672005 -0.36984305 -0.40237204 H -0.53341168 -0.89532582 1.89306896 H -0.57699052 0.87150647 1.86490683 N 0.26394261 1.30983438 -0.53936550 H 1.15060033 1.67928134 -0.20148335 H 0.29201553 1.28581964 -1.55588181 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 232 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.38713418 C 1.20260710 0.00000000 2.09826216 C 2.39328369 0.00000000 1.36701569 C 2.36183160 -0.00000000 -0.01915610 N 1.17602892 -0.00000000 -0.69939730 O 1.17494056 -0.00000000 -1.99581004 H 1.21241695 0.00000000 3.18701238 H 3.36333550 -0.00000000 1.86286142 H 3.24310339 -0.00000000 -0.65427638 H -0.89674450 0.00000454 -0.61557760 H -0.96070374 0.00000000 1.90069743 H -2.01713632 0.81644068 -3.47330144 N -1.76167848 0.00019299 -2.91996593 H -0.74087042 0.00014938 -2.83531600 H -2.01720903 -0.81612046 -3.47317133 1 2 1.5 6 1.5 11 1.0 2 3 1.5 12 1.0 3 4 1.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 7 15 0.5 8 9 10 11 233 12 13 14 1.0 14 15 1.0 16 1.0 15 16 Title Card Required 0 1 C 0.29559837 0.87136522 -0.43021896 C -1.05103923 0.67864067 -0.97815448 C -1.79952739 -0.32504785 -0.37870319 C -1.18035814 -1.22794646 0.51430257 C 0.22457122 -1.30823919 0.50249516 N 0.96815787 -0.36142294 -0.09564354 O 2.21545004 -0.54341990 -0.51743360 H -2.84520623 -0.47343145 -0.65540416 H -1.74981729 -1.97639848 1.06143361 H 0.78103285 -2.17202959 0.86055305 H 0.98559300 1.50772189 -0.98314788 H -1.33432223 1.15271301 -1.91551113 H -0.40618769 0.94581874 1.59033751 N 0.09853757 1.63013108 1.01327175 H 0.95893969 1.91112408 1.49040481 H -0.51596948 2.43824960 0.88907896 1 2 1.5 6 1.0 11 1.0 13 0.5 14 0.5 2 3 1.0 12 1.0 13 0.5 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 234 6 7 1.0 7 13 0.5 15 0.5 8 9 10 11 12 13 14 0.5 14 15 1.0 16 1.0 15 16 $END TS3_X (without NH3) Zero-point correction= 0.087392 (Hartree/Particle) Thermal correction to Energy= 0.092390 Thermal correction to Enthalpy= 0.093335 Thermal correction to Gibbs Free Energy= 0.059082 Sum of electronic and zero-point Energies= -323.256273 Sum of electronic and thermal Energies= -323.251275 Sum of electronic and thermal Enthalpies= -323.250331 Sum of electronic and thermal Free Energies= -323.284584 %mem=4GB %Nprocs=1 %chk=TS3_wo_NH3.chk # opt=(calcall,tight,qst3,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 235 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.33245884 C 1.50432484 0.00000000 1.69175469 C 2.08727514 -1.35610873 1.22999200 C 1.99543813 -1.29644196 -0.09795846 N 1.41643063 0.02860668 -0.47727030 H 1.80285761 0.38558690 2.66984929 H -0.79521921 -0.04736275 -0.73689479 H -0.83408406 -0.02452976 2.02628810 H 2.44967219 -2.15799575 1.86508456 H 2.22269736 -2.00811192 -0.88504794 O 1.99485944 0.83597270 0.62029410 1 8 1.0 2 2.0 6 1.0 2 3 1.0 9 1.0 3 4 1.0 7 1.0 12 1.0 4 5 2.0 10 1.0 5 11 1.0 6 1.0 6 12 1.0 7 8 9 10 11 12 Title Card Required 0 1 236 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.38643103 C 1.20497892 0.00000000 2.09414021 C 2.39280371 0.00000000 1.35800248 C 2.35986439 0.00000000 -0.02803720 N 1.17167373 0.00000000 -0.70912580 H 1.21791134 0.00000000 3.18264927 H -0.89484737 0.00000000 -0.61567460 H -0.95905480 0.00000000 1.90316112 H 3.36386446 0.00000000 1.85180115 H 3.23983176 0.00000000 -0.66479811 O 1.15636363 0.00000000 -1.99776224 1 2 1.5 6 1.5 8 1.0 2 3 1.5 9 1.0 3 4 1.5 7 1.0 4 5 1.5 10 1.0 5 6 1.5 11 1.0 6 12 1.0 7 8 9 10 11 12 Title Card Required 0 1 C -0.45413252 -0.59244330 -1.21169369 C -0.45413252 0.75528443 -1.22649645 237 C 0.10301631 1.31963632 0.00000000 C -0.45413252 0.75528443 1.22649645 C -0.45413252 -0.59244330 1.21169369 N 0.14456339 -1.11657663 0.00000000 H 0.59931236 2.28966917 0.00000000 H -0.63418117 -1.26853146 -2.04299117 H -0.71047197 1.36146904 -2.09295689 H -0.71047197 1.36146904 2.09295689 H -0.63418117 -1.26853146 2.04299117 O 1.41989160 -0.56642742 0.00000000 1 2 1.5 6 1.5 8 1.0 2 3 1.5 9 1.0 3 4 1.0 7 1.0 12 0.5 4 5 2.0 10 1.0 5 6 1.0 11 1.0 6 12 1.0 7 8 9 10 11 12 $END TS_Biradical (N-O bond cleavage) Zero-point correction= 0.083679 (Hartree/Particle) Thermal correction to Energy= 0.089330 Thermal correction to Enthalpy= 0.090274 238 Thermal correction to Gibbs Free Energy= 0.053863 Sum of electronic and zero-point Energies= -323.228569 Sum of electronic and thermal Energies= -323.222918 Sum of electronic and thermal Enthalpies= -323.221974 Sum of electronic and thermal Free Energies= -323.258385 %mem=4GB %Nprocs=4 %chk=TS_Triplet_tight.chk # opt=(calcall,tight,qst3,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 3 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.26385229 C 0.88541595 0.00000000 0.99573347 H 0.10459459 -0.04736275 -1.07909569 H 1.96976683 -0.02452976 0.95997829 C -1.55626460 -1.29644196 1.25276083 H -2.24911242 -2.00811193 0.81558980 C -0.74247336 -1.35610873 2.30615072 H -0.59127153 -2.15799575 3.02156123 H 0.42685107 0.38558690 3.19314719 O -1.07855491 0.83597270 1.78911942 N -1.37562983 0.02860667 0.58455560 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 239 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 1.0 12 Title Card Required 0 3 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 2.49530166 C 0.71177590 0.00000000 1.17287906 H 0.53019650 0.02042814 -0.95494646 H 1.80125402 0.03337534 1.17687504 C -2.05780787 -0.00025861 1.08394351 H -3.14521709 0.01987853 0.98105555 C -1.49321045 -0.00025188 2.33434877 H -2.10617356 0.03285028 3.23505977 H 0.29501441 -0.93725722 3.05540626 O 0.45853923 0.97451118 3.36649154 N -1.35910551 -0.00643468 -0.08489379 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 240 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 Title Card Required 0 3 C 0.78867248 1.07835322 0.39651059 C -1.12628970 -0.00000263 -0.28043453 C -0.61056669 1.06402309 0.64855498 H 1.55703755 1.76468157 0.73889480 H -1.17222025 1.62675705 1.38792936 C 0.78867755 -1.07834941 0.39651125 H 1.55704553 -1.76467559 0.73889342 C -0.61056195 -1.06402519 0.64855592 H -1.17221296 -1.62676083 1.38793101 H -2.17457132 -0.00000534 -0.58428307 O -0.23144223 -0.00000096 -1.39435188 N 1.12526702 0.00000234 -0.48181997 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 241 8 9 1.0 9 10 11 12 0.5 12 $END With TiCl4 in 1,4-dioxane SM Zero-point correction= 0.135120 (Hartree/Particle) Thermal correction to Energy= 0.153040 Thermal correction to Enthalpy= 0.153984 Thermal correction to Gibbs Free Energy= 0.085761 Sum of electronic and zero-point Energies= -3070.620773 Sum of electronic and thermal Energies= -3070.602853 Sum of electronic and thermal Enthalpies= -3070.601909 Sum of electronic and thermal Free Energies= -3070.670132 %chk=CAR_TiCl4.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 1.59557709 0.97189487 -1.31371403 C 2.71092069 1.76621794 -0.96237094 C 2.51421677 2.02613990 0.36454098 O 1.37492898 1.46680547 0.79122371 242 H 1.33452797 0.53341361 -2.26971316 H 3.53465276 2.07891264 -1.59191137 N 0.80723987 0.78136651 -0.27424235 H 3.07831072 2.57614612 1.11057016 C 3.82332869 -0.99215444 1.10840806 H 3.74324093 -0.70631283 2.15490508 H 4.76216582 -0.78156417 0.59260810 C 2.79992486 -1.62083168 0.50055616 H 1.87775619 -1.81809232 1.04852214 N 2.78947306 -2.11380735 -0.79448770 H 1.88505303 -2.20350187 -1.23823384 H 3.52184489 -1.79719340 -1.41770876 Ti -1.30180986 -0.04206899 0.02282558 Cl -0.59642544 -0.64098572 2.03424965 Cl -1.88954868 2.08958943 -0.23087979 Cl -3.37434974 -0.86755704 0.18705184 Cl -0.72426239 -1.30288476 -1.75068063 1 2 1.0 5 1.0 7 2.0 2 3 2.0 6 1.0 3 4 1.0 8 1.0 10 0.5 4 7 1.0 10 0.5 5 6 7 17 0.5 8 9 10 1.0 11 1.0 12 2.0 10 11 12 13 1.0 14 1.0 13 243 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- I1A_M_endo Zero-point correction= 0.138517 (Hartree/Particle) Thermal correction to Energy= 0.154247 Thermal correction to Enthalpy= 0.155191 Thermal correction to Gibbs Free Energy= 0.094347 Sum of electronic and zero-point Energies= -3070.600144 Sum of electronic and thermal Energies= -3070.584414 Sum of electronic and thermal Enthalpies= -3070.583470 Sum of electronic and thermal Free Energies= -3070.644315 %chk=CAIN_TiCl4.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 2.40230243 -0.94563332 0.97596667 C 3.28541075 0.22161324 1.00593100 C 2.77371458 1.31369960 -0.08601274 C 2.80473744 0.76111258 -1.46862348 244 C 1.57286474 0.22307472 -1.64953398 N 0.74761280 0.48449157 -0.57764892 O 1.39106973 1.53664624 0.15364387 H 3.32051109 2.24113573 0.10900984 H 3.66054022 0.71727603 -2.13292330 H 1.19474499 -0.38438525 -2.46370107 H 1.49309198 -0.97120924 1.57191581 H 3.23615632 0.71248130 1.98274811 H 4.32311442 -0.02989247 0.75484946 N 2.63685406 -1.98216306 0.21736443 H 3.44595096 -2.01564440 -0.39398376 H 1.91884628 -2.69007215 0.08407031 Ti -1.16291025 0.03823426 -0.02312059 Cl -1.63011491 2.23217286 -0.35401693 Cl -3.33783488 -0.58029785 -0.34118273 Cl -0.90138637 -0.15094975 2.18422979 Cl -0.53436597 -2.06995548 -0.92296287 1 2 1.0 11 1.0 14 2.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 17 0.5 7 8 9 10 11 12 13 245 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- I1A_M_exo Zero-point correction= 0.138385 (Hartree/Particle) Thermal correction to Energy= 0.154343 Thermal correction to Enthalpy= 0.155287 Thermal correction to Gibbs Free Energy= 0.092845 Sum of electronic and zero-point Energies= -3070.597165 Sum of electronic and thermal Energies= -3070.581207 Sum of electronic and thermal Enthalpies= -3070.580263 Sum of electronic and thermal Free Energies= -3070.642705 %chk=CAIX_TiCl4.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 1.47687997 -1.44685823 1.10866310 C 2.71832527 -1.76154040 0.67428429 C 2.88036239 -1.00291013 -0.60251257 O 1.54028808 -0.77028828 -1.02179750 246 H 0.99164705 -1.69244988 2.04630963 H 3.48127686 -2.33717889 1.18622821 N 0.79168720 -0.66531913 0.19684323 H 3.41644841 -1.49828667 -1.41914044 C 3.57059149 0.42669415 -0.37681183 H 4.53615561 0.23453279 0.10913898 H 3.73292793 0.89870702 -1.35402753 C 2.73664198 1.27515962 0.48383127 H 2.55673501 1.00450602 1.52289896 N 2.20425809 2.38662742 0.06744181 H 1.54640783 2.90137013 0.64402497 H 2.29185606 2.68429772 -0.89942223 Ti -1.16247066 -0.04274200 -0.01043023 Cl -1.51861951 -1.90719453 -1.22762714 Cl -1.04569840 0.13635403 2.27827460 Cl -0.54084119 1.72439531 -1.27169060 Cl -3.39894844 0.51201601 0.04416748 1 2 2.0 5 1.0 7 1.0 2 3 1.0 6 1.0 3 4 1.0 8 1.0 9 1.0 4 7 1.0 5 6 7 17 0.5 8 9 10 1.0 11 1.0 12 1.0 10 11 12 13 1.0 14 2.0 13 247 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- I1_M_endo Zero-point correction= 0.140085 (Hartree/Particle) Thermal correction to Energy= 0.155035 Thermal correction to Enthalpy= 0.155980 Thermal correction to Gibbs Free Energy= 0.096807 Sum of electronic and zero-point Energies= -3070.599313 Sum of electronic and thermal Energies= -3070.584362 Sum of electronic and thermal Enthalpies= -3070.583418 Sum of electronic and thermal Free Energies= -3070.642590 %chk=I1N_N_TiCl4_2.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 2.03212536 -1.11128662 0.48273468 C 3.33995999 -0.35625333 0.81928027 C 2.97722701 1.10097230 0.44330829 C 2.85203359 1.16408712 -1.06686250 248 C 1.71017592 0.53023988 -1.33653488 N 1.10394793 0.11164053 -0.06282110 O 1.58225764 1.14024414 0.83772118 H 3.52608810 1.89639473 0.95217792 H 3.58177453 1.56033827 -1.76615284 H 1.23167583 0.25539823 -2.26857518 H 1.48947763 -1.41798390 1.37649334 H 3.56210393 -0.43268503 1.88851576 H 4.19104500 -0.74387729 0.24911501 N 2.19921021 -2.20430489 -0.39558819 H 2.69573650 -1.97378232 -1.25082831 H 1.33700439 -2.69255396 -0.61111721 Ti -1.21205052 0.02895029 0.02789219 Cl -1.08821968 2.12380481 -0.68455302 Cl -3.45430158 -0.10397850 0.09039640 Cl -0.88564414 -0.41401719 2.18423558 Cl -0.93648719 -1.57804523 -1.51523873 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 17 0.5 7 8 9 10 11 12 13 249 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- I1_M_exo Zero-point correction= 0.140576 (Hartree/Particle) Thermal correction to Energy= 0.155312 Thermal correction to Enthalpy= 0.156257 Thermal correction to Gibbs Free Energy= 0.097721 Sum of electronic and zero-point Energies= -3070.598870 Sum of electronic and thermal Energies= -3070.584134 Sum of electronic and thermal Enthalpies= -3070.583189 Sum of electronic and thermal Free Energies= -3070.641725 %chk=I1X_N_TiCl4.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -2.05815499 -1.09967682 0.55139662 C -3.41231400 -0.68760453 -0.07941188 C -3.09194738 0.70548331 -0.66425543 C -2.83447634 1.64416123 0.50303910 250 C -1.64907602 1.26655696 0.97709347 N -1.14119633 0.16455754 0.13400116 O -1.74197607 0.48429250 -1.14530576 H -3.72164748 1.05494542 -1.48573342 H -3.51755877 2.38382485 0.90833643 H -1.08184168 1.56360848 1.85113106 H -2.04975384 -1.07959500 1.64268845 H -4.22436329 -0.67048167 0.65430828 H -3.67183062 -1.38653242 -0.88171514 N -1.59481006 -2.35191396 0.08801730 H -1.52855375 -2.40105253 -0.92402806 H -0.70736865 -2.62331818 0.49964564 Ti 1.17946685 0.04854087 -0.02474363 Cl 1.06198529 2.23013888 -0.38685251 Cl 0.88217126 -0.76237407 2.05990265 Cl 3.41797631 -0.10537015 0.03938656 Cl 0.86835613 -1.21213960 -1.82062070 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 17 0.5 7 8 9 10 11 12 13 251 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- I2_M_X Zero-point correction= 0.137768 (Hartree/Particle) Thermal correction to Energy= 0.153394 Thermal correction to Enthalpy= 0.154338 Thermal correction to Gibbs Free Energy= 0.094571 Sum of electronic and zero-point Energies= -3070.569049 Sum of electronic and thermal Energies= -3070.553423 Sum of electronic and thermal Enthalpies= -3070.552479 Sum of electronic and thermal Free Energies= -3070.612246 %chk=I2-2_TiCl4_NH3.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -2.02590892 -0.89689588 1.02112376 C -3.39449852 0.64706708 0.07466280 C -3.27558569 -0.46335874 1.13883548 H -1.45077101 -1.68546695 1.48599169 252 H -4.06260089 -0.82046226 1.79415604 C -2.04237484 -0.48410081 -1.35071054 H -1.50577628 -1.12105741 -2.04064122 C -3.29306955 -0.03579774 -1.30360556 H -4.09320037 -0.17266031 -2.02330471 H -4.14362648 1.42841403 0.21756628 O -2.05600747 1.19455901 0.15781056 N -1.36206154 -0.07534061 -0.06563302 N 0.80994132 0.38411982 -2.20509835 H -0.07436411 0.81878342 -2.46872606 H 0.92791226 -0.46206377 -2.76153565 H 1.54357877 1.03555089 -2.48301755 Ti 1.02053077 0.02384030 0.02966862 Cl 0.77985394 2.29332667 0.04892852 Cl 0.91744997 -0.25375285 2.25900294 Cl 3.24409441 -0.05292222 -0.30721649 Cl 0.64146625 -2.21400067 -0.54320904 1 3 2.0 4 1.0 12 1.0 2 3 1.0 8 1.0 10 1.0 11 1.0 3 5 1.0 4 5 6 7 1.0 8 2.0 12 1.0 7 8 9 1.0 9 10 11 12 1.0 12 17 0.5 13 14 1.0 15 1.0 16 1.0 17 0.5 253 14 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- I2_M_]_endo Zero-point correction= 0.139609 (Hartree/Particle) Thermal correction to Energy= 0.155428 Thermal correction to Enthalpy= 0.156372 Thermal correction to Gibbs Free Energy= 0.094102 Sum of electronic and zero-point Energies= -3070.639981 Sum of electronic and thermal Energies= -3070.624162 Sum of electronic and thermal Enthalpies= -3070.623218 Sum of electronic and thermal Free Energies= -3070.685488 %chk=I2-1N_O_TiCl4.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 2.62191535 -1.09990439 0.41743348 C 3.70209378 -0.66903103 -0.57380122 C 4.19284059 0.72962473 -0.34738314 C 3.39317957 1.66127758 0.20845678 254 C 2.03266523 1.32252496 0.57074302 N 1.64460220 0.08652986 0.61317526 O 0.41811886 -0.26574134 0.95542173 H 5.18943218 0.99677136 -0.70046570 H 3.70382691 2.69652697 0.33575224 H 1.28453294 2.07875320 0.80383971 H 3.03908465 -1.23379887 1.42481063 H 4.52314760 -1.39234342 -0.50576221 H 3.30955436 -0.74082895 -1.60414927 N 1.96749084 -2.28708934 0.00611038 H 1.27322725 -2.59916488 0.67852604 H 1.51308939 -2.17871120 -0.89795525 Ti -1.34960246 0.02738163 0.02769112 Cl -0.12138578 -0.01125942 -1.89797067 Cl -1.54175833 2.04775408 0.98651758 Cl -2.01413786 -1.74299600 1.24160374 Cl -3.28921276 0.15551874 -1.14043700 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 17 0.5 8 9 10 11 12 13 255 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- I2_M_]_exo Zero-point correction= 0.139814 (Hartree/Particle) Thermal correction to Energy= 0.155602 Thermal correction to Enthalpy= 0.156546 Thermal correction to Gibbs Free Energy= 0.094578 Sum of electronic and zero-point Energies= -3070.640028 Sum of electronic and thermal Energies= -3070.624240 Sum of electronic and thermal Enthalpies= -3070.623296 Sum of electronic and thermal Free Energies= -3070.685263 %chk=I2-1X_O_TiCl4.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -2.67876663 1.12716710 -0.32010476 C -4.06868556 0.54654494 -0.59887953 C -4.28086977 -0.80054008 0.02262919 C -3.23843101 -1.62673847 0.24361349 256 C -1.89361385 -1.21221044 -0.09074507 N -1.64212937 0.01743081 -0.43454294 O -0.43368680 0.47186514 -0.71787319 H -5.29949795 -1.12281789 0.23951784 H -3.36467085 -2.63140711 0.64220668 H -1.05546677 -1.90327306 -0.06563280 H -2.37908460 1.83609903 -1.09570700 H -4.22004085 0.44918466 -1.68713753 H -4.81018240 1.27204098 -0.24204943 N -2.59370816 1.75755696 0.96185993 H -2.81573144 1.12011391 1.72342721 H -1.67325702 2.15500044 1.13115567 Cl 3.47408938 -0.37995950 0.81645528 Cl 0.42740072 -0.15919613 1.97795497 Ti 1.42368828 0.03178987 -0.06310201 Cl 2.00698457 1.97674943 -1.00479388 Cl 1.40795754 -1.80697567 -1.36284282 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 19 0.5 8 9 10 11 12 13 257 14 15 1.0 16 1.0 15 16 17 19 1.0 18 19 1.0 19 20 1.0 21 1.0 20 21 --------------------------------------------------------------------------------------------------------------------- I3_M Zero-point correction= 0.139406 (Hartree/Particle) Thermal correction to Energy= 0.155678 Thermal correction to Enthalpy= 0.156622 Thermal correction to Gibbs Free Energy= 0.094200 Sum of electronic and zero-point Energies= -3070.686696 Sum of electronic and thermal Energies= -3070.670423 Sum of electronic and thermal Enthalpies= -3070.669479 Sum of electronic and thermal Free Energies= -3070.731901 %chk=I3_NH3_TiCl4.chk # opt=(calcall,tight,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 2.41641319 -1.26140355 0.07185339 C 3.72391567 -1.19510782 -0.38370483 C 4.44055020 -0.00252597 -0.25869876 C 3.82222972 1.10034920 0.33328655 258 C 2.51165106 0.99767298 0.77583673 N 1.84511210 -0.17079825 0.63403076 O 0.59683620 -0.27085021 1.09732912 H 5.46759539 0.06469738 -0.61482370 H 4.34236817 2.04837906 0.45474901 H 1.94980651 1.80054902 1.23876271 H 1.78128024 -2.13884160 0.01713102 H 4.16599571 -2.08156320 -0.83414348 Ti -1.12694661 -0.00393722 -0.01461512 Cl -0.33393472 -1.26623228 -1.73505521 Cl -0.13317896 2.01129279 -0.74415478 Cl -1.96660291 -1.72215694 1.29473134 Cl -3.15357672 0.56600061 -0.88371994 N -1.68506579 1.23306265 1.78808493 H -1.02421152 1.05889458 2.54481366 H -2.61392212 0.98946606 2.12917127 H -1.67567389 2.23070845 1.58036686 1 2 2.0 6 1.0 11 1.0 2 3 1.0 12 1.0 3 4 2.0 8 1.0 4 5 1.0 9 1.0 5 6 2.0 10 1.0 6 7 1.0 7 13 0.5 8 9 10 11 12 13 14 1.0 15 1.0 16 1.0 17 1.0 18 0.5 259 14 15 16 17 18 19 1.0 20 1.0 21 1.0 19 20 21 --------------------------------------------------------------------------------------------------------------------- TS1A_M_endo Zero-point correction= 0.136165 (Hartree/Particle) Thermal correction to Energy= 0.152273 Thermal correction to Enthalpy= 0.153217 Thermal correction to Gibbs Free Energy= 0.089738 Sum of electronic and zero-point Energies= -3070.597550 Sum of electronic and thermal Energies= -3070.581442 Sum of electronic and thermal Enthalpies= -3070.580498 Sum of electronic and thermal Free Energies= -3070.643977 %mem=4GB %Nprocs=4 %chk=TSCA1N_TiCl4.chk # opt=(calcall,tight,qst3,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.41364132 C 1.32820809 0.00000000 1.73428166 260 O 2.08101064 -0.02127551 0.62715644 H -0.83565367 0.00075089 -0.68994851 H -0.85126506 0.01477073 2.08279242 N 1.23155236 -0.00000648 -0.47069764 H 1.87079180 0.01272012 2.67380798 C 1.40225003 3.33813872 1.25613310 H 2.42916575 3.30986576 1.61379262 H 0.61260026 3.52324019 1.98688891 C 1.14037052 3.18766165 -0.05567887 H 1.95537998 3.00775088 -0.75779357 N -0.10168101 3.28135853 -0.66296870 H -0.21745749 2.78619644 -1.53723491 H -0.91593221 3.24761141 -0.06224089 Ti 2.17509420 -0.33142551 -2.52356837 Cl 3.78912411 1.00226388 -1.80365282 Cl 2.26382474 -2.45171808 -1.85256115 Cl 2.98141136 -0.67398337 -4.58180212 Cl 0.23848372 0.58350149 -3.21711624 1 2 1.0 5 1.0 7 2.0 2 3 2.0 6 1.0 3 4 1.0 8 1.0 10 0.5 4 7 1.0 10 0.5 5 6 7 17 0.5 8 9 10 1.0 11 1.0 12 2.0 10 11 12 13 1.0 14 1.0 261 13 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.35360026 C 1.43705374 0.00000000 1.74791907 O 2.10250403 -0.51174350 0.59777682 H -0.82504326 0.10098707 -0.69551596 H -0.85383712 0.06454603 2.01908823 N 1.28074477 -0.10820509 -0.50539051 H 1.72011425 -0.61302147 2.60978997 C 2.00073667 1.49030232 2.03901065 H 3.04628187 1.37942050 2.34193211 H 1.40573078 1.90808424 2.86090586 C 1.90286565 2.28847216 0.81501689 H 2.69880835 2.27153194 0.07105422 N 0.84235170 2.97629438 0.51114845 H 0.72536796 3.34072717 -0.43453897 H 0.03692758 3.00488466 1.12906562 Ti 2.08731877 0.19204273 -2.29321350 Cl 3.72514401 1.77206162 -2.36451794 262 Cl 1.25005280 -0.79108189 -4.14047339 Cl 3.56821756 -1.48815612 -1.87703285 Cl 0.40893269 1.91815501 -2.53015352 1 2 2.0 5 1.0 7 1.0 2 3 1.0 6 1.0 3 4 1.0 8 1.0 9 1.0 4 7 1.0 5 6 7 17 0.5 8 9 11 1.0 10 1.0 12 1.0 10 11 12 13 1.0 14 2.0 13 14 15 1.0 16 1.0 15 16 17 19 1.0 21 1.0 20 1.0 18 1.0 18 19 20 21 Title Card Required 0 1 C -1.56068986 -0.41664602 -1.55361634 C -2.77633891 -1.01776356 -1.32042825 263 C -2.71824683 -1.40057851 0.06161079 O -1.39714089 -1.36734281 0.43638921 H -1.21200954 0.10514862 -2.43665484 H -3.62851656 -1.08074752 -1.98611160 N -0.74304431 -0.50303347 -0.48266572 H -3.25492460 -2.24187252 0.49843314 C -3.55013926 -0.00680850 1.13259172 H -3.40607530 -0.42274451 2.12922938 H -4.57512029 -0.06262986 0.75830454 C -2.81715977 1.15702597 0.84869328 H -1.90693894 1.38809445 1.39953871 N -3.08839624 1.95520439 -0.18165922 H -2.44782244 2.68802268 -0.45626632 H -3.90900642 1.81443759 -0.75652388 Ti 1.26299334 0.00503499 0.00074951 Cl 0.60589467 0.49433624 2.09107805 Cl 3.43120503 0.63755397 0.30615553 Cl 1.75319148 -2.15895659 -0.31819991 Cl 0.97954525 1.53198939 -1.66846805 1 2 1.5 5 1.0 7 1.5 2 3 1.5 6 1.0 3 4 1.0 8 1.0 9 0.5 10 0.5 4 7 1.0 10 0.5 5 6 7 17 0.5 8 9 10 1.0 11 1.0 12 1.5 10 11 264 12 13 1.0 14 1.5 13 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 $END --------------------------------------------------------------------------------------------------------------------- TS1A_M_exo Zero-point correction= 0.136296 (Hartree/Particle) Thermal correction to Energy= 0.152371 Thermal correction to Enthalpy= 0.153315 Thermal correction to Gibbs Free Energy= 0.090657 Sum of electronic and zero-point Energies= -3070.594139 Sum of electronic and thermal Energies= -3070.578064 Sum of electronic and thermal Enthalpies= -3070.577120 Sum of electronic and thermal Free Energies= -3070.639778 %mem=4GB %Nprocs=4 %chk=TSCA1X_TiCl4.chk # opt=(calcall,tight,qst3,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 265 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.41172325 C 1.31975392 0.00000000 1.73616980 O 2.07684079 -0.00276001 0.62985397 H -0.83276626 0.00886339 -0.68322591 H -0.84931611 0.00806009 2.07184349 N 1.22834756 -0.00803815 -0.46717500 H 1.86014311 0.00446907 2.66894333 C 0.35409351 3.40690756 0.07023131 H 1.25111496 2.85138149 0.30429845 H -0.25454744 3.76206708 0.89563480 C 0.03579263 3.65602568 -1.20747613 H 0.67455875 3.28133826 -2.00149417 N -1.02005847 4.42781997 -1.66929801 H -1.37274730 4.18234523 -2.58264492 H -1.76169439 4.60745663 -1.00604945 Ti 2.27047699 -0.01327902 -2.47964372 Cl 3.19357088 1.86816994 -1.76241962 Cl 3.16342605 -1.92205518 -1.74959399 Cl 3.25911651 -0.02644722 -4.50608769 Cl 0.17797785 0.16649766 -3.24751194 1 2 1.0 5 1.0 7 2.0 2 3 2.0 6 1.0 3 4 1.0 8 1.0 10 0.5 4 7 1.0 10 0.5 5 6 7 17 0.5 266 8 9 10 1.0 11 1.0 12 2.0 10 11 12 13 1.0 14 1.0 13 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.34241083 C 1.42952972 0.00000000 1.76826169 O 2.13834566 -0.34640085 0.57525590 H -0.83394854 0.06997895 -0.67793530 H -0.85017274 0.06513217 2.00120256 N 1.27243975 -0.08363540 -0.53374716 H 1.69397333 -0.72850566 2.53650706 C 1.94942137 1.40540769 2.29794795 H 1.30854101 1.68236805 3.13955475 H 2.97793402 1.29488720 2.64279224 C 1.84110604 2.42543733 1.24988819 H 0.86451775 2.72120851 0.88074720 267 N 2.86055245 2.96468761 0.68225222 H 2.75788794 3.60793058 -0.09504000 H 3.81000839 2.71572665 0.94183523 Ti 2.15656119 -0.24606450 -2.32019258 Cl 2.83168787 -2.34432776 -1.78833603 Cl 0.10225628 0.38242858 -3.15459370 Cl 3.81781924 1.18714710 -1.73049201 Cl 2.97027972 -0.43956851 -4.54390678 1 2 2.0 5 1.0 7 1.0 2 3 1.0 6 1.0 3 4 1.0 8 1.0 9 1.0 4 7 1.0 5 6 7 17 0.5 8 9 10 1.0 11 1.0 12 1.0 10 11 12 13 1.0 14 2.0 13 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 268 Title Card Required 0 1 C 1.36184068 -1.64145690 0.88793038 C 2.57015346 -1.99196093 0.34455669 C 2.76419053 -1.06226095 -0.73630996 O 1.55405065 -0.46030317 -0.97240208 H 0.86999144 -2.02945817 1.77229713 H 3.28751407 -2.71115597 0.72088414 N 0.74357370 -0.66724818 0.17851990 H 3.29501512 -1.29505413 -1.65929275 C 3.98238758 0.35033506 -0.17394078 H 4.74702924 -0.24733024 0.32031756 H 4.28422119 0.76093612 -1.14084906 C 3.22689866 1.20126861 0.65105863 H 3.06195491 0.95286792 1.69975007 N 2.58193858 2.27332142 0.21275855 H 1.86977417 2.71973281 0.77538574 H 2.61916690 2.54262881 -0.76299492 Ti -1.25944409 0.00886510 -0.00070970 Cl -1.46245088 -1.49484945 -1.65963180 Cl -1.35207622 -0.50509022 2.20985369 Cl -0.50733598 2.02564530 -0.65276832 Cl -3.47053184 0.58700991 -0.04506456 1 2 1.5 5 1.0 7 1.5 2 3 1.5 6 1.0 3 4 1.0 8 1.0 9 0.5 10 0.5 4 7 1.0 10 0.5 5 6 269 7 17 0.5 8 9 10 1.0 11 1.0 12 1.5 10 11 12 13 1.0 14 1.5 13 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 $END --------------------------------------------------------------------------------------------------------------------- TS1B_M_endo Zero-point correction= 0.138167 (Hartree/Particle) Thermal correction to Energy= 0.153197 Thermal correction to Enthalpy= 0.154141 Thermal correction to Gibbs Free Energy= 0.093916 Sum of electronic and zero-point Energies= -3070.597091 Sum of electronic and thermal Energies= -3070.582061 Sum of electronic and thermal Enthalpies= -3070.581117 Sum of electronic and thermal Free Energies= -3070.641342 270 %mem=4GB %Nprocs=4 %chk=TSCA2N_TiCl4.chk # opt=(calcall,tight,qst3,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.46398179 C 1.53477539 0.00000000 2.00369583 C 2.27322098 -1.21242491 1.55352784 C 2.84326523 -0.84867460 0.37774769 N 2.63585520 0.48690498 0.11030542 O 2.21294573 1.06519233 1.35231457 H 1.49621962 0.20911482 3.07698166 H 2.26486376 -2.19059067 2.02122026 H 3.37272877 -1.45112674 -0.35134077 H 0.05668454 0.93241582 -0.55665139 H -0.46348186 0.91491679 1.84563731 H -0.49409839 -0.88450006 1.88428216 N -0.02970606 -1.10151641 -0.70047476 H -0.04617341 -2.01132975 -0.25161632 H 0.15254435 -1.07539438 -1.70074482 Ti 3.08716230 1.79544412 -1.38662238 Cl 4.52582626 2.76389495 0.07402412 Cl 4.23552720 2.57856030 -3.19825968 Cl 1.27657371 3.09760990 -1.33452384 Cl 2.48194591 -0.08609230 -2.70676701 271 1 2 1.0 11 1.0 14 2.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 17 0.5 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.54837528 C 1.52062342 0.00000000 1.85553659 C 2.06368987 -1.35658163 1.45228294 C 2.04356718 -1.34408843 0.12009376 N 1.56259466 -0.02057838 -0.31772685 272 O 2.00746149 0.82715312 0.76959244 H 1.83212173 0.42513617 2.81215755 H 2.30845296 -2.18334905 2.11153410 H 2.24538662 -2.10597407 -0.62153171 H -0.30229373 0.97027824 -0.39974861 H -0.47283286 0.90878619 1.93482587 H -0.50721622 -0.87778232 1.96533002 N -0.65841123 -1.11453039 -0.59797428 H -1.34074878 -1.55614443 0.00417907 H -1.05810768 -0.92052877 -1.50787405 Ti 2.41829419 0.82285527 -2.32124507 Cl 4.37937968 0.37204019 -1.38672868 Cl 3.23228077 1.63086058 -4.25462986 Cl 1.29332550 2.66206314 -1.75684391 Cl 1.30665674 -0.89204811 -3.21285923 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 17 0.5 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 273 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 Title Card Required 0 1 C 2.19128531 -1.18346434 0.58831223 C 3.32450429 -0.23826008 0.87015847 C 2.89883627 1.18570546 0.34696348 C 2.81225967 1.14345831 -1.15538150 C 1.62780196 0.55735496 -1.39660112 N 0.95928793 0.30236063 -0.16904587 O 1.52215047 1.27233309 0.72819191 H 3.46080390 2.00007411 0.81101461 H 3.58517288 1.42369059 -1.86314848 H 1.18103606 0.21845888 -2.32423216 H 1.47165366 -1.37679084 1.37834906 H 3.48011598 -0.17293387 1.95254795 H 4.25387582 -0.56809993 0.39142197 N 2.37917919 -2.18744912 -0.28348041 H 3.05629994 -2.07250253 -1.02802190 H 1.60315887 -2.80409216 -0.49087761 Ti -1.18431698 0.02748401 0.02308521 Cl -1.34680714 2.13049800 -0.70549586 Cl -3.42388320 -0.35733400 0.06108517 Cl -0.84487354 -0.26772152 2.20979675 Cl -0.77924449 -1.68334033 -1.41912070 274 1 2 1.0 6 0.5 11 1.0 14 1.5 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 17 0.5 7 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 $END --------------------------------------------------------------------------------------------------------------------- TS2_M_X_endo Zero-point correction= 0.136494 (Hartree/Particle) Thermal correction to Energy= 0.151615 Thermal correction to Enthalpy= 0.152559 Thermal correction to Gibbs Free Energy= 0.093175 275 Sum of electronic and zero-point Energies= -3070.500495 Sum of electronic and thermal Energies= -3070.485374 Sum of electronic and thermal Enthalpies= -3070.484430 Sum of electronic and thermal Free Energies= -3070.543814 %chk=PathA_1N_TS.chk # opt=(calcall,tight,ts,verytight,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -2.02538849 0.79253838 0.84043547 C -3.23364755 0.08558855 1.04490892 C -2.99961034 -1.18215474 0.26347671 C -2.92372437 -0.84542777 -1.22369263 C -1.77445650 -0.19102055 -1.38511799 N -1.11513308 -0.13393534 -0.04347466 O -1.52456714 -1.40998599 0.49335305 H -3.55268991 -2.07738378 0.55410740 H -3.69840381 -1.02919348 -1.96217018 H -1.30585867 0.30364451 -2.22654124 H -1.45862779 1.24429939 1.65226495 H -3.61345843 0.00413021 2.06125879 H -2.91461636 2.00553505 -0.88163930 N -2.21289720 2.22868957 -0.17494454 H -1.36621584 2.60722422 -0.61060758 H -2.60965793 2.92271468 0.45669724 Ti 1.18998134 -0.05150255 0.03164518 Cl 1.09851267 -1.83843848 -1.26743103 Cl 3.43155927 0.11350867 0.11466150 276 Cl 0.88858988 -0.21487461 2.22806616 Cl 0.90920005 1.92871915 -1.03985644 1 2 1.5 6 1.0 11 1.0 14 0.5 2 3 1.0 12 1.0 13 0.5 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 17 0.5 7 8 9 10 11 12 13 14 0.5 14 15 1.0 16 1.0 17 0.3 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- TS2_M_ X_exo Zero-point correction= 0.136305 (Hartree/Particle) Thermal correction to Energy= 0.151471 Thermal correction to Enthalpy= 0.152415 Thermal correction to Gibbs Free Energy= 0.092685 277 Sum of electronic and zero-point Energies= -3070.501130 Sum of electronic and thermal Energies= -3070.485964 Sum of electronic and thermal Enthalpies= -3070.485020 Sum of electronic and thermal Free Energies= -3070.544749 %chk=PathA_1X_TS.chk # opt=(calcall,tight,ts,verytight,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -2.16477139 -0.96631168 0.63386387 C -3.43763593 -0.66271067 0.10027893 C -3.16086876 0.63371589 -0.66661200 C -2.84322306 1.71116403 0.38224144 C -1.65883590 1.36410358 0.88683732 N -1.20564893 0.14421432 0.15279271 O -1.80631943 0.38015529 -1.15243289 H -3.80038151 0.91571064 -1.50754363 H -3.49701358 2.51402283 0.71110038 H -1.06967015 1.71788480 1.72288306 H -1.97600790 -1.24477626 1.67051251 H -4.30564863 -0.72119879 0.75533404 H -1.48935590 -2.20878618 -1.14460802 N -1.46450400 -2.40109782 -0.14246000 H -2.14560279 -3.13179338 0.05756645 H -0.52771827 -2.71074851 0.13344644 Ti 1.17528140 0.07667113 -0.00569187 Cl 0.90589735 -1.15457532 -1.83737635 278 Cl 1.07018264 2.24375671 -0.39360009 Cl 3.40668080 -0.10736957 0.10851402 Cl 0.83423004 -0.77827680 2.05505106 1 2 1.5 6 1.0 11 1.0 14 0.5 2 3 1.0 12 1.0 13 0.5 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 17 0.5 7 8 9 10 11 12 13 14 0.5 14 15 1.0 16 1.0 17 0.3 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- TS3_M_X_endo Zero-point correction= 0.133665 (Hartree/Particle) Thermal correction to Energy= 0.150077 Thermal correction to Enthalpy= 0.151021 279 Thermal correction to Gibbs Free Energy= 0.088695 Sum of electronic and zero-point Energies= -3070.531927 Sum of electronic and thermal Energies= -3070.515515 Sum of electronic and thermal Enthalpies= -3070.514571 Sum of electronic and thermal Free Energies= -3070.576897 %chk=PathA_2_TS.chk # opt=(calcall,tight,ts,verytight,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -2.36852656 -1.26367176 0.69756181 C -2.73402031 -0.16676650 1.39305042 C -2.71911842 1.01220239 0.54818072 C -3.42083322 0.88618429 -0.72666298 C -3.05882638 -0.23614400 -1.37157332 N -2.03173823 -1.00618513 -0.69100954 O -1.03639558 0.08575310 -0.50539660 H -2.41161858 1.98359010 0.93619965 H -4.04386546 1.68054204 -1.13084838 H -3.30817397 -0.52102733 -2.39024823 H -2.08298698 -2.22827889 1.10732386 H -2.80822813 -0.11570983 2.47565515 Ti 0.95347565 0.01465249 -0.00904371 Cl 0.57118458 -0.21737631 2.22610277 Cl 0.57569773 2.33415708 -0.08836526 Cl 0.87984802 -2.23368965 -0.53393770 Cl 3.23517899 0.17915335 0.06186079 280 N 1.24239344 0.26615707 -2.24000060 H 0.34157712 0.24155014 -2.71557452 H 1.82322052 -0.47575743 -2.62761591 H 1.68568023 1.15792529 -2.45525658 1 2 2.0 6 1.0 11 1.0 2 3 1.0 12 1.0 3 4 1.5 7 0.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 13 0.3 7 13 0.3 8 9 10 11 12 13 14 1.0 15 1.0 16 1.0 17 1.0 18 0.5 14 15 16 17 18 19 1.0 20 1.0 21 1.0 19 20 21 --------------------------------------------------------------------------------------------------------------------- TS3_M_]_endo Zero-point correction= 0.136324 (Hartree/Particle) Thermal correction to Energy= 0.151727 281 Thermal correction to Enthalpy= 0.152672 Thermal correction to Gibbs Free Energy= 0.090921 Sum of electronic and zero-point Energies= -3070.553699 Sum of electronic and thermal Energies= -3070.538296 Sum of electronic and thermal Enthalpies= -3070.537352 Sum of electronic and thermal Free Energies= -3070.599102 %chk=PathB_1N_TS.chk # opt=(calcall,tight,ts,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C 2.54499835 0.90978691 -0.55626679 C 2.99366118 -0.41481963 -1.29552682 C 2.61558063 -1.56839012 -0.47165981 C 2.81218923 -1.46576847 0.94093781 C 2.24862706 -0.35081324 1.48279854 N 1.62323191 0.53137654 0.53987309 O 0.69038202 -0.32432547 -0.09986487 H 2.32972419 -2.51984745 -0.92178517 H 3.11086122 -2.31403842 1.55540452 H 2.04615345 -0.21477287 2.54262714 H 1.91495010 1.47040215 -1.25380588 H 2.60588881 -0.48684628 -2.31527526 H 4.09540666 -0.39031778 -1.34222469 N 3.65696526 1.71932630 -0.13983251 H 3.34286660 2.60075624 0.25875331 H 4.25256602 1.25143489 0.53908618 Ti -1.27429379 0.00685217 -0.02078907 282 Cl -3.54825802 0.16564218 -0.08895001 Cl -1.16664005 -0.08965243 2.22966140 Cl -0.93138634 2.05454878 -0.89242638 Cl -1.26187609 -1.85805659 -1.31937226 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.5 7 0.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 17 0.3 7 17 0.3 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 --------------------------------------------------------------------------------------------------------------------- TS3_M_ ]_exo Zero-point correction= 0.137014 (Hartree/Particle) Thermal correction to Energy= 0.152008 283 Thermal correction to Enthalpy= 0.152953 Thermal correction to Gibbs Free Energy= 0.093783 Sum of electronic and zero-point Energies= -3070.550126 Sum of electronic and thermal Energies= -3070.535132 Sum of electronic and thermal Enthalpies= -3070.534187 Sum of electronic and thermal Free Energies= -3070.593357 %chk=PathB_1X_TS.chk # opt=(calcall,tight,ts,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -2.41541502 -0.92162261 0.57227359 C -3.17612466 -0.51862512 -0.71829355 C -2.77688716 0.85828656 -1.12516812 C -2.57697350 1.81902434 -0.07956260 C -1.74977420 1.36059638 0.89142962 N -1.19949778 0.04645299 0.57210843 O -0.82691062 0.10348486 -0.81427705 H -2.92000102 1.17484314 -2.16072602 H -2.91322950 2.85088579 -0.15615678 H -1.46798375 1.82888557 1.82825535 H -2.96551659 -0.66593867 1.48419765 H -4.26358055 -0.49847904 -0.53341902 H -2.99578889 -1.23555376 -1.52529757 N -2.10280744 -2.30242941 0.57236067 H -1.52232655 -2.56218935 -0.22213378 H -1.60606449 -2.57592072 1.41616075 Ti 0.98378004 -0.01651334 -0.06935692 284 Cl 1.87445395 -0.35612910 1.98796881 Cl 0.82528633 2.33559749 0.37511507 Cl 0.99379797 -2.29992051 -0.51919528 Cl 2.47786169 0.40426149 -1.68778091 1 2 1.0 6 1.0 11 1.0 14 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.5 7 0.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 17 0.3 7 17 0.3 8 9 10 11 12 13 14 15 1.0 16 1.0 15 16 17 18 1.0 19 1.0 20 1.0 21 1.0 18 19 20 21 I1_M_endo (with pyrrolidine) 285 Zero-point correction= 0.231786 (Hartree/Particle) Thermal correction to Energy= 0.250714 Thermal correction to Enthalpy= 0.251658 Thermal correction to Gibbs Free Energy= 0.180932 Sum of electronic and zero-point Energies= -3226.551358 Sum of electronic and thermal Energies= -3226.532429 Sum of electronic and thermal Enthalpies= -3226.531485 Sum of electronic and thermal Free Energies= -3226.602211 %chk=I1_M_endo.chk # opt=(calcall,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 Title Card Required 0 1 C -1.93456022 0.23221586 -0.55042571 C -1.65492295 1.69040358 -1.02910806 C -0.43072309 2.05141835 -0.15500803 C -0.90689560 2.18969569 1.27459818 C -1.23191040 0.94977791 1.64534356 N -0.91758679 0.01036258 0.57010286 O 0.19949765 0.71836730 -0.07822399 H 0.28001973 2.77596762 -0.55006529 H -1.02248301 3.11783185 1.82455768 H -1.68258542 0.56572079 2.55341307 H -1.63635238 -0.48828006 -1.33193023 H -1.39874442 1.71003556 -2.09297074 H -2.49152025 2.36850949 -0.83936016 Ti 2.18463428 -0.24419775 -0.05867590 Cl 2.02817466 -0.19998824 2.15486247 286 Cl 4.22998935 -1.13601806 -0.16447546 Cl 2.72636362 1.63736128 -1.15246635 Cl 1.13748827 -1.89463930 -1.12102294 C -4.32203408 0.17911328 -1.05265825 C -3.46651338 -1.39381994 0.43217592 C -5.56297467 -0.44333206 -0.38919012 H -4.07655313 -0.35751859 -1.99239037 H -4.44717484 1.24128847 -1.29250998 C -4.98996209 -1.48581543 0.61198902 H -2.90293739 -1.56890486 1.35565493 H -3.11318508 -2.12688591 -0.32091128 H -6.13925139 0.32626486 0.13889800 H -6.22412846 -0.89809989 -1.13676491 H -5.26910231 -1.22754350 1.64088754 H -5.35263195 -2.50197140 0.41556881 N -3.26135558 -0.01652149 -0.05138511 1 2 1.0 6 1.0 11 1.0 31 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.0 7 1.0 8 1.0 4 5 2.0 9 1.0 5 6 1.0 10 1.0 6 7 1.0 7 14 0.5 8 9 10 11 12 13 14 15 1.0 16 1.0 17 1.0 18 1.0 287 15 16 17 18 19 21 1.0 22 1.0 23 1.0 31 1.0 20 24 1.0 25 1.0 26 1.0 31 1.0 21 24 1.0 27 1.0 28 1.0 22 23 24 29 1.0 30 1.0 25 26 27 28 29 30 31 TS3_M_ ]_endo (with pyrrolidine) Zero-point correction= 0.228554 (Hartree/Particle) Thermal correction to Energy= 0.247681 Thermal correction to Enthalpy= 0.248625 Thermal correction to Gibbs Free Energy= 0.177734 Sum of electronic and zero-point Energies= -3226.517823 Sum of electronic and thermal Energies= -3226.498695 Sum of electronic and thermal Enthalpies= -3226.497751 Sum of electronic and thermal Free Energies= -3226.568643 %chk= TS3_M_beta_endo.chk # opt=(calcall,ts,noeigentest,maxcycle=500) freq b3lyp/aug-cc-pvdz scrf=(smd,solvent=1,4-dioxane) geom=connectivity empiricaldispersion=gd3 288 Title Card Required 0 1 C 0.00000000 0.00000000 0.00000000 C 0.00000000 0.00000000 1.58494837 C 1.38948506 0.00000000 2.05453270 C 2.30790100 -0.86339612 1.38110784 C 2.29792145 -0.70920337 0.03122402 N 1.36608591 0.26692192 -0.46082480 O 1.71889576 1.43527033 0.26184788 H 1.68024680 0.51889340 2.96860406 H 3.11364927 -1.38272096 1.89744110 H 3.06112485 -1.08608216 -0.64446686 H -0.57430093 0.89043461 -0.31536748 H -0.58794885 0.81744909 2.00987597 H -0.43180507 -0.96025311 1.90792759 C -0.44334838 -1.23744698 -2.06110831 C -1.90037580 -1.51525709 -0.26971483 C -1.28370957 -2.46709504 -2.43618115 H 0.59026412 -1.28587783 -2.41779535 H -0.89475916 -0.31150678 -2.46681393 C -2.26954436 -2.64319354 -1.24856940 H -2.52856932 -0.62030792 -0.45544401 H -2.02941893 -1.80566634 0.77988326 H -1.79849589 -2.31725094 -3.39262913 H -0.64176895 -3.35055081 -2.54005262 H -3.31905046 -2.56644642 -1.55701874 H -2.13494672 -3.62189586 -0.77197913 N -0.48877602 -1.22842351 -0.58253676 Ti 2.42849226 3.03515331 -0.68573137 289 Cl 4.09051235 1.76237474 -1.53053762 Cl 0.55655930 3.09778903 -1.93285935 Cl 2.45111215 3.82293572 1.44633279 Cl 3.26464799 4.98968770 -1.52166394 1 2 1.0 6 1.0 11 1.0 26 1.0 2 3 1.0 12 1.0 13 1.0 3 4 1.5 7 0.5 8 1.0 4 5 1.5 9 1.0 5 6 1.5 10 1.0 6 7 1.0 27 0.3 7 27 0.3 8 9 10 11 12 13 14 16 1.0 17 1.0 18 1.0 26 1.0 15 19 1.0 20 1.0 21 1.0 26 1.0 16 19 1.0 22 1.0 23 1.0 17 18 19 24 1.0 25 1.0 20 21 22 23 24 25 26 290 27 28 1.0 29 1.0 30 1.0 31 1.0 28 29 30 31 291