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"(1.: 3'3““ 5137"" m Y1 _;‘1}_) ‘5' fl $.32" "I ,.v~f"" l HIGAN SYAT BRARIES '- ‘lulil llllallilllllflllllllllllllll 3 1 93 00897 1990 This is to certify that the thesis entitled PllOTOCl fliMIST RY OF ORTHO-ALKOXY BENZOPl-lENONhS presented by GUY JAMES LAIDIG has been accepted towards fulfillment of the requirements for MASTERS . SCIENCE degree in 0%» 56%: profe‘éor DateJ/Jvr %/ 77° 0-7639 MS U is an Affirmative Action/Equal Opportunity Institution M l' i LIBRARY Michigan Stat. l University “\_._ PLACE IN BET URN BOX to remove this checkout from your record. TO AVOID FINES return on or betore date due. r——————————- DATE DUE DATE DUE DATE DUE F IL 11—— MSU I. An Affirmative Action/Equal Opportunity Inuitmion cWMS-o: PHOTOCHEMISTRY OF ORTHO-ALKOXY BENZOPHENONES BY Guy James Laidig A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1990 Co%~¢34 ABSTRACT PHOTOCHEMISTRY OF ORTHO-ALKOXY BENZOPHENONES BY Guy James Laidig The photochemistry of several o-alkoxybenzophenones was studied. The major products formed from the 5-hydrogen abstraction reactions were the corresponding diastereomeric 2-alkyl-3-phenyl-2,3-dihydro-3- benzofuranols. The diastereomeric ratio of the photoproducts varied substantially from irradiations in non-polar, non—Lewis basic solvents, such as benzene, to highly polar, Lewis basic solvents such as methanol. The kinetics of several o-alkoxybenzophenones were measured and the lifetime of the 1,5-biradical was estimated by utilizing the cyclopropylmethyl radical rearrangement as an internal clock. The mechanism for the formation of 2,2-dimethyl-4-phenyl-l,3-benzodioxane from the irradiation of o-isopropoxybenzophenone was determined. The product formation occurred by the acid catalyzed addition of the benzhydryl hydroxyl function to the olefin of the enol disproportionation intermediate, o-(2-propenyl)benzhydrol, giving the substituted 1,3-benzodioxane. To Sheba for all of your love and support during my times of need. iii ACKNOWLEDGEMENTS The author would like to extend his thanks to Dr. P.J. Wagner for his guidance throughout this project. Also, the author would like to thank the National Science Foundation and Michigan State University for financial support in the form of teaching and research assistantships. Thanks to the following for all of their help during my stay at M.S.U.: Dr. Stille, Dr. Reusch, Dr. Jackson, Boli Zhou, Keepyung Nahm, Jim Defrancesco, Mark Mc Mills, Paul Weipert, Brian Merril, Ken Rehder, Judy Eglin, John Young, Art Harms, and to the current Wagner Group members. Also thanks to all the others at M.S.U. who have made this an enjoyable time in my life. Special thanks to my family for their support during the years I spent at M.S.U. Table of Contents Page List of Tables ---------------------------------------------------- vii List of Figures --------------------------------------------------- x Introduction ------------------------------------------------------ 1 Results A. General Preparation of Ketones --------------------- 15 Identification of Photoproducts -------------------- 15 Solvent Effect on Stereochemistry of Photoproducts ----------------------------------- 21 D. Solvent Effects on Product Distribution ------------ 21 E. Spectroscopy --------------------------------------- 21 F. Kinetic Results ------------------------------------ 22 6. Calculation of Quantmm Yields ~ ---22 H. MMZ Calculations ----------------------------------- 23 I. 1H NOE Studies ------------------------------------- 25 Discussion A. Solvent Effects on Stereochemistry ----------------- 30 B. Solvent Effects on Quantum.Yield ------------------- 30 C. Lifetimes of Triplet Excited States and 1,5-Biradicals ------------------------------------- 31 D. Reactivity of the Triplet Excited State Towards Hydrogen Abstraction ------------------------------- 32 E. Mechanistic Discussion on the Formation of 2,2- Dimethyl-4-phenyl-1,3-benzodioxane from the Irradiation of o-Isopropoxybenzophenone ------------ 35 Experimental I Purification of Chemicals A. Solvents ------------------------------------------- 38 3. Internal Standard and Quenchers -------------------- 39 II Equipment and Procedures Page A. Photochemdcal Glassware ---------------------------- 40 8. Sample Preparation --------------------------------- 40 C. Degassing Procedures ------------------------------- 40 D. Irradiation Procedures ----------------------------- 40 E. Analysis Procedures -------------------------------- 41 F. Quantum Yield Analysis ----------------------------- 41 G. Spectroscopic Measurements ------------------------- 42 III Starting Ketone Synthesis ----------------------------- 43 IV Isolation and Identification of Photoproducts A. General Isolation Methods -------------------------- 53 8. Identification of Photoproducts 1. o-(a-Methylbenzyloxy)benzophenone --------------- 53 2. o-Ethoxybenzophenone ---------------------------- 54 3. o-Allyloxybenzophenone — - — -------------- 55 4. o-(Cyclopropylmethoxy)benzophenone -------------- 56 5. o-Isopropoxybenzophenone - --------- 57 6. o-(Isopropoxy-Zdl)benzophenone ------------------ S9 7. o-(Isopropoxy-1,l,l,3,3,3-d5)benzophenone ------- 60 Appendix -------------------------- 62 References -------------------------------------------------------- 97 vi Table 10 List of Tables Page Solvent Effects on Photoproducts ---------------------------- 26 Triplet Energies of o-Alkoxybenzophenones in 2-Me-THF at 77°K ----------------------------------------- 27 Ultraviolet-Visible Absorption Maxima ----------------------- 28 Quantum Yields and kqt Values of o-Alkoxybenzophenones ------ 29 Reactivities of C-H Bonds Towards Abstraction by Triplet Benzophenone and t-Butoxy Radical ---------------- 33 Response Factors for GC and HPLC ---------------------------- 62 Quenching of 2-Methyl-3-phenyl-2,3-dihydro-3- benzofuranol Formation from o-Ethoxybenzophenone with 2,5-Dimethyl-2,4-hexadiene in Acetonitrile at 313 nm -------- 83 Quenching of 2,2-Dimethyl-3-phenyl-2,3-dihydro-3- benzofuranol Formation from o-Isopropoxybenzophenone with Naphthalene in Benzene at 365 nm. ---------------------------- 84 Quenching of 2,2-Dimethyl-3-phenyl-2,3-dihydro-3- benzofuranol(-OD) Formation from o-(Isopropoxy-Zd) benzophenone with Naphthalene in Benzene at 365 nm. ---------- 85 Quenching of 3-Phenyl-2-vinyl-2,3-dihydro-3- benzofuranol Formation from o-Allyloxybenzophenone with 2,5-Dimethyl-2,4-hexadiene in Benzene at 313 nm -------- 86 vii 11 12 13 14 15 16 17 18 19 Page Quenching of 3-Phenyl-2-vinyl-2,3-dihydro-3- benzofuranol Formation from o-Allyloxybenzophenone with 2,5-Dimethyl-2,4-hexadiene in Methanol at 313 nm ------- 87 Quantum Yield for the Formation of 2-Methyl-3-phenyl -2,3-dihydro-3-benzofuranol from o-Ethoxybenzophenone in Methanol at 313 nm --------------------------------------- 88 Quantum Yield for the Formation of 2-Methyl-3-pheny1 -2,3-dihydro-3-benzofuranol from o-Ethoxybenzophenone in Acetonitrile at 313 nm ----------------------------------- 89 Quantum Yield for Formation of 3-Phenyl-2-vinyl-2,3- dihydro-B-benzofuranol Formation from o-Allyloxybenzophenone in Benzene at 313 nm ----------------- 90 Quantum Yield for Formation of 3-Phenyl-2-vinyl-2,3- dihydro-B-benzofuranol Formation from o-Allyloxybenzophenone in Methanol at 313 nm ---------------- 91 Quantum Yield for Formation of 2,2-Dimethyl-3- phenyl-Z,3-dihydro-3-benzofuranol from o-Isopropoxybenzophenone in Benzene at 365 nm --------------- 92 Quantum Yield for Formation of 2,2-Dimethy1-3- phenyl-Z,3-dihydro-3-benzofuranol from o-Isopropoxybenzophenone in Methanol at 365 nm -------------- 93 Quantum Yield for Formation of 2,2-Dimethyl-3- phenyl-Z,3-dihydro-3-benzofuranol from o-Isopropoxybenzophenone in Acetonitrile at 365 nm ---------- 94 Quantum Yield for Formation of 2,2-Dimethyl-3- phenyl-Z,3-dihydro-3-benzofuranol from o-(Isopropoxy-Zd)benzophenone in Benzene at 365 nm ---------- 95 viii Page 20 Quantum Yield for Formation of 2,2-(Dimethyl-d5)-3-phenyl -2,3-dihydro-3-benzofuranol from o-(Isopropoxy- 1,1,l,3,3,3-d6)benzophenone in Methanol at 365 nm ----------- 96 ix Figure 10 11 List of Figures Page The Jablonski Diagram. -------------------------------------- 2 Resonance Contributors for the 3n-n* and.3n—u* Excited States. --------------------------------------------- 3 Stereochemical Induction in Cyclization of 1,4-Biradicals. ------------------------------------------ 5 Stereochemical Determinations Using 1H NMR. ----------------- 13 Ketones Studied and Their Corresponding Photoproducts. ------ 20 The Lowest Energy Conformation of 2,2-Dimehtyl-4- phenyl-1,3-benzodioxane. ------------------------------------ 24 Energies and Rotational Angles of Reactive Conformations for Ketones 8 and 44 ------------------------ 23 Rotational Conformations of o-Alkoxybenzophenones ----------- 34 18 NMR Spectrum of o-(a-Methylbenzyloxy)benzophenone prior to Irradiation in methanol-d4. ------------------------ 63 1H NMR Spectrum of o-(a-Methylbenzyloxy)benzophenone Following Irradiation in Benzene-d5 with TMS Added. --------- 64 1H NMR Spectrum of o-Ethoxybenzophenone Prior to Irradiation in Benzene-d5.— == ---------------- 65 12 13 14 15 16 17 18 19 20 21 22 Page in NMR Spectrum of o-Ethoxybenzophenone Following Irradiation in Benzene-d6 with TMS Added. ------------------- 66 18 NMR Spectrum of o-Allyloxybenzophenone Prior to Irradiation in Benzene—d6. ---------------------------------- 67 1H NMR Spectrum of o-Allyloxybenzophenone Following Irradiation in Benzene-d6 with TMS Added. ------------------- 68 1H NMR Spectrum of o-Allyloxybenzophenone Following Irradiation in Methanol-d4 ---------------------------------- 69 la NMR Spectrum of o-(Cyclopropylmethoxy)benzophenone Prior to Irradiation in Benzene-d5. ------------------------- 70 1H NMR Spectrum of o-(Cyclopropylmethoxy)benzophenone Following Irradiation in Benzene-d5. ------------------------ 71 18 NMR Spectrum of o-Isopropoxybenzophenone Prior to Irradiation in Benzene-d5.= --------------- 72 18 NMR Spectrum of o-Isopropoxybenzophenone Following Irradiation in Benzene-d5 with TMS Added. ------------------- 73 1H NMR Spectrum of o-Isopropoxybenzophenone Following Irradiation in Benzene-d6 and Addition of 2-Naphthalenesulfonic acid with TMS Added. ------------------ 74 18 NMR Spectrum of o-(Isopropoxy-Zdl)benzophenone Prior to Irradiation in Benzene-d5. ------------------------- 75 1H NMR Spectrum of o-(Isopropoxy-Zdl)benzophenone Following Irradiation in Benzene-dgiwith TMS Added. --------- 76 xi 23 24 25 26 27 28 Page 1H NMR Spectrum of o-(Isopropoxy-Zdl)benzophenone Following Irradiation in Benzene-d6 and Addition of 2-Naphthalenesulfonic acid with TMS Added. ------------------ 77 1H NMR Spectrum of o-(Isopropoxy-1,1,1,3,3,3-d5) benzophenone Prior to Irradiation in Benzene-d5. ------------ 78 18 NMR Spectrum of o-(Isopropoxy-1,l,1,3,3,3-d6)benzophenone Following Irradiation in Benzene-d5 with TMS Added. --------- 79 1H NMR Spectrum of o-(Isopropoxy-1,l,l,3,3,3-d5)benzophenone Following Irradiation in Benzene-d6 and Addition of 2-Naphthalenesulfonic acid with TMS Added.------------—--é--80 18 NMR Spectrum of o-(Isopropoxy-1,1,1,3,3,3-d6)benzophenone and Anisole Prior to Irradiation in Benzene-d5. ------------- 81 18 NMR Spectrum of o-(Isopropoxy-1,1,1,3,3,3-d6)benzophenone and Anisole Following Irradiation in Benzene-d5 with Added 2-Naphthalenesulfonic acid. --------------------------------- 82 xii Introduction The carbonyl moiety is one of the most versatile and extensively used functional groups in chemistry. Photochemical studies of ketone behavior is one method of probing the fundamental chemical properties of excited state carbonyl reactions, leading to a greater understanding of photochemistry. The basis of all photochemistry revolves around the absorption of light radiation by a chromophore, creating an excited state. The excited state then decays through radiationless, light emitting, and product forming pathways. This is best illustrated through examination of the Jablonski diagram; (Figure 1). The radiation (hv) is absorbed by the ground state chromophore, giving rise to the singlet electronic excited state (Sn) of the chromophore. This singlet excited state decays through a vibrational relaxation (kvr), caused by intermolecular collisions, to its lowest singlet vibrational excited state (81). kvr-1011-1014 s'l.2 From this (81) state several decay pathways are available. A radiationless decay can occur to the singlet ground state, ksd-los-lo8 3'1.2 Also, fluorescence can occur, which is the spin allowed decay from an excited singlet state to its corresponding singlet ground state with the emission of a photon, kf-lo8 s'l.3 Singlet excited state chemical reactions (ksr) are possible, giving ground state products. And finally, the (81) state can undergo intersystem crossing (kisc), which is the spin forbidden radiationless transformation of one electronic excited state to another of different multiplicity (Tn) without the loss of energy, hum-3x108 s'1 and ruse-1011 3'1 4 for aliphatic ketones and aromatic ketones, respectively. Direct population of the lowest triplet excited state by radiation is forbidden by spin selection rules, but due to the high quantum yield5 for intersystem crossing for aromatic ketones (¢-1.00) excitation efficiently gives rise to the triplet electronic excited state. 2 In the event that the intersystem.crossing terminates in an upper triplet excited state, internal conversion (kic) occurs giving rise to the lowest electronically excited state, hie-101° s'l.6 The triplet excited state (Tn) decays through vibrational relaxation to the lowest triplet excited state (T1). From this state, several pathways are available. This excited state can undergo phosphorescence, which is the spin forbidden decay from the triplet excited state to its corresponding singlet ground state kp-102-103 s'l.7 The triplet excited state can be quenched by energy transfer, or electron transfer, at the diffusion controlled rate for a given solvent, qulOloMfls'1.8I9 In the case that a high concentration of a triplet excited state is formed, decay by triplet-triplet annihilation occurs at the diffusion controlled rate for the given solvent.10 A radiationless decay can occur from the triplet excited state to the singlet ground state kid-105 3'1.11 And triplet excited state chemical reactions (ktr) are possible, giving rise to ground state products. 3n V Products from 30 1 Products from singlet state triplet state Figure 1 The Jablonski Diagram There are two low lying triplet reactive species from which carbonyl chemical reactions take place. The two species important in 3 carbonyl photochemistry are the 3n-x* and the 3u-n* excited states. The 3n-n* species occurs when a non-bonding electron from the carbonyl oxygen is promoted into an anti-bonding orbital. This electron promotion creates an electron deficient oxygen that reacts in the same fashion as a t-butoxy radical.12 The 3n-x* species arises from the promotion of an electron from a x-bonding orbital to a n* anti-bonding orbital. This electronic promotion results in a transfer of electronic charge from the u-system of the aromatic ring, to the carbonyl oxygen, creating an electron rich oxygen. The 3n-x* is less likely to undergo radical reactions at the carbonyl oxygen than is the 3n-u* (Figure 2). C) 0. dB H ma 31r-1c* major contributor :0. : .- @R <—> Gin 3n-1t"' major contributor Figure 2 Resonance Contributors for the 3n-n* and 3n-n* Excited States Ketones with a 3n-u* triplet can abstract hydrogens in both intermolecular and intramolecular fashions. The first reported intermolecular hydrogen abstraction by an excited carbonyl, by Ciamician 0H ph Ph 0 10* k; 30' 2pm.. H°+—<-°+ )K )K h )K + CZHSOH Ph Ph Ph Ph Ph Ph Ph Ph . + ca3cnoa + ca3cao Reaction 1 4 and Silber,13 occurred during the irradiation of benzophenone in ethanol (Reaction 1). One of the products reported was benzpinacol, which was formed by the abstraction of a hydrogen from ethanol by the triplet carbonyl and coupling of two benzophenone hemipinacol radicals. The best known 3n-u* intramolecular hydrogen abstraction is that of the Norrish type II (Reaction 2).14 In this reaction the ybhydrogen is abstracted giving a 1,4-biradical,15 which can disproportionate to the unstable enol and an olefin, or bond rotation can occur allowing overlap of the radical orbitals, followed by biradical coupling, giving the cyclobutanol. H CH3 OH OH 0 G 0““ 1.x ' ”‘08-‘43“ 00H CHa Reaction 2 It is important to look closely at the orbitals involved in the 3n-n* excitation. In theory, the two orbitals which contain the electron density of the 3n-n* state are orthogonal, therefore, when the “radical like" oxygen abstracts a 15H, the radical produced on the 7- carbon is contained in an orthogonal p-orbital in relation to the p- orbital of the carbonyl carbon. A necessity for cyclization is a near parallel alignment of these two radical orbitals. This can be achieved by a 90° rotation around either the arfl, or the B-7 carbon-carbon bond.16 The stereochemistry of the cyclobutanol is determined by several factors. Lewis and Hilliard showed that both a— methylbutyrophenone (1) and valerophenone (3) gave 2-methyl-l-phenyl- cyclobutanol (2) upon irradiation in benzene}.7 Photolysis of the a- substituted butyrophenone (1) gave the z isomer (2:) as the only photoproduct while valerophenone (3) gave a z to E ratio of 3:1 (Figure 3). This can be explained by looking at the involvement of the methyl group in the formation and cyclization of the 1,4-biradical. With a- methylbutyrophenone (1) the phenyl group and the methyl group are 5 “aware" of each other, due to their close proximity, before the biradical is formed. Because of this prior interaction, the phenyl group and the methyl group will relieve steric congestion by taking up a trans relationship after the formation of the 1,4-biradical, thereby leading to only the trans or z-cyclobutanol (23). Whereas with valerophenone (3) the phenyl group and the methyl group are spacialy far apart from each other. Due to this increased distance the steric interaction prior to irradiation and immediately after formation of the 1,4-biradical is nearly nonexistent. This results in the phenyl and methyl groups becoming “aware" of each other only as the orbitals of the biradical are being aligned prior to cyclization. This shorter interaction time of the phenyl and methyl groups results in reduced stereospecificity in the formation of the 2-methyl-l-phenyl-cyclobutanol (2). 2! U A) N U H Figure 3 Stereochemical Induction in Cyclization of 1,4-Biradicals The quantum yield and the product ratios can be influenced by the polarity and the Lewis base character of the solvent. Wagner18 discovered that the quantum yield for the disappearance of valerophenone (3) increased from (¢-0.37-0.40) in hydrocarbon solvents to (¢=1.00) in alcohols (t-butyl alcohol, ethanol) and acetonitrile. The formation of the z and E cyclobutanols made up 15% of the products in both acetonitrile and hexane but dropped to 10% in alcohol solvents. It was also found that the z:E ratio decreased from 3:117 in hydrocarbon solvents to 1:1 in the Lewis base alcohols. These findings are explained by the hydrogen bonding of the solvent to the newly formed hydroxyl moiety of the 1,4-biradical. This hydrogen bonding slows the reverse hydrogen abstraction reaction, thereby forcing the 1,4-biradical to go on to products, other than returning back to the starting ketone. The increased size of the solvated hydroxyl moiety creates large steric interactions that alter the stereochemistry of the cyclobutanol formation. Also, this increased size favors the cleavage reaction leading to acetophenone formation over cyclization to the cyclobutanol. The photochemdstry of o-alkoxyphenylaldehydes and ketones has been investigated. Pappas and Blackwell19 irradiated o-benzyloxy- benzaldehyde (4) in acetonitrile giving rise to two photoproducts, both of which dehydrated under acidic conditions to give 2-phenylbenzofuran (Reaction 3). The structures of the products were determined by 1H NMR spectroscopy to be cis(Z) and trans(E) 2-phenyl-2,3-dihydro-3- benzofuranol (5) in a 2:1 ratio. Ph Ph )tH )- Ph Ph 0 0 0H0 0 on o “of ‘ 53 5: Reaction 3 Further studies by Pappaszo showed that methyl-o-benzyloxy- phenylglyoxylate (6) undergoes intramolecular 5-hydrogen abstraction upon irradiation to give an isomeric mixture of 3-carboxymethyl-2- phenyl-2,3-dihydro-3-benzofuranol (7) (Reaction 4). The isomeric ratio is highly dependent on the solvent and temperature at which the photolysis occurs. In acetonitrile, the isomeric mixture changes from a 2:3 ratio of 2.5:1 at -35°C to 1.5:1 at 80°C. In heptane, the 2:3 ratio changes from >20:1 at 0°C to 3:1 at 100°C. In benzene, the 2:8 ratio is >20:1 at 15°C, and in t-butyl alcohol the 2:3 ratio is 1:1 at 80°C. This information suggests that the z isomer is both the kinetically and thermodynamically favored product. Ph Ph )~H ) Ph Ph ("3 0 o 0 HO O OH 0 coon. OCH OCH3 cyclize ’ ’5 ’9 ~ 3 ' coon3 0“ C) (3 £5 6 73 71' Reaction 4 The photochemistry of substituted o-benzyloxybenzophenones has been studied by a few groups.21v22123v24 Recently, the photochemistry of several o-alkoxybenzophenones were studied, including o- allyloxybenzophenone (8) which was also studied in this thesis. Sumathi21 found that 2-vinyl-3-phenyl-2,3-dihydro-3-benzofuranol (9) was formed in the irradiation of o-allyloxybenzophenone (8), although no Stereochemical information of the photoproducts was reported (Reaction 4). 4? H .— 0 O 0 OH O 0.. m hv>290nm > Ph Ph pyrex filter 3 98 9! Reaction 5 Lappin and Zannucci22 found that upon a 7 hour photolysis of 2- (benzyloxy)-4-(dodecyloxy)benzophenone (10), in cyclohexane, 6- (dodecyloxy)-2,3-dihydro-2,3-dipheny1-3-benzofuranol (11) was formed in 67% yield (8-0.56) and 4-(dodecyloxy)-2-hydroxybenzophenone (12) was formed in 6% yield (¢-0.07) (Reaction 6). The 4-(dodecyloxy)-2-hydroxybenzophenone (12) is formed by a carbon-oxygen bond cleavage followed by radical addition to the phenolic benzene ring. It was shown by Hashimoto, et al.25 that when benzyl phenyl ether was irradiated in isopropanol, the ether was cleaved at the ET Ph H )I o o . o cyclize > KT?“ —» ”“53" E312*"250 C12H250 C.2l-IZ50'-"312H250 1° 11 Reaction 6 alkyl carbon-oxygen bond, which then forms o-benzyl phenol, p-benzyl phenol, and phenol in 28.5%, 16.9%, and 15.8% respectively. The phenol was formed when the phenolic radical escaped the solvent cage and abstracted a proton from the solvent. Wagner, Meador, and Scaiano23 found that upon irradiation of o- benzyloxybenzophenone (13), 2,3-diphenyl-3-benzofuranol (14) was formed with a 2:3 ratio of 8:1 with a combined quantum yield (¢-0.95) (Reaction 7). Irradiation in the presence of pyridine lowered both the quantum yield to (¢=0.61) and the 2:8 ratio to 1.2:1. Ph Ph ). Ph Ph 0) H0 0 0H 0 Ph cyclize > ‘9 an m .. 0+ 148 14! Reaction 7 Sullivan and Jones26 found that upon irradiation of o- allyloxyacetophenone (15) in methanol, three products were formed (Reaction 8). The major product isolated was 2-methoxyacetophenone (16) in 12% yield. The authors suggested a mechanism for 16 arising from.a 3x~u* excited state intermediate which contained a positive charge on the same aromatic carbon to which the allyloxy group was attached. This charged intermediate then underwent nucleophilic attack by the methanol followed by displacement of the allyloxy group, giving 16. Also formed was o-hydroxyacetophenone (17) in 9% yield, which was most likely formed in a photo-cleavage type reaction as in Reaction 5, and 3-methyl-2-vinyl benzofuran (18) was formed in 1% yield, which was 9 thought to be the dehydration product of 3-methyl-2-vinyl-3- benzofuranol. M _. O 0 H300 O HO 0 O \ hv (3H GAGE. £57 GROW @073 3 15 16 17 18 Reaction 8 Carless and Haywood showed that cyclization of B-allyloxyketones to the 2-alkenyl-3-tetrahydrofuranols proceeded in high yields.27 Irradiation of B-allyloxy-Z-butanone (19) gave the corresponding tetrahydrofuranols (20) in 94% yield, with a 2:3 ratio of 1.4:1 (Reaction 9). Ra F“ C) HMO“ __>hV 3 Ckfls R2 19 20‘ 20! Z:E total yield Rl'Rz'R3'H 1 . 4:1 94% Rl-R3-H, Rz-Me 1 . 65:1 85% Rl-Me, R2'R3-H 0 . 65:1 80% Rl-Rz-H, R3=Me 1 . 5:1 8 8% Reaction 9 Lappin and Zannucci22 also studied the photochemistry of 2- isopropoxy-4-methoxybenzophenone (21). They found that after irradiation in benzene for 7 hours, three products were formed (Reaction 10). The expected 2,2-dimethyl-3-phenyl-2,3-dihydro-3—benzofuranol (22) and 2-hydroxy-4-methoxybenzophenone (23) were formed in 44% and 14% yield, with the unexpected 7-methoxy-2,2-dimethyl-4-phenyl-1,3- benzodioxane (24) formed in 28% yield. The 2-hydroxy-4- methoxybenzophenone was shown to be a photo-cleavage product of benzofuranol 22. Independent irradiation of compound 22 gave only 10 compound 23. Lappin and Zannucci did not postulate a possible mechanism for the formation of 24, but did report that the photoproduct ratio of 22 to 24 remained constant throughout a wide range of ketone 21 concentrations, thereby ruling out a bimolecular reaction. ’LO 0 oyo cuao Reaction 10 Internal clock reactions can be used to obtain rates of studied reactions relative to that of the known clock reactions. The secondary l-cyclopropylethyl radical has been calculated to open with a high rate constant28 (k-2x107 3‘1) 8 25°C (Reaction 11). The l-cyclopropylethyl radical can therefore be used as an "internal clock" to directly measure rates of reactions which generate an alkyl cyclopropyl radical as an intermediate. Therefore, in experiments where the secondary cyclopropylethyl radical is generated, the reaction mixture can be analyzed either for the unrearranged cyclopropyl moiety or for the distinct rearrangement of the cyclopropyl moiety. Then it is possible to determine the relative lifetime of the biradical produced as compared to the known rate for rearrangement of the secondary cyclopropylethyl radical. isomerization >1. » AA Reaction 11 Carlson looked at the photochemistry of 2-cyclopropyl- cyclohexanone (25), which upon irradiation gave type I cleavage adjacent to the carbonyl.29 This biradical rearranged to give the expanded cyclononenone 26 in 73% yield, and the acyclic aldehyde 27 in 21% yield (Reaction 12). In this reaction, Carlson took advantage of 11 the reaction rates for the decay of the biradical by the two competing product decay pathways. From the product distribution, the rate constant for biradical disproportionation to the aldehyde 27 must be lower than the rate constant for the rearrangement of the cyclopropyl methyl radical. UL. UL Mic» 62> cis trans H 3 27 Reaction 12 Carlson then attempted a six carbon ring expansion by opening two cyclopropylmethyl radicals in tandem.30 Irradiation of a dilute solution of 2-(2-cyclopropylcyclopropyl)cyclohexanone (28) in iso- octane to 80% conversion followed by catalytic hydrogenation gave 61% cyclododecanone (29), 20% 2-cyclopropylcyclononanone (30), and 19% of the starting ketone 28. .Experimental results suggested that the reaction proceeded primarily through a single photon mechanism, with a small amount of the cyclododecanone coming from the secondary photocleavage and expansion of the cyclononenone 30 (Reaction 13). M M we”... 2.H2 30 Reaction 13 12 Wagner, Liu, and Noguchi31 prepared and irradiated y- cyclopropylbutyrophenone (31) in order to look at the behavior of the biradical formed. They wanted to determine if the biradical underwent typical mono-radical rearrangements. The ketone 31 was irradiated in benzene at 313 nm and produced three photoproducts (Reaction 14). The products were characterized to be acetophenone (32), l-pheny1-4-hepten- l-one (33), and 1-phenyl-4-cycloheptenol (34). The isolation of the rearranged products showed that during the typical 1,4-biradical lifetime (30 ns in benzene32), there was adequate time for the cyclopropyl methyl radical to open and isomerize. 0 OH OH I - 0 WV I Wearrange w —" ©)\ 31 l \ 32 Ph Chi () W 34 33 Reaction 14 The photocyclization reaction arising from.8-hydrogen abstraction has been utilized by Kraus33'34 towards the synthesis of natural products. Kraus and Chen found that irradiation of a benzene solution of ketone 35 gave paulowin (36) in 68% yield (Reaction 15). After chromatographic separation of the photosolution, compound 36 was found to be the only product formed. Ar CY’ (3 Ar Hbo m ”go“ N- 00) ----ID- (3 N 0 benzene N 0 35 36 Reaction 15 13 In this thesis the bulk of the stereochemical data was derived from.relative positions of signals in the 1H NMR. Previous workers have carefully studied the 1H NMR spectra of diastereotopic mixtures of substituted 2,3-dihydro-3-benzofuranols. Pappas3s has reported the 1H NMR chemical shift values for both diastereomers of 3-methy1-2-phenyl- 2,3-dihydrobenzofuran. The isomer in which the methyl and the phenyl substituents were cis gave a methyl signal at 50.74, whereas the trans isomer gave a methyl signal at 51.37. Lewis and Hilliard17 reported similar trends for the diastereomers of 2-methy1-1-phenylcyclobutanols. The isomer in which the phenyl and methyl substituents are trans gave a methyl signal at 51.10, whereas the cis isomer gave a methyl signal at 50.60. CH3 ”EH3 -cu3 80.74 -cn3 81.37 CH Ph Lewis17 9,, Q Ph ‘5 OH ‘c... c... -ca3 50.60 -CH: 51.10 Meador:36 O P" 0 Ph CH3 OH OH CHa -CI'13 51.10 ‘CH3 51.70 -H 85.52. -H 85.30 Wagner24 @0ch GLOFCHS Ph 0“ Meador Chi Ph 5 Park Figure 4 Stereochemical Determdnations Using 1H NMR Meador36'24 has reported the chemical shifts for the 3-methyl-2- phenyl—Z,3-dihydro-3-benzofuranols. The 2 isomer (hydroxy and phenyl are cis) gave the following signals, methine 55.3, methyl 51.7, and 14 hydroxy 51.5. The E isomer gave the following signals, methine 55.5, methyl 51.1, and hydroxy 52.5. Wagner, Meador, and Park24 also recently reported the stereochemical relationship between the z and E isomers of 2-methy1-3- phenyl-2,3-dihydro-3-benzofuranol. The z isomer gave the following signals, methyl 51.30 and methine 54.44, while the E isomer gave the following signals, methyl 50.81 and methine 54.58. The stereochemical assignments of the 2,3-dihydro-3-benzofuranols studied were based on these examples (See Figure 4). The trend seen was that the C-2 substituents aliphatic protons that were adjacent and cis to the C-3 phenyl ring were upfield compared to the C-2 substituents that are trans to the C-3 phenyl ring. Research Goals There were several goals envisioned at the onset of the work for this thesis. Previous workers had determined reactivities of the methyl, benzyl and ethyl groups towards 5-hydrogen abstraction in o- alkoxybenzophenones. This work was intended to fill in the gaps left by the isopropyl and the allyl groups, in completing a list of hydrogen atom reactivities in a variety of environments. The second goal was to determine the effects of solvent polarity and Lewis basicity on the stereochemistry of the photoproducts. A third goal was to determine a rate of bond rotation of 1,5- biradicals formed, immediately following 5-hydrogen abstraction of o- alkoxybenzophenones, by the triplet excited state of the ketone. The cyclopropyl methyl radical was chosen to study this rate because the new products formed by rearrangement of the radical species could easily be identified by 1H NMR. This study quickly gave a lower value for the biradical lifetimes. And finally, during the course of the experimental work for this thesis, a mechanistic puzzle, left unsolved by others, was undertaken. Lappin and Zannucci unexpectedly found 7-methoxy-2,2-dimethyl—4-phenyl- 1,3-benzodioxane (24) in the reaction mixture after irradiation of ketone 21. The mechanism for this odd product formation was probed and solved during the course of the work for this thesis. Results A. General Preparation of Retones The ketones used were prepared by o-alkylation at the phenolic oxygen of o-hydroxybenzophenone. The best yields of o- alkoxybenzophenones were generally prepared by creating the phenoxide in acetone using anhydrous potassium carbonate followed by addition of the alkyl halide to the reaction mixture. These reactions typically required heating at reflux temperatures for 24-96 hours to get yields up to 75%. B . Identification of Photoproducts Degassed 0.01 to 0.02 M benzene solutions of o-alkoxybenzophenones were irradiated using a medium pressure Hanovia mercury lamp fitted with a pyrex sleeve (hv>290 nm) giving the corresponding 2 and E-2,3-dihydro- 3-phenyl-3-benzofuranols as the major products (Figure 5). Structural assignments were made from.the following spectroscopic data (1H NMR, 13C NMR, IR, and mass Spectrum). After irradiation of ketones 37-44 the photoproducts were separated using column chromatography with the eluent being solutions of hexane/ethyl acetate. Photoproducts from ketone 44 were separated using preparative TLC with a 60:40 mixture of CH2C12/2,2,5-trimethylhexane as solvent. 1H NMR proved to be the most valuable in assigning the stereochemistries of the substituted dihydrobenzofuranol photoproducts. 1H NMR assignments were made from irradiations in benzene-d5 directly. Representative 18 NMR spectra are shown in figures 9-28. It should be noted that the signal at 50.50 in all spectra prior to irradiation is due to an impurity in the benzene-d5. 1. o-(a-Methylbenzyloxy)benzophenone (37): .A benzene-d5 solution of o-(a-methylbenzyloxy)benzophenone was degassed and irradiated at >290 nm with complete conversion to 2-methyl-2,3-diphenyl- 2,3-dihydro-3-benzofuranol (38), as monitored by 1H NMR. The z to E ratio for photoproduct 38 was determined in both benzene-d6 and 15 16 methanol-d4 by integration of the 1H NMR spectrum. After irradiation in benzene-d5 (see Figure 10), the signal at 51.25 was assigned to the E isomer because it is positioned farthest upfield, corresponding to the isomer with the methyl group in a cis relationship to the C-3 phenyl group. The signal at 51.87 was assigned to the z isomer, corresponding to the isomer with the methyl group in a trans relationship to the C-3 phenyl group. The integration was performed by comparing the areas of the methyl signals at 51.87 and 51.25 giving a z to E ratio of 7:1. The signals at 56.10, 54.80, and 54.25 were assigned to the enol ether 39. The singlet at 56.10 was assigned to the benzhydryl proton that is benzylic to both aromatic rings. The upfield doublet at 54.25 was assigned to the olefinic proton that is cis to the phenyl group due to it being in the deshielding region of the aromatic ring. The downfield doublet at 54.80 was assigned to the olefinic proton cis to the ether oxygen due to it being in the shielding region of the oxygen. 2. o-lthoxybenzophenone (40): A benzene-d5 solution of o- ethoxybenzophenone was degassed and irradiated at >290 nm with complete conversion to 2-methyl-3-phenyl-2,3-dihydro-3-benzofuranol (41), as monitored by 1H NMR. The 2 to E ratio for photoproduct 41 was determined in benzene-d5 and methanol-d4 by integration of the 1H NMR spectrum as well as by HPLC analysis. After irradiation in benzene-d5 (see Figure 12), the signals at 50.81 and 54.61 were assigned to the E isomer. The singlet at 50.81 is due to the methyl group being in a cis relationship to the C-3 phenyl group. The signal at 54.61 was assigned to the proton at C-2 which is in a cis, shielding relationship to the oxygen at C-3. The signal at 51.3 was assigned to the methyl group being in a trans relationship to the C-3 phenyl group, and the signal at 54.55 was assigned to the proton at C-2 which is in the deshielding region of the C-3 phenyl group. The integration was performed by comparing the areas of the methyl signals at 51.3 and 50.80 giving a Z to E ratio of 11:1. 3. o-Allyloxybenzophenone (8): A benzene-d5 solution of o- allyloxybenzophenone was degassed and irradiated at >290 nm with complete conversion to 3-phenyl-2-vinyl-2,3-dihydro-3-benzofuranol (9), 17 as monitored by 1H NMR (see Figure 14). The 2 to E ratio could not be determined by 1H NMR due to overlapping signals. The signal at 56.05 was assigned to the single proton of the vinyl group, and the signal at 55.20 was assigned to the terminal protons of the vinyl group, and the signal at 54.85 was assigned to the proton at C-2. The 2 to E ratio was determined by using HPLC analysis. The larger of the two new peaks, appearing after irradiation in benzene, on the HPLC trace was assigned to the z isomer. The 2 to E ratio was determined to be 5:1 from the areas of these two new peaks. 4. o-(Cyclopropylmethoxy)benzophenone (42): A benzene-d5 solution of o-(cyclopropylmethoxy)benzophenone was degassed and irradiated at >290 nm with complete conversion to 2-cyclopropyl-3- phenyl-2,3-dihydro-3-benzofuranol (43), as monitored by 1H NMR. The 2 to E ratio for the photoproduct 43 was determined in benzene-d5 and methanol-d4 by integration of the 1H NMR spectrum. After irradiation in benzene-d5 (see Figure 17) the signal at 53.75 was assigned to the proton at C-2 of the z isomer because it is in the deshielding region of the phenyl group at C-3. The signal at 53.9 was assigned to the proton at C-2 of the E isomer because it is in the shielding region of the oxygen at C-3 causing the signal to be downfield of the z isomer. The integration was performed by comparing the areas of the methine signals at 53.9 and 53.7 giving a z to E ratio of 12:1. Also visible were a few signals at 5 3.2, 5 3.4 and 5 4.8. These signals were not assigned, but were most likely due to a compound derived from the opening of the cyclopropyl group. These signals made up approximately 5% of the reaction mixture. 5. o-Ieopropoxybenzophenone (44): A benzene-d5 solution of o- isopropoxybenzophenone was degassed and irradiated at >290 mm with complete conversion to 2,2-dimethy1-3-phenyl-3-benzofuranol (45) and o- (2-propenyl)benzhydrol (47), as monitored by 1H NMR. The signals at 5 0.8 and 51.5 were assigned to the methyl groups of the 2,2-dimethyl-3- phenyl-2,3-dihydro-3-benzofuranol (45) (see Figure 19). The signal at 51.7 was assigned to the methyl group of the 2-propenyl moiety. The signals at 53.96 and 53.94 were assigned to the protons of the terminal 18 olefin of the 2-propenyl moiety. Inspection of the magnified region of the spectrum revealed that the signal at 53.96 is a doublet of quartets while the signal at 53.94 is a broad doublet. The signal at 53.96 was assigned to the proton trans to the methyl group due to the stronger coupling which is apparent by the finer structure. Therefore, the signal at 53.94 was assigned to the olefin proton which is cis to the methyl group. Also present is the signal at 56.1 which was assigned to the aliphatic proton which is benzylic to both benzene rings. Upon addition of a catalytic amount of 2-naphtha1enesulfonic acid the signals from the 2-propenyl moiety disappeared (see Figure 20). Signals appeared at 55.75, 51.60, and 51.39 which were assigned to 2,2- dimethy144-phenyl-1,3-benzodioxane (45). The singlet at 55.75 was assigned to the benzhydryl proton and the signals at 51.60 and 51.39 were assigned to the new methyl groups of the benzodioxane. Separation of these products by preparative TLC (see Experimental) and 1H NMR analysis in CDC13 allowed for direct comparison to previous work. The spectrum of the benzofuranol 45 and benzodioxane 46 both matched those obtained by Lappin and Zannucci.22 The product ratio of the benzofuranol 45 to the benzodioxane 46 was detemmined by integration of the 1H NMR spectrum, comparing the areas of the methyl group of the benzofuranol 42 at 50.80 and the methyl group of the benzodioxane 46 at 81.39. 6. o-(Isopropoxy-2d1)benzophenone (44-d1): A benzene-d5 solution of o-(isopropoxy-Z-dl)benzophenone was degassed and irradiated at >290 nm with complete conversion to 2,2-dimethyl-3-phenyl-3- benzofuranol (45-OD) and o-(2-propenyloxy)benzhydrol (47-OD) as monitored by 1H NMR. After irradiation in benzene-d6 the 1H NMR spectrum.(see Figure 22) was identical to that of the non-deuterated ketone 44 (see Figure 19). Upon addition of a catalytic amount of 2- naphthalenesulfonic acid the signals from the 2-propeny1 moiety disappeared (see Figure 23). The new signals that appeared identically matched those of the non-deuterated compounds in Figure 22. 7. o-(Isopropoxy-1,1,1,3,3,3-d‘)benzophenone (44—d5): A benzene-d6 solution of o-(isopropoxy-l,1,1,3,3,3-d5)benzophenone was l9 degassed and irradiated at >290 nm with complete consumption of the ketone as monitored by 18 NMR. Analysis of the 1H NMR spectrum showed no signals at 56.10 which corresponded to the aliphatic proton benzylic to both benzene rings, therefore, a deuterium atom.must have occupied this position (see Figure 25). Upon addition of a catalytic amount of 2-naphthalenesulfonic acid two broad signals appeared at 51.3 and 51.6 (see Figure 26). These signals were assigned to the methyl groups of the benzodioxane. Also visible in the 1H NMR spectrum are two signals from the methyl groups of the benzofuranol. The product ratio of benzofuranol 45-d5 to benzodioxane 46-d5 was determined by G.C. analysis to be 3:1. This was performed by irradiating the ketone 44-d5 to 16% conversion, adding a catalytic amount of 2-naphthalenesulfonic acid, and waiting approximately 1 hour before injecting the sample into the G.C. The areas were normalized by using the standardization factors in the appendix, and the product ratio was determined. A benzene-d5 solution of 44-d5 and anisole was degassed and irradiated at >290 nm with complete consumption of the ketone as 'monitored by 1H NMR. The anisole was used as an internal standard to determine the percentage of hydrogen atoms each signal contained. The benzene-d5 solution prior to irradiation had 10% of one hydrogen atom present as impurity in the region between 50.85 and 50.65 as determined by 1H NMR (see Figure 27). The impurity of ketone 44-d5 was also determined by mass spectrum to be 16% of one hydrogen atom. After irradiation and addition of a catalytic amount of 2-naphthalenesulfonic acid, all signals in the region between 50.5 and 52.2 were integrated and normalized to the integration values prior to irradiation (see Figure 28). It was found that the 10% of one hydrogen atom could be found in the methyl group signals at 51.5 and 50.8 corresponding to the benzofuranol 45-dg. The majority of the proton signal from the starting ketone was incorporated in the broad hydroxyl signal spanning from.5l.6 to 52.2. The signals assigned to the methyl groups of the 1,3-benzodioxane at 51.6 and 51.4 incorporated roughly 14% of one hydrogen atom. This amounted to 43% of the expected hydrogen atom 20 Ph Ph Ph Ph )‘CH CH3 CH )= C) C) 3 ‘3 (”1 C) CW1 C) (3H hv>290 nm Ph pyrex filter ’ PD 37 383 38! 39 /~\ 0 O O OH O OH hv>290 run > Ph Ph pyrex filter 40 412 413 J H _ o o 0 0H 0 OH hv>290 nm , Ph Ph pyrex filter 3 92 91 H o o’\V 0 OH 0 OH hv>290 nm ’ Ph Ph ‘ * pyrex filter 42 438 43! 00A °i‘°“ a. 9:. hv>290 nm. , / m pyrex filter.- Ph 45 46 47 44 Figure 5 Ketones Studied and Their Corresponding Photoproducts 21 incorporation, with the assumption that the 1,3-benzodioxane was formed as 1/3 of the total products from the starting ketone. C. Solvent Effects on Stereochemistry of Photoproducts The o-alkoxybenzophenones 8, 37, 40, and 44 were degassed and irradiated in solvents of different polarities and Lewis base properties. The 2 to E ratios of the substituted 3-phenyl-2,3-dihydro- 3-benzofuranols generally decreased both with solvents of increasing polarity and increasing Lewis base character.2°'23v24'36 These trends are reported in Table 1. D. Solvent Effects on Product Distributions The choice of solvent for irradiation of ketones 8, 37, 40, 42, and 44 influenced the products obtained. Irradiations performed in benzene-d5 tended to give the cleanest photoreactions, i.e. there were few, if any, side products other than substituted 2,3-dihydro-3-benzofuranols formed. Irradiations done in methanol-d4«generally gave the largest ampunt of side products. The ratio for the formation of photoproducts 45 and 46 from ketone 44 varied significantly frdm non-polar, non-Lewis basic solvents such as benzene-dg‘to highly polar, Lewis basic solvents such as methanol-d4. These solvent effects are summarized in Table 1. E. Spectroscopy A. Phosphorescence Spectra: Spectra for the ketones studied were recorded at 77°K in a 2-methyltetrahydrofuran solvent glass. The triplet energies were calculated from the highest energy (0,0) band and are reported in Table 2. B. Ultraviolet-Visible Absorption Spectra: The ultraviolet- visible absorption spectra for the ketones studied were recorded in n- heptane and benzene. The wavelength of the absorption maxima and the respective extinction coefficients are summarized in Table 3. 22 F . Kinetic Results Triplet lifetimes of the ketones studied were measured by Stern- Volmer quenching.37 In these studies, a conjugated diene, 2,5-dimethyl- 2,4-hexadiene or naphthalene, was used to quench the triplet excited state by energy transfer. A mathematical relationship holds for the ratio of photoproduct produced with and without quencher present and the concentration of the quencher used. The relationship is shown in Equation 1. ¢°/ oe.~a map mo. mum oe.~ azm am. «pm il 3.: 8.02 was: oumzuuom mceuom moo: coaumaaaacez .o.~e Amaozom 25 I . 13 nor Studies An 1H NOE experiment was performed on the photoproduct 46. Irradiation of the benzhydryl proton at 55.75 showed a 6% enhancement at the methyl signal at 51.4, with no enhancement for the methyl signal at 51.6. The reverse irradiations gave the same relative enhancements. Irradiation of the methyl signal at 51.4 gave an enhancement of 6% at the benzhydryl signal, while irradiation of the methyl signal at 51.6 showed no enhancement of the benzhydryl signal. This experiment confirmed that the methyl group responsible for the signal at 51.6 was at a greater distance to the benzhydryl proton than was the methyl group giving the signal at 51.4. Therefore, the signal at 51.4 was from the methyl group in the axial position, and the signal at 51.6 was due to the methyl group in the equatorial position. Batons o-Methoxy benzophenone o-(a-Me-benzyloxy) benzophenone(37) o-Ethoxy benzophenone(40) o-Allyloxy benzophenone(8) o-(Cyclopropyl methyloxy) benzophenone(42) o-Isopropoxy benzophenone(44) o-(Isopropoxy-dg) benzophenone(44-d5) 3 Analysis performed by HPLC with a Si column, flow 1.0 mL/min. 26 Table 1 Solvent Effects on Photoproducts: Salient Benzene Methanol Benzene Methanol Benzene Methanol MeCN t-Butanol Benzene Methanol MeCN t-Butanol Dioxane Benzene Methanol Benzene Methanol MeCN t-Butanol Dioxane Benzene Productsc _ziE srd many products BF/BDe 7:1 BF/BD 8:13 BF 11:1b' BF/many others 6:4b* BF 3:1b BF 5:6a BF 5:1a BF 4:5a BF 1:1a BF 1:2a BF 9:7a BF 12:1b BF 1:1b aF/BD/o-OHBZPf BF/BD BF/BD/o-OHBZP BF/o-OHBZP BF BF/BD/O-OHBZP 95.5:4.5 hexanes:EtOAc, UV detector 270 nm. eD’QHQQOU measured by Mr. B.S. Park. z:E ratio determined by integration of 1H NMR spectra. products found after complete conversion of starting ketone. formation of the corresponding 2,3-dihydrobenzofuranol. formation of 2,2-dimethyl-4-phenyl-l,3-benzodioxane. formation of o-hydroxybenzophenone. product ratio determined by integration of 1H NMR product ratio determined by G.C. MUN 10:1a 1:1a 5:4a BF/BDg 1 1 1 :1h 27 Table 2 Triplet Energies of o-Alkoxybenzophenones in 2-Me-THF at 77°Ka: Seton: 10,0 E 0,0 nm kcal/mole o-Methoxybenzophenone 418.8 68.3 o-(a-Methylbenzyloxy)benzophenone(37) 416.8 68.6 o-Ethoxybenzophenone(40) 418.8 68.3 o-Allyloxybenzophenone(8) 417.6 68.5 o-Cyclopropylmethoxybenzophenone(42) 418.8 68.3 o-Isopropoxybenzophenone(44) 418.8 68.3 Benzophenone7b 417 68.6 aexcitation 320 nm, scan 360-510 nm, scan rate 120 nm/min conversion factor 2.85915x104 kcal-nm/mole 28 Table 3 Ultraviolet-Visible Absorption Maxima: Eetone o-Methyloxy benzophenone o-(aeMe-benzyloxy) benzophenone(37) o-Ethoxy benzophenone(40) o-Allyloxy benzophenone(8) o-(Cyclopropyl methyloxy) benzophenone(42) o-Isopropoxy benzophenone(44) Benzophenone7b Valerophenone salient Heptane Benzene Heptane Heptane Benzene Heptane Benzene Heptane Heptane Benzene Heptane Heptane Benzene AmaLian‘ n:1r.:.band We 245(14093) 245(17419) 245(14475) 245(13233) 245(13769) 244(13509) 254(17000) 341.5(241) 340.0(158) 343.0(161) 344.0(159) 343.0(240) 343.0(141) 321.5(57.6) 318(49.5) 333(899), 366(79) 366(88) 313(1223), 281(4818) 366(81) 313(1277),366(78), 285(3424) 366(80) 313(1039),366(90), 282(2943) 366(100) 313(1267),366(111) 285(3163) 313(1200),396(72), 284(2880) 366(86) 313(50), 366(70) 313(57.9),366(5.9) 313(49.1),366(6.3) 6Values in parentheses are molar extinction coefficients. 29 Table 4 Quenching Studies and kqt‘Values of o-Alkoxybenzophenones: o-Methoxy Benzene 25801230 0.30 benzophenone“ o-Benzyloxy“ Benzene 100 0.94 benzophenone o-Ethoxy Benzene 564b 0.62b benzophenone(40) MeOH 0.29 MeCN 1135 0.43 o-Alloxy Benzene 458 0.57 benzophenone(8) MeOH 938 0.28 o-Isopropoxy Benzene 127 0.42 benzophenone(44) MeOH 0.71 MeCN 0.29 o-(Isopropoxy-Zdl) Benzene 478 0.56 benzophenone(44-2d1) o-(Isopropoxy-dg) Benzene 0.57 benzophenone(44-d5) “Measured by Dr. M. Meador. bMeasured by Mr. B.S. Park. Discussion A. Solvent Effects on Stereochemistry The photolysis of benzene solutions of ketones 8, 37, 40, and 42 produces the Z isomer preferentially over the E isomer of the corresponding substituted benzofuranol. The effect of Lewis basic and polar solvents lowers the z to E ratio to near unity. This decrease in stereospecificty is due to the solvent complexation with the hydroxyl function of the biradical, thereby increasing the size of the hydroxyl group and decreasing the difference in size between the phenyl and hydroxyl substituents (see Reaction 16). These effects of added Lewis Sol-.. R “1...“... .. Reaction 16 basic solvents have been previously noted by a few groups.22'23'24'3°'4° B. Solvent Effects on Quantum Yield As previously mentioned, the addition of weak Lewis bases to irradiation solutions creates a solvated biradical. The solvation of the hydroxyl group not only increases bulk but also hinders the possibility of back hydrogen abstraction. The quantum yields for the formation of 2-alkyl-2,3-dihydro-3-benzofuranols from the o- alkoxybenzophenones 8 and 40 decreases in polar and Lewis basic solvents similarly to the results seen by Wagner“!36 and Lappin.22 Oddly though, the quantum yield for formation of 2,2-dimethyl-2,3- dihydro-3-benzofuranol (45) from o-isopropoxybenzophenone (44) increases in going from non-polar, non-Lewis basic solvents such as benzene to polar, Lewis basic solvents such as methanol and acetonitrile. The changes in quantum yields for ketones 8, 40, and 44 are accompanied by the appearance of new photoproducts which could not 30 31 be isolated. The increase in cyclization efficiency to 2,2-dimethyl-3- phenyl-2,3-dihydro-3-benzofuranol (45) from o-isopropoxybenzophenone (44) is the result of blocking one of two competing product forming pathways from the biradical. The effect of the polar and Lewis basic solvents hinders the formation of the o-(2-propenyl)benzhydrol (47) thereby allowing more of the 1,5-biradicals to form 2,2-dimethyl-3- phenyl-2,3-dihydro-3-benzofuranol (45). C. Lifetimes of Triplet Excited States and 1,5-Biradicals The rate constant for the cyclization of the 1,5-biradical has not been directly measured. Using the l-cyclopropylethyl radical as an internal clock,28 the lower value for the rate of aryl-carbon bond rotation and cyclization can be measured. Since the cyclopropyl group remains mostly intact during and throughout the irradiation of o- cyclopropylmethoxybenzophenone in benzene-d6 and methanol-d4, the rate for bond rotation, spin inversion from the triplet biradical to the singlet biradical, and finally, ring closure must be on the order of 4x108 sec'l. The rate value was estimated from the assumption of a 2x107 sec“1 opening of the 1-cyclopropylethyl radical,28 an oxygen was attached to the same carbon atom that the radical was produced, assuming a maximum of 5% of the ring opened product. The irradiation of o-allyloxybenzophenone (8) gave only one product as a mixture of diastereomers. These E and z isomers of 3- phenyl-2-vinyl-2,3-dihydro-3-benzofuranol come directly from the coupling on the hemipinacol radical and the secondary allylic radical. There was no production of the seven member ring that would occur from the rearrangement of the allylic radical. There are several possible explanations for this preference. It is possible that the secondary radical is formed and immediately goes on to cyclization products, but this is unlikely due the rapid delocalization of the radical throughout the pi system. The product ratio suggests that the equilibrium between the secondary and primary sites of the allylic radical favors the former, most likely due to the stabilization of the oxygen adjacent to the secondary radical and the inherent stability of secondary over primary radicals. Another important influence on the products is the 32 thermodynamic preference for formation of five member rings over seven member rings. One or more of these factors combine to allow for only the formation of the five member benzofuranol. D. Reactivity of the Triplet Excited State Towards Hydrogen Abstraction The reactivity of the C-H bond broken during the hydrogen abstraction is controlled by two factors, the inductive electronic contribution by substituents attached to the same carbon atom which the abstracted hydrogen is attached and the molecular conformation which is required for abstraction to occur. Wagner has shown that the electronic inductive contribution is not a major factor in the reactivity of the C- H bond toward abstraction.24 Careful examination of the kqt values (1/1 = kg, kn - the rate of hydrogen abstraction) for ketones 8, 13, 40, 44, and 48 show a trend of normal reactivity except that ketone 8 is not as reactive as might be expected: O-CH2C586> O-CH(CH3)2> O-CHZCH2CH2> O- CHZCH3> O-CH3. Previous work by Wagner41 has shown that the allyl hydrogens are nearly as reactive as the tertiary hydrogen of the isopropyl group towards intramolecular hydrogen abstraction by the 3n-n* excited phenyl ketones, compare ketones 49 to 53. The lower reactivity of ketone 8 is not due to electronic factors since the same electronic environment is found in ketone 52 which has the expected reactivity as compared to ketone 51. Therefore the lowering in reactivity must be due to conformational factors. The o-alkoxybenzophenones can equilibrate between four conformations which Wagner24 has designated, anti-anti', anti-syn', syn-anti', and syn-syn', with anti and syn referring to rotation about the benzene-ether oxygen bond, and anti’ and syn' referring to rotation about the benzoyl-benzene bond (see Figure 8 ). 33 Table 5 Reactivities of C-H Bonds Toward Intramolecular y and 5—Hydrogen Abstraction by Triplet Excited Benzophenone Ph 0 3"! 0 0&H o 0*H o o’QH 0 0'ME W C) C) H C) (3 49 50 51 52 C) Ph m 53 Ketone______kqihfl Ketone____kaihf1 g. 458 .52: 10 13 100 .53. 13 40 564 50 4o 44 121 51. 10 43?, 2580 42; 660 34 R K oo’\n oo anti-syn' syn-syn' 1‘ ll anti-anti' syn-anti' Figure 8 IRotational Conformations of o-Alkoxybenzophenones Wagner24 has carefully examined the factors for the rate depression from acyclic phenyl ketones to o-alkoxyphenyl ketones and suggested that the major source of rate depression is due to the low equilibrium of the syn conformation in the triplet excited state of the ketone. In the comparison between ketones 8 and 44, the lowered reactivity of ketone 8 versus 44 must be either related to the rotational equilibrium about the benzene-ether oxygen bond, or to the steric differences between the allyloxy and isopropoxy groups. The steric argument immediately draws question due to the fact that the benzyloxy group of ketone 13 does not retard the rate of hydrogen abstraction relative to ketone 40, compared to the substituted butyrophenones 53 and 50. Molecular mechanics reveals that the difference between the anti-syn' and syn-syn' for ketones 8 and 44 are 2.8 and 2.4 kcal/mole respectively. The lowest energy conformation of ketone 8 places the pi system of the allyl group orthoganal to the abstracted hydrogen atom. This orthoganal geometry would lead to little stabilization of the developing radical by the pi system of the allyl group, although it is important to note that the barrier to rotation about the a-carbon-CH-CHZ bond is no more than 1.4 kcal/mole, therefore_rotation about the bond in question could occur 35 immediately upon the development of the radical. Also noteworthy is the 94° angle from which the triplet ketone must abstract the hydrogen atom in ketone 8, this is far from the 0° angle preferred for hydrogen atom abstraction, which would result in minimal overlap of the oxygen and hydrogen orbitals. In summary the depression from the expected kqt value for ketone 8 could be due to one or both of the following factors: the development of the radical in an orthoganal orbital in relation to the pi system of the allyl group, but the barrier for rotation about the a-carbon-CH3CH2 bond is very small and could negate the lack of pi interaction. And also, the angle for hydrogen abstraction is nearly orthoganal between the ketone oxygen and the abstracted hydrogen creating poor orbital overlap which is unfavorable for hydrogen abstraction. The deuterium isotope effect for 5-hydrogen abstraction was analyzed in the irradiation of a benzene solution of o-(isopropoxy- 2d1)benzophenone (41-d1) resulting in a kg: value of 475, compared to the kqx of 127 for the hydrogen containing ketone 44. This corresponds to a deuterium isotope effect of 3.7; therefore, the rate determining step in the formation of the benzofuranol is the abstraction of the proton in the formation of the biradical. E. Mechanistic Discussion on the Formation of 2,2- Dimethy1-4-pheny1-1, 3-benzodioxane from the Irradiation of o-Isopropoxybenzophenone The formation of 2,2-dimethyl-4-phenyl-1,3-benzodioxane (46) from o-isopropoxybenzophenone (44) has been determined to be a two step process as postulated by Wagner24'42 (Scheme I). The first step is the photochemical formation of the 1,5-biradica1 followed by disproportionation giving the o-(2-propenyloxy)benzhydrol (47). The second step is an acid catalyzed addition of the benzhydrol hydroxyl moiety to the enol olefin. The formation of the enol from the biradical is the key step in the conversion to the benzodioxane. At the biradical stage the molecule can cyclize to form the benzofuranol or undergo disproportionation to give the enol. 36 abeqe 6634-535. 45 Scheme I The enol formation is very solvent dependent as can be seen from the quantum yield for benzofuranol formation (Chg) and examination of the product ratio of benzofuranol to benzodioxane (BF/BD) (see Tables 1&4). In benzene, the quantum yield $31:- is 0.42 with the product ratio (BF/ED) being 2:1, while irradiation in methanol produces a 45; of 0.72 and the (BF/BD) increases to 5:1. In all the other o-alkoxybenzophenones studied, the ¢BF decreases when irradiation takes place in polar and Lewis basic solvents (see Table 4).22'23I35 This decrease in cyclization efficiency to the benzofuranol is most likely due to the generation of new photoproducts. In the case of ketone 44, the increase in cyclization efficiency to 45 must be due to the decrease in the efficiency of the biradical forming the enol 47, thereby forming less enol and allowing a larger percentage of the biradicals to cyclize to the benzofuranol. The role of the Lewis basic solvent is not entirely clear. The Lewis basic solvent most likely bonds to the hydroxyl moiety creating steric hindrance which affects the required geometry for the hydrogen atom to transfer in the disproportionation step. This hindrance reduces the amount of disproportionation allowing the 1,5- biradical to cyclize to the 2,2-dimethyl-3-phenyl-2,3-dihydro-3— benzofuranol (45). Conclusion There were four major points that were studied in the work for this thesis. Firstly, a table of reactivities for hydrogen atom 37 abstraction by 3n-x* benzophenones was completed by adding the isopropoxy and the allyl groups to the known methyl, ethyl, and benzyl hydrogen groups. The reactivities of the hydrogen atoms towards abstraction by the 3n-n* benzophenones nearly parallels the reactivities of similar abstraction by acyclic phenyl ketones. Secondly, the effects of solvent polarity and Lewis base character towards the stereochemistry of the photoproducts was studied. It was found that in non-polar and non-Lewis basic solvents the Z isomer of the alkyl substituted benzofuranol is formed in preference to the E isomer. As the solvent polarity increases, the z to E ratio of the photoproducts decreases due to complexation of the solvent to the hydroxyl moiety of the 1,5-biradical. When highly Lewis basic solvents were used as solvents, the z to E ratio often drops to nearly 1:1, and in some cases, the z to E ratio lowers to favor the E isomer. Thirdly, the 1,5-biradical lifetime was probed with the use of the cyclopropylmethyl radical as an internal clock. It was found that the cyclopropyl ring underwent minimal if any rearrangement during photolysis of o-(cyclopropylmethoxy)benzophenone (42). This experiment leads to a biradical lifetime of 4x108 sec’1 or 2.5 ns. And lastly, the mechanism for the formation of 2,2-dimethyl-4- phenyl-1,3-benzodioxane 46 from the irradiation of o- isopropoxybenzophenone (44) was elucidated. The first step in the reaction towards formation of the benzodioxane is the disproportionation step in which a hydrogen atom is transferred from one of the two methyl groups of the 1,5-biradical to the carbon atom between the two aromatic rings. Then, the acid catalyzed addition of the hydroxyl moiety of the disproportionation product o-(2-propenyl)benzhydrol (47) to the olefin of the iso-propenyl group gives the benzodioxane 46. The disproportionation step was confirmed in the irradiation of ketone 44-d5 by following the reaction using 1H NMR, specifically looking for the appearance of the signal at 55.75, which is due to the hydroxyl proton of the benzodioxane 46-d5. After irradiation of the ketone 46-d5, no signal was present at the 55.75 position showing that the proton transferred in the disproportionation step is a deuterium atom. Experimental I . Purification of Chemicals A. ‘ Solvents: Benzene: One gallon of thiophene free reagent grade benzene was stirred with 200 mL. portions of conc. sulfuric acid for 12-24 hour periods until the sulfuric acid remained colorless. The benzene and sulfuric acid were separated and the benzene washed, with 400 mL. of distilled water followed by enough saturated aqueous sodium bicarbonate that the aqueous phase remained basic to pHydrion paper. The benzene was separated from the sodium bicarbonate solution, dried over magnesium sulfate, and filtered into a clean, dry 5.0 liter round bottom flask. Phosphorous pentoxide (100 grams) was added to the benzene and the solution was heated at reflux overnight. The benzene was then distilled through a one meter column (packed with stainless steel helices) at a rate of 100 mL. per hour, discarding the first and last 10% of the distillate. Methanol: Spectral grade methanol was refluxed over Magnesium turnings for four hours and then distilled through a 0.5 meter column packed with glass helices, discarding the first and last 10% of the distillate. Hexanes: Reagent grade hexane was stirred over sulfuric acid until the sulfuric acid remained colorless. The hexanes and acid were separated, and the hexanes washed with saturated NaHC03, dHZO, and then dried over M9804. The dried hexanes were distilled through a 0.5 meter column discarding the first and last 10% of the distillate. t-Butyl alcohol: Reagent grade t-butyl alcohol was prepared in the same manner as methanol and stored over 4A.molecular sieves. 1,4-Dioxane: Reagent grade 1,4-dioxane was heated at reflux over sodium metal, under an argon atmosphere, for eight hours and then 38 39 distilled through a 0.5 meter column (packed with glass helices), discarding the first and last 10% of the distillate. B. Internal Standards and Quenchers ethyl benxoate was prepared by Dr. R.J. Truman and used without further purification. n-octyl benxoate was prepared by Dr. R.J. Truman and used without further purification. hexadecane was purchased from Aldrich and was used without further purification. 2,5-dimethy1-2,4-hexadiene was purchased from Aldrich and only the sublimed material at the top of the bottle was used. naphthalene was recrystallized twice from methanol and dried under vacuum. 40 II . Equipment and Procedures A. Photochemical Glassware: .All glassware (volumetric flasks, pipets, test tubes, and syringes) was boiled in an AlconoxG’solution overnight, prepared with distilled water. The glassware was then rinsed with distilled water five times, boiled in distilled water for approximately 3-5 hours, followed by a final rinse and oven dried at 150°C over night. The ampoules used in irradiations were prepared, using the previously cleaned test tubes (13mm x 100mm), by heating with an oxygen- natural gas torch, just below the teflon label, and stretching to a uniform 15 cm. It should be noted that Kimax® and Pyrex® test tubes transmit light differently, so mixing of brands during irradiations will taint results. B. Sample Preparation: Ail solutions were prepared either by directly weighing of the samples into the volumetric flasks or by dilution of stock solutions. Internal standards were weighed directly into the ketone stock solutions. Equal volumes (2.8 mL) of each sample were introduced via syringe into the stretched test tubes. C. Degassing Procedures: A mechanical pump fitted with a diffusion pump was used for all degassing procedures. The filled irradiation tubes were attached snugly to the 00 size one hole rubber stoppers of the degassing cow. The samples were then slowly frozen using a liquid nitrogen bath. When the solutions were completely frozen, they were evacuated to remove oxygen. The samples were then removed from the vacuum and allowed to thaw. This freeze, pump, thaw cycle was repeated three times, and then the tubes were sealed while frozen and under vacuum. D. Irradiation Procedures: To assure equal light absorption, all samples were irradiated in an immersed merry-go—round apparatus, with constant water bath temperature. Actinometer solutions were irradiated concurrently with the ketone samples. The light source was a water cooled Hanovia medium pressure mercury lamp with a chemical filter 41 of 313 nm. The filter was prepared by diluting 0.388 grams of KZCroq and 10.0 grams of K2CO3 up to 1 liter. Preparative scale irradiations were performed in serum capped degassed test tubes using a water cooled Hanovia medium pressure mercury lamp, fitted with a pyrex sleeve (hv>290 nm). It should be noted that if the irradiation is to take place over more that 1-2 hours, the sample should be continuously degassed by bubbling a steady stream of nitrogen or argon through the solution. NMR scale irradiations were performed by dissolving the sample in the appropriate deuterated solvent, capping the NMR tube with a serum cap and bubbling nitrogen or argon through the solution. The sample was then attached to the outside of the water cooled Hanovia medium pressure mercury lamp, fitted with a pyrex sleeve. Again, this method is good only if the irradiation is to take place over less than 1-2 hours. E. Analysis Procedures: Gas chromatograph analysis were performed on either a Varian Aerograph 1430 FID equipped with a Megabore DBl column, or a Varian 3400 FID equipped with a Megabore D8210 column. Integration was performed by either a Hewlett-Packard 3393A or 3392A Integrating Recorder. HPLC analysis was performed using a Beckman 335 Gradient Liquid Chromatograph System and a Perkin-Elmer LC-75 Ultraviolet-Visible Detector with a Dupont 860 Column Compartment. The analysis was performed using a Ranin Si column with a variety of Hexane/Ethyl Acetate ratios. The integration was done by a Hewlett-Packard 6080 Integrating Recorder. The melting point temperatures were taken using a Thomas Hoover capillary melting point apparatus, the temperatures were uncorrected. F. Quantum Yield Analysis: The analysis of the photoproducts was performed at approximately 10% conversion relative to the starting ketone, in order to keep the photoproducts from absorbing a major portion of the irradiation light. The intensity of the light was determined by use of a chemical actinometer. The light intensity (I) was calculated using the following equation: 42 I-[PP]/¢ where <9 is the quantum yield for the actinometer, and [PP] is the concentration of the photoproduct of the actinometer. The actinometer used for all kinetic experiments was 0.1 M valerophenone, which has a quantum yield of 0.33 for the formation of acetophenone.38I41“ In the event that the actinometer and the ketone, under study, do not equally absorb light at a given wavelength, the following equation must be used to calculate the corrected light intensity value (I): I - [PP] (1-10'“) / o (1-10'A°°°) where Ak is the absorbance of the ketone under study, and Aact is the absorbance of the actinometer at the irradiation wavelength. In order to calculate the concentration of the photoproducts, an internal standard must be used. A response factor for each compound analyzed can be determined using the following equation: RF - (AREA STANDARD / AREA PRODUCT) x ([PRODUCT] / [STANDARD]) A table of response factors can be found in the appendix. G . Spectroscopic Measurements : 1H NMR spectra were recorded on the following instruments: Varian T-60, Bruker WM-ZSO Fourier Transform Spectophotometer, Varian Gemini 300 Fourier Transform Spectophotometer, Varian VXR 500 Fourier Transform Spectophotometer, and Varian VXR 300 Fourier Transform Spectophotometer. Ultraviolet-Visible spectra were recorded on a Shimadzu UV—160 Spectrophotometer. Phosphorescence spectra were recorded on a Perkin- Elmer MPF-44A Flourescence Spectrophotometer. IR spectra were recorded on a Nicolet IR/42 Fourier Transform Spectrophotometer with an IBM IR/3OS upgrade unit. Mass spectra were recorded on one of the following instruments: Finnigan 4000 GC/MS, JEOL JMS-HXllO (FAB),and JEOL JMS- AXSOSH (EI) mass spectrometers. Special thanks to Mr. Kenneth Render for operating the Finnigan 4000 GC/MS, and to the staff of the 43 Biochemistry Department for operation of the JEOL JMS-HXllO and the JEOL JMS-AXSOSH instruments. III Retone Synthesis: General information: In the experimental section, distilled water was used exclusively for all washing procedures in product isolations and in preparing all aqueous solutions. In this thesis distilled water will be denoted dHQO. Valerophenone: was prepared by Dr. K. Nahm and used without further purification. o-Eydroxybensophenone: An oven dried, three-neck round bottom flask, fitted with a condenser, was charged with 5.0 grams (25 mmol) of phenylbenzoate. Under an atmosphere of N2, the flask was heated to 185°C, using a heating mantle, then 6.65 grams (50 mmol) of aluminum chloride was carefully added. Upon addition a great amount of HCl was produced, and the temperature rose to 220°C. After heating for 1 hr., the dark solid in the flask was allowed to cool, then dissolved in 4N HCl, and extracted with ether. The organic layer was washed with 10% NaOH, and the aqueous layer was acidified with dilute HCl. The aqueous layer was extracted with ether, the organic layer separated, dried over M9804 and the ether was removed on the rotovap. The remaining liquid was distilled, using no water in the condenser, at 140-145°C 8 2 Torr, giving 2.8 grams of product (56% yield). The 1H NMR matched that of Aldrich o- hydroxybenzophenone. o-(a-Methylbensyloxy)benzophenone (37)43: To an oven dried 100 mL. three-neck round bottom flask containing 50 mL. of CHZClz, 1 gram (5 mmol) of o-hydroxybenzophenone, 1.85 grams (10 mmol) of 1-bromo-1- phenylethane, and 50 mL. of dH20 was added. This was followed by 0.3 grams (7.5 mmol) of NaOH, and 4.8 mL. (10 mmol, MCB) of benzyltrimtheylammonium.hydroxide. The round bottom flask equipped with a condenser was lowered into an ultrasound cleaning bath containing water. The ultrasound was run for 21.5 hrs. The mixture was then 44 separated, and the aqueous layer was extracted with 2x50 mL. of CHZClz. The organic layers were combined and extracted with 100 mL. of 10% NaOH, to remove any unreacted o-hydroxybenzophenone. The organic layer was washed with 100 mL. of dHZO and then dried over Mg304. The solvent was removed on the rotovap, and the product was isolated using flash grade silica gel and a solvent system of 95:5 hexanes/ethyl acetate. The product was recrystallized using hexanes to give 0.7 grams product (2.3 mmol, 23% yield,), mp. 49°C-51.5°C. A Second Procedure (Best Yield): To an oven dried 100 mL. three-neck round bottom flask under an atmosphere of N2, 0.15 grams (1.1 mmol) of KQCO3 was dissolved in 50 mL. of acetone. To this solution, 0.2 grams (1 mmol) of o-hydroxybenzophenone was added and heated at reflux for 6 hrs., then 0.19 grams (1 mmol) of l-bromo-l-phenylethane, dissolved in 5 mL of acetone, was slowly added using a pressure equalizing dropping funnel. The reaction was followed by TLC (90% hexanes / 10% EtOAc) and was completed in 38 hrs. The reaction mixture was poured into 25 mL. of dH20 and then extracted with ether. The layers were separated, and the aqueous layer was extracted three times with 10 mL. of ether. All the ether extractions were combined and washed with 10% NaOH until the o-hydroxybenzophenone was removed, as determined by TLC (90:10 hexanes/ethyl acetate). The ether layer was then washed with 50 mL. of dH20 and dried over Mg804. The ether was removed on the rotovap and the residual oil was recrystallized from.5-7 mL. of hot hexanes giving 0.10 grams of product (0.34 mmol, 33% yield, relative to the bromide), mp. 51.5°C-52.5°C. Spectral Data: IR cm‘l (CDC13): 3067, 3033, 2985, 1674, 1599, 1483, 1449, 1292, 1244. In NMR (300 MHz, Caps): 8 3.05 (dd, J-8.3, 1.33 Hz, 211).- 7.45 (dd, J57.48, 1.65 Hz, 1H); 7.25-7.00 (m, 9H); 6.79 (dt, J57.48, 0.95 Hz, 1H): 6.88 (d, J-8.30 Hz, 1H): 4.95 (q, J-6.32 Hz, 1H): 1.15 (d, J-6.38 Hz, 3H). 13c NMR (75 MHz, CDc13): 8197.1, 155.7, 142.7, 133.5, 132.7, 131.7, 129.8, 129.63, 129.61, 128.5, 128.1, 127.5, 125.4, 120.6, 114.1, 76.8, 23.8. Mass (EI) m/z, (relative intensity): 302(0.36)(M+), 287(0.53), 198(28), 105(100), 77(32). 45 o-Allyloxybenxophenone. (8): To an oven dried, 50 mL. three- neck round bottom flask containing 20 mL. of anhydrous methanol at 0°C, 0.65 grams, (25 mmol) of sodium metal was added, and allowed to stir until the metal had dissolved. To this mixture, 5 grams (25 mmol) of o- hydroxybenzophenone was added, and allowed to stir for 1 hr. To this solution, 3 grams (25 mmol, MCB) of allyl bromide, dissolved in 25 mL. of methanol, was slowly added. The mixture was heated at reflux for 5 hrs. The solvent was then removed on the rotovap, and the residue taken up into ether. The organic layer was washed with enough 10% NaOH to remove all unreacted o-hydroxybenzophenone, as followed by TLC (85:15 hexanes/ethyl acetate). The NaOH washings were extracted with ether and all of the ether portions were combined, dried over M9504, and the ether removed on the rotovap. The resulting liquid was distilled (Kuglerohr apparatus, 1 Torr, 140°C) giving 4.3 grams (18 mmol, 72% yield) of a yellow liquid. Further filtration through silica gel using benzene as a solvent gave the ketone as a colorless liquid. Spectral Data: IR curl (neat): 3050, 3020, 2900, 2850, 1665 (C-O), 1580, 1480, 1300, 1250, 1000, 910. 1H NMR (500 MHz, c605): 87.95 (dd, J58.l9, 1.51 Hz, 23); 7.49 (dd, J57.32, 1.94 Hz, 1H): 7.20 (m, 2H): 7.12 (t, Jh7.96 Hz, 2H); 6.87 (dt, J57.54, 1.08 Hz, 1H); 6.61 (d, J58.18 Hz, 1H): 5.50 (ddt, J54.74, 10.56, 17.24 Hz, 1H): 4.95 (dddt, Jhl.73, 1.73, 10.56, 17.24 Hz, 2H): 4.00 (ddd, J54.74, 1.73, 1.73 Hz, 2H). 13c NMR (75 MHz, CDc13): 8 196.5, 156.4, 138.2, 132.7, 132.4, 131.9, 129.8, 129.6, 128.1, 120.8, 116.8, 112.8, 88.0, 69.0. Mass (FAB) m/z, (relative intensity): 238(100)(M+), 197(10), 154(40), 136(30), 121(20), 105(70), 77(10). o-(Cylopropylmethoxy)benzophenone (42):44 To a single arm 50 mL. pear shaped flask under an atmosphere of N2, 2.57 grams (26.0 mmol) of cuprous cloride and 1.69 grams (26.0 mmol) of freshly washed zinc were added and heated to reflux in 30 mL. of freshly distilled ether for 45 minutes. The zinc used was cleaned immediately before use by stirring in 10% HCl for three minutes. It was then filtered, washed with dH20, washed with acetone, and air dried. To the Zn-Cu couple 0.224 46 grams (1 mmol) of o-allyloxybenzophenone followed by 3.48 grams (1.05 mL. 13.0 mmol, MCB) of methylene iodide were slowly added through a septum by syringe. The mixture was heated at reflux for 19 hrs. and then quenched with saturated aqueous ammonium chloride. The mixture was then extracted with three equivalent portions of ether. The ether extracts were combined and washed three times with equivalent volumes of sat. K2CO3, once with brine, and then dried over MgSO4. The ether was removed on the rotovap and then'recrystallization was attempted using ethanol.. This method generated an inseparable mixture of cyclopropanated product and unreacted olefin. 'This reaction was run with poor conversion to the cyclopropyl compound. This was most likely due to impure Copper(I) Bromide. The impurity was thought to be the Copper(II) species. A Second Procedure (Best Yield): To a 50 mL. round bottom flask, 0.38 grams (1.9 mmol) of o-hydroxybenzophenone was dissolved in 20 mL. of spectral grade acetone. To this flask, 0.28 grams (2.0 mmol) of K2C03 was added, fitted with a condenser, and heated at reflux for 30 minutes under an atmosphere of N2. The solution was allowed to cool to room temperature, and 0.25 grams (1.9 mmol, 0.180 mL., Aldrich) of (bromomethyl)cylopropane was slowly added via syringe. The mixture was again heated at reflux for 72 hours, the solvent removed on the rotovap, and the sludge was taken up into 15 mL. of ether. The ether layer was washed with 30 mL. of dHZO, 75 mL of 10% NaOH, and dried over Mg504. The ether was removed on the rotovap giving 0.32 grams (1.26 mmol, 66% yield) of a yellow-brown oil. Further filtration through silica gel using benzene as a solvent gave the ketone as a colorless liquid. Spectral Data: IR cm.’1 (neat): 3090, 3000, 2910, 2850, 1663 (C=O), 1600, 1590, 1480, 1470, 1310, 1300, 1250, 1010, 950. 1H NMR (300 MHz, CDC13): 56.9-7.8 (m, 9H); 3.72 (d, J56.7 Hz, 2H); 0.86 (m, 1H): 0.32 (m, 2H): 0.00 (m, 2H). in NMR (300 MHz, c556): 87.95 (dd, J-7.25, 1.68 Hz, 214),- 7.51 (dd, J57.26, 1.68 Hz, 1H); 7.20 (m, 2H): 7.14 (dt, J57.26, 1.67 Hz, 2H); 6.75 (dt, J57.59, 1.12 Hz, 1H): 6.60 (d, J58.25 Hz, 1H): 0.70 (m, 1H): 0.15 (m, 2H): -0.10 (m, 2H). Attempts were made to determine the splitting patterns and coupling constants for the cyclopropyl methyl portion of 47 the molecule. The splitting patterns were determined to be 0.70 (ddddt, 1H): 0.15 (dddd, 2H); -0.10 (dddd, 2H). The coupling constants were analyzed manually and by computer using the simulation program.supplied with the software of the Varian VXR system, neither method delivered acceptable coupling constants. 13c NMR (75 MHz, CDC13): 5196.8, 156.8, 138.4, 135.3, 132.5, 131.9, 129.7, 129.5, 128.1, 120.7, 112.8, 72.7, 9.7, 2.7. Mass (EI) m/z, (relative intensity): 252(2)(M+), 234(1), 222(3), 207(5), 197(42), 181(7), 168(2), 147(2), 133(4), 121(25), 115(5), 105(23). 91(19), 77(36), 55(100). o-Isopropoxybenzophenone 044): An oven dried 100 mL. round bottom flask was charged with 50 mL. of methanol, and cooled to 0°C, followed by the addition of 0.6 grams (26 mmol) of sodium metal. After the sodium had dissolved, 5.0 grams (25 mmol) of o-hydroxybenzophenone was slowly added using a pressure equalizing dropping funnel, and heated at reflux for six hours. After allowing the mixture to cool to room temperature, 4.42 grams (26 mmol, 2.54 mL., Aldrich) of 2—iodopropane, dissolved in 10 mL. of methanol, was slowly added using a pressure equalizing dropping funnel. The mixture was heated at reflux for 36 hours. The reaction was cooled to room.temperature and the solvent was removed on the rotovap. The yellow oil was taken up into 150 mL. of ether and washed with 10% NaOH (3x 100 mL). The ether layer was dried over Nazso4 and the ether removed on the rotovap. The oil was distilled (115°C 8 .OlTorr) giving 2.0 grams (8.3 mmol, 33% yield). A Second Procedure (Best Yield): To an oven dried 250 mL. three-necked flask, 3.8 grams (27.5 mmol, CCI) of K2C03 and 125 mL. of reagent grade acetone were added, followed by 5.0 grams (25mmoles) of o- hydroxybenzophenone. The flask was fitted with a condenser and drying tube. The mixture was heated at reflux for 4 hours, at which time, 4.42 grams (30 mmol, 2.54 mL., Aldrich) of 2-iodopropane was added via syringe, while the mixture was still at reflux temperature. The mixture was heated for 96 hours. A solid, other than K2C03, coated the inside of the flask. The solvent was removed, using a rotovap, and the sludge was taken up into 100 mL. of ether and 100 mL. of dHZO. The ether/water 48 suspension was washed with 300 mL. of 10% NaOH, 100 mL.of dHZO, 100 mL. of brine, and dried over Na2C03, and the ether removed on the rotovap. The remaining yellow viscous liquid was distilled (Kuglerohr apparatus, 0.25 Torr, 150°C) giving 3.36 grams (14 mmol, 56% yield). Spectral Data: IR cm'l (neat): 3070, 3010, 2990, 2940, 1663 (C-O), 1600, 1590, 1500, 1480, 1390, 1290, 1250, 1060, 970, 910. In NMR (300 MHz, C605): 8 7.95 (dd, J56.95, 1.65 Hz, 28); 7.50 (dd, J57.37, 1.99 Hz, 1H): 7.20 (m, 2H); 7.14 (dt, J57.07, 1.32 Hz, 2H); 6.87 (dt, 7.49, 0.99 Hz, 1H): 6.65 (d, J58.45 Hz, 1H); 4.10 (septet, J56.05 Hz, 1H); 0.90 (d, Jh6.05 Hz, 6H). 13c NMR (75 MHz, coc13): 8197.2, 155.8, 138.4, 132.6, 131.9, 130.0, 129.9, 129.6, 128.0, 120.4, 113.9, 70.8, 21.6. Mass (FAB) m/z, (relative intensity): 240(100)(M+), 199(80), 181(7), 154(10), 136(10), 121(27), 105(30), 77(7). 2-Deutero-2-iodopropane:45 An oven dried 100 mL. flask was charged with 0.895 grams (21.5 mmol, Norell Chemical Co.) of LiAqu and fitted with a claisen adapter, condenser, and 25 mL. addition funnel. Under an atmosphere of argon, 20 mL. of ether was added with the addition funnel, causing the LiAlD4 to foam slightly. To the LiAlD4 suspension, 5.0 grams (86 mmol, 6.3 mL., J.T. Baker) of acetone, dissolved in 30 mL. of ether, was added dropwise using the addition funnel, maintaining a gentle reflux. At this time the claisen adapter was removed and the solution was heated at reflux for an additional two hours, at which time the solvent was removed on the rotovap. To the dry aluminum.salts, at liquid nitrogen temperature, 20 mL. of dHZO was added and the solids were allowed to warm to room temperature. The aqueous solution of 2-deutero-2-propanol was vacuum.transferred* to another 100 mL. round bottom flask which was treated with 50 mL. (47%, MCB) hydriodic acid.46 The round bottom flask was fitted with a short path distillation apparatus and heated until approximately 20 mL. of liquid had distilled through the apparatus. The bottom organic layer of the distillate was washed with an equal volume of concentrated hydrochloric 49 acid, water, 5% NaHC03, water, and dried over CaClz, yielding 2.67 grams (15.6 mmol, 18% yield, relative to acetone) of product. *The vacuum transfer was performed using a mechanical pump capable of pulling down to 0.05 Torr, and the typical glassware. The hydrated aluminum salts and the receiving flask were cooled to liquid nitrogen temperature, subjected to the vacuum, then closed off from the vacuum. The flask containing the hydrated aluminum salts was allowed to slowly warm to room.temperature (if this flask was warmed too fast the contents bumped violently), while the receiving flask was kept at liquid nitrogen temperature. As the movement of liquids slows, the flask containing the hydrated aluminum salts was again cooled, flushed with argon, and the pumping procedure repeated. At this point ,the flask containing the hydrated aluminum salts can be immersed into warm water to quicken the transfer. The transfer was deemed finished when the aluminum salts appeared flaky dry. Spectral Data: 1H NMR (300 MHz, coc13): 81.88 (t, J=0.95 Hz, 6H). o-(Iaopropoxy-2-d1)benzophenone (ll-d1): To an oven dried 100 mL. three-necked flask, 3.8 grams (27.5 mmol, CCI) of K2C03 and 50 mL. of reagent grade acetone were added. Then 5.0 grams (25 mmol) of o- hydroxybenzophenone was added. The flask was fitted with a condenser and placed under an argon atmosphere. The mixture was heated at reflux for 1 hour, at which time, 2.67 grams (15.6 mmol) of 2-deutero-2- iodopropane, in 10 mL. of acetone was added while the mixture was still at reflux temperature. The mixture was heated at reflux for 72 hours, at which time a solid, other than K¢C03, coated the inside of the flask. The solvent was removed using the rotovap, and the sludge taken up into 100 mL. of ether and 100 mL. of ngO. The ether/water suspension was washed with 300 mL. of 10% NaOH, 100 mL. of dnzo, 100 mL. of brine, and . dried over Na2CO3, and the ether removed on the rotovap. The remaining yellow viscous liquid was distilled (Kuglerohr apparatus, 0.50 Torr, 175°C) giving 2.14 grams (8.9 mmol, 57% yield) of product. 50 Spectral Data: IR curl (neat): 3062, 3033, 2975, 2930, 2178 (c-o), 1665(C=-O), 1600, 1590, 1500, 1480, 1390, 1310, 1260, 1180, 1160, 970, 920. 1H NMR (300 MHz, c506): 87.97 (dd, J-6.93, 1.58 Hz, 2H).- 7.50 (dd, J57.67, 1.90Hz, 1H); 7.20 (m, 2H); 7.12 (dt, J57.41, 1.52 Hz, 2H); 6.85 (dt, Jh6.53, 0.92 Hz, 1H); 6.65 (d, Ji8.27 Hz, 18); 0.89 (s, 6H). 13C NMR (75 MHz, coc13): 8197.4, 155.8, 138.4, 132.6, 131.9, 130.0, 129.7, 129.6, 128.0, 120.4, 113.8, 21.5. The 13c NMR signal for the carbon atom with the deuterium attached, 70.8 (t), does not appear due to the following: the spin number for deuterium is 1 so that the signal is split into a triplet, the C-D bond has a longer T1 than the C-H bond, the magnetic moment for deuterium is only 15% that of hydrogen, and any NOE effect is lost because there is no irradiation of deuterium.47 Mass (FAB) m/z , (relative intensity): 241(100)(M+), 199(100), 181(10), 154(20), 136(15), 121(35), 105(40), 77(10). Mass (81) m/z , (relative intensity): 244(3.28), 243(24.55), 242(84.77), 241(100)(M+), 240(3.66). This corresponds to 96% d1, 4% do. (1,1,1,3,3,3-dg)-2-Iodopropane: .An oven dried 100 mL. flask was charged with 3.27 grams (86 mmol, EM) of LiAlH4 and fitted with a claisen adapter, condenser, and 25 mL. addition funnel. Under an atmosphere of argon, 20 mL. of ether was added with the addition funnel, causing the LiAlH4 to foam.slightly. To the LiA134 suspension, 5.5 grams (86 mmol, 6.3 mL., Cambridge Isotope Laboratories) of Acetone-d5, dissolved in 30 mL. of ether, was added dropwise using the addition funnel, maintaining a gentle reflux. At this time the claisen adapter was removed and the solution was heated at reflux for an additional two hours, at which time the solvent was removed on the rotovap. To the dry aluminum salts, at liquid nitrogen temperature, 20 mL. of dHZO was added and the solids were allowed to wamm to room temperature. The aqueous solution of (1,1,l,3,3,3-d5)-2-propanol was vacuum transferred to another 100 mL. round bottom flask which was treated with 50 mL. (47%, MCB) hydriodic acid. The round bottom flask was fitted with a short path distillation apparatus and heated until approximately 20 mL. of liquid had distilled through the apparatus. The bottom organic layer of the distillate was separated and the upper aqueous layer was redistilled. 51 The organic portions were combined and washed with an equal volume of concentrated hydrochloric acid, water, 5% NaHC03, water, and dried over CaClz, yielding 6.21 grams (35.3 mmol, 41% yield, relative to acetone-d5) of product. Spectral Data: 1H NMR (300 MHz, coc13): 84.28 (s, 1H, broad). o-(Isopropoxy-l,l,l,3,3,3-d5)benzophenone (44-d5): To an oven dried, 100 mL., three-necked flask, 3.8 grams (27.5 mmol, CCI) of K2C03 and 50 mL. of reagent grade acetone were added. Then 5.0 grams (25 mmol) of o-hydroxybenzophenone was added. The flask was fitted with a condenser and placed under an argon atmosphere. The mixture was heated at reflux for 1 hour, at which time, 2.67 grams (15.6 mmol) of (1,1,1,3,3,3-d5)-2-iodopropane, in 10 mL. of acetone was added while the mixture was still at reflux temperature. The mixture was heated at reflux for 72 hours, at which time a solid, other than K2C03, coated the inside of the flask. The solvent was removed, on the rotovap, and the sludge taken up into 100 mL. of ether and 100 mL. of dflzo. The ether water suspension was washed with 300 mL. 10% NaOH, 100 mL. of d320, 100 mL. of brine, and dried over Nazcog, and the ether removed on the rotovap. The remaining yellow viscous liquid was distilled (Kuglerohr apparatus, 0.50 Torr, 175°C) giving 2.86 grams (11.63 mmoles, 75% yield) of product. Spectral Data: IR cmrl (neat): 3062, 3033, 2912, (c-o) 2230, (c=0) 1664, 1600, 1590, 1500, 1480, 1300, 1250, 1030, 930. 1H NMR (300 MHz, C606): 87.97 (dd, Ja6.99, 1.53 Hz, 2H); 7.50 (dd, J57.45, 1.65 Hz, 18); 7.20 (m, 2H); 7.14 (dt, Jh7.51, 1.37 Hz, 2H); 6.87 (dt, J57.48, 0.88 Hz, 1H); 6.67 (d, Ji8.24 Hz, 1H): 4.07 (s, 1H, broad due to fine splitting by the neighboring -CD3 substituents). 13c NMR (75 MHz, 00013): 8197.2, 155.8, 138.4, 132.5, 131.8, 130.1, 129.9, 129.6, 128.0, 120.4, 113.8, 70.5. The 13c NMR signal for the carbon atom with the deuterium attached, 21.5 (septet), does not appear due to the same reasoning as for o-(isopropoxy-Zdl)benzophenone (44-d1). Mass (FAB) m/z, (relative intensity): 246(100)(M+), 199(100), 182(17), 165(10), 152(12), 136(10), 122(65), 105(85), 77(20). 52 Mass (BI) m/z, (relative intensity): 249(5.23), 248(27.39), 247(24.05), 246(80.10)(M+), 245(9.79), 244(1.35), 242(0.l7), 241(0.16), 240(0.36). This corresponds to 84% d5, 13% d5, 2% d3, 0.3% d2, 0.2% d1, 0.5% do. In comparison to the impurity as determined by 18 NMR of 10% of one hydrogen atom, the mass spectrum data gives an impurity of 16% of one hydrogen atom. 53 IV. Isolation and Identification of Photoproducts A. General Isolation lhthods: All photoproducts from ketones 8- 42 were separated by column chromatography. Attempts to separate the diastereomeric mixtures of the 2-alkyl-3-phenyl-2,3-dihydro-3- benzofuranol photoproducts failed. All photoproduct spectoscopic data are supplied as the diastereomeric mixture. Thin layer chromatography was performed using AldrichGN212,278-5) pre-coated silica gel on polyester plates with a 254 nm fluorescent indicator. Flash grade silica gel was used with 95:5 hexanes/ethyl acetate as solvent, except in the case of o-isopropoxybenzophenone 44 which required a different solvent system (see o-isopropoxybenzophenone in this section). B . Identification of Photoproducts The spectral data reported for the diastereomeric mixtures are reported as if the diastereomers had been separated and analyzed individually. The reported number of protons accounting for each signal was not the integrated value, but reflects the number of protons the signal would have had the compound been, isolated. The 18 NMR spectra are displayed as Figures 9-26. 1. o-(a-flethylbenzyloxy)benzophenone (37): A 0.01 hi benzene-d5 solution of o-(a-methylbenzyloxy)benzophenone was degassed and irradiated at >290 nm with complete conversion to 2-methyl-2,3-diphenyl-2,3-dihydro- 3-benzofuranol (38), as monitored by 1H NMR. The spectrum showed the disappearance of the signals at 58.05, (d, 2H); 56.65, (d, 18) due to the hydrogens ortho to the carbonyl on the non-substituted benzene ring and the hydrogen ortho to the phenolic ether respectively. Also seen was the disappearance of the signals at 54.95, (q, 13); and 51.15, (d, 33) which were replaced by the signals at 56.10, (s, 1H); 54.80, (d, 18); 5 4.25, (d, 1H), which are due to the formation of o-(2-phenylethylenoxy) benzhydrol (39). The signal at 52.16 is most likely due to the methyl group of the 2-methyl-2,4-diphenyl-1,3-benzodioxane that would form if a trace of acid was present. The signal at 51.90, (3, BH) was assigned to 54 the E isomer of the corresponding benzofuranol, and the signal at 51.25, (s, 3H) was assigned to the z isomer. The photoproducts of a 1H NMR scale irradiation in methanol-d4 were isolated and then dissolved in benzene-d5 to check that the methyl group signals for the z and E isomers had not interchanged positions. The signal position and signal ratio of the methyl groups checked in benzene- d6 matched those checked in methanol-d4. Spectral Data: 2-methyl-2,3-diphenyl-2,3-dihydro-3—benzofuranol (both diastereomers): IR cmrl (cc14): 3459 (broad, -OH), 3096, 3064, 3038, 2980, 1599, 1477, 1244. 1H NMR (300 MHz, c506): 87.43 (m, 2H); 7.15 (m, 4H); 7.04 (m, 2H); 6.79 (dt, J-7.4, 1.0 Hz, 18); 6.10 (s, 1H, Ar-Cfl-Ar benzhydrol); 4.80 (d, 18, Ji2.53 Hz, CsC-fl cis to oxygen); 4.25 (d, 18, Jh2.51 Hz, c-C-H cis to phenyl); 2.16 (s, 3H, methyl of benzodioxane); 1.90 (s, 38, E isomer); 1.35 (s, 314, z isomer). 13c NMR (75 MHz, c606): 8130.8, 129.0, 128.3, 128.2, 128.0, 127.9, 127.8, 127.9, 127.8, 127.7, 127.2, 127.1, 126.2, 126.0, 125.8, 125.4, 121.3, 111.0, 25.8 (-CH3 2 isomer), 21.9 (-CH3 E isomer). Mass (BI) m/z, (relative intensity): 302(6)(M+), 287(9), 207(18), 198(66), 197(45), 181(60), 121(16), 105(100). 2. o-lthoxybenzophenone (40).: A 0.01 M benzene-d5 solution of o-ethoxybenzophenone was degassed and irradiated at >290 nm with complete conversion to 2-methy1-3-phenyl-2,3-dihydro-3-benzofuranol (41), as monitored by 1H NMR. The spectrum showed the disappearance of the signal at 57.9, (d, 2H); 56.6, (d, In) due to the hydrogens ortho to the carbonyl on the non-substituted benzene ring and the hydrogen ortho to the phenolic ether respectively. Also seen was the disappearance of the signals at 53.5, (q, 2H); 50.8, (t, 33) which were replaced by the signals at 84.59, (q, 1H); and 81.46, (d, 3H) corresponding to the z isomer, and 54.7, (q, 13); and 51.22, (d, 3H) corresponding to the E isomer. The 2:3 ratio was determdned by integration of the 1H NMR to be 11:1. The 2:8 ratio decreased to 3:1 in acetonitrile and to 3:2 in methanol as determined by integration of the 1H NMR, and to 5:6 in t-BuOH as determined by HPLC. The benzofuranol 55 photoproducts showed the characteristic broad (-OH) band at 3475 cm.‘1 in the IR. The benzofuranol was dehydrated to 2-methy1-3-phenylbenzofuran by heating a benzene solution, containing a catalytic amount of p- toluenesulfonic acid, at reflux temperature for one hour. The mixture was then washed with water, dried over Mgsoq and the solvent removed using the rotovap giving only the dehydrated product. .Special thanks to Mr. Bong-Ser Park for providing the ultra pure o-ethoxybenzophenone used in this thesis. Spectral Data: . 2-methy1-3-phenyl-2,3-dihydro-3-benzofuranol (both diastereomers): IR cmrl (neat): 3474 (broad, -oH), 3025, 3015, 2985, 2970, 1609, 1476, 1227, 1063. ' 1H NMR (300 MHz, c606): 87.5, (dt, Jh6.7, 1.4 Hz, 2H); 7.1-7.3 (m, 4H); 6.9 (q, Jh 8.3 Hz, 2H); 6.7 (dt, J57.4, 1.0 Hz, 1H); 4.5 (q, J56.54 Hz, 1H, 2 isomer); 4.6 (q, Ji6.6 Hz, 1H, E isomer): 1.3 (d, J56.56 Hz, 3H, z isomer),- 0.9 (d, J-6.6 Hz, 3H, 15: isomer). 130 NMR (75 MHz, 0606): 5130.6, 128.3, 128.2, 128.0, 127.8, 127.7, 127.4, 126.9, 125.3, 121.3, 110.3, 90.7, 11.6. Mass (FAB) m/z, (relative intensity): 226(M+)(7), 208(100), 197(15), 189(5), 178(15), 165(7), 152(5), 131(15), 121(7), 104(7, 89(10), 76(7). 2-methyl-3-phenylbenzofuran: IR cm'l (neat): 3050, 2920, 1456.44, 1251.96, 1207.59 1H NMR (300 MHz, coc13): 86.9-7.4 (m, 9H); 2.3 (s, 3H). 13c NMR (75 MHz, coc13): 8153.7, 132.5, 128.6, 128.5, 128.4, 128.4, 126.6, 123.2, 122.2, 118.9, 116.5, 110.3, 12.1. 3. o-Allyloxybenzophenone (8): A 0.011: benzene-d5 solution of o-allyloxybenzophenone was degassed and irradiated at >290 nm with complete conversion to 3-phenyl-2-vinyl-2,3-dihydro-3-benzofuranol (9), as monitored by 1H NMR. The spectrum.showed the disappearance of the signals at 57.9, (d, 2H); 56.6, (d, 1H) due to the hydrogens ortho to the carbonyl on the non-substituted benzene ring and the hydrogen ortho to the phenolic ether respectively. Also seen was the disappearance of the three signals at 55.5, (ddt, 1H): 54.9, (ddt, 2H); and 54.0, (ddd, 2H) from the allyl group which were replaced by the three signals at 5 56 6.0, (m, 1H); 55.2, (m, 2H); and 54.9, (m, 1H) from the new vinyl group. A separately prepared 0.01 M(benzene solution was degassed and irradiated to complete conversion as monitored by HPLC. The 2 to E ratio was determined by HPLC to be 5:1 in benzene, decreasing to 1:1 in acetonitrile, 4:5 in methanol, and 1:2 in t-BuOH. Irradiation in an identical methanol solution gave rise to more signals in the 1H NMR, the most identifiable were the growth of the signals from the E isomer of the benzofuranol (see Figure 15). The benzofuranol showed the characteristic broad (-OH) band at 3500 cm.‘1 in the IR. Spectral Data: 3-phenyl-2-vinyl-2,3-dihydro-3-benzofuranol (both diastereomers): IR cm"1 (neat): 3480 (broad, -OH), 3060, 3020, 2900, 1600, 1480, 1210, 930. 1H NMR (300 MHz) (c505): 87.45 (dt, J58.2, 1.7 Hz, 2H); 7.05-7.2 (m, 4H); 6.90 (q, J58.3 Hz, 2H); 6.72 (dt, J57.4, 1.0 Hz, 1H); 6.02 (ddd, Jh17.2, 10.8, 6.3 Hz, 1H): 5.25 (ddd, Jil7.3, 2.0, 1.4 Hz, 1H); 5.13 (ddd, Ji10.7, 1.9, 1.2 Hz, 1H): 2.7 (s, 1H, broad). 13c NMR (75 MHz) (coc13): 5156.8, 141.7, 130.3, 129.8, 127.8, 127.6, 127.30, 127.27, 126.7, 126.1, 124.6, 121.2, 119.7, 110.3, 93.7. Mass (FAB) m/z, (relative intensity): 238(H+)(80), 223(40), 209(40), 194(70), 181(100), 165(22), 152(40), 133(20), 121(70), 115(20), 105(70), 77(50). 4. o-(Cyclopropylnethoxy)benzophenone (42): A 0.01 a benzene-d6 solution of o-(cyclopropylmethoxy)benzophenone was degassed and irradiated at >290 nm with complete conversion to 2-cyclopropyl-3- phenyl-2,3-dihydro-3-benzofuranol (43), as monitored by 1H NMR. The spectrwm showed the disappearance of the proton signals at 57.9 and 5 6.6 due to the hydrogens ortho to the carbonyl on the non-substituted benzene ring and the hydrogen ortho to the phenolic ether, respectively. Also seen was the disappearance of the four signals at 53.4, (d, 2H); 5 0.7, (m, 1H); 50.1, (m, 2H); 5-0.1, (m, 2H) from the cyclopropylmethyl moiety which were replaced by the signals at 53.8, (d, 1H); 53.7, (d, 1H); 51.8, (s, 1H); 81.4, (m, 1H); 80.5, (m, 1H); 80.2, (m, 2H); and 8 -0.1, (m, 1H) from the new cyclopropyl moiety. The 2 to E ratio was determined by integration of the 1H NMR spectrum, using the doublet pair 57 at 53.8 and 53.7, E and 2 respectively, to be 12:1. An identical irradiation in methanol-d4 gave similar results with the 1H NMR spectrum missing the broad signal at 51.8, as found in benzene-d6. The z to 8 ratio was determined by integration of the 1H NMR spectrum using the doublet pair at 53.9 and 53.7. The ratio was 1:1. To determine that the product seen in the 1H NMR was the major product and not some polymerization reaction, the photolysis was followed by G.C. After irradiation to 65% consumption of the ketone, using the ketone peak as a reference, the benzofuranol product made up 54% of the irradiation mixture. At 73% consumption of thefiketone, the benzofuranol made up 60% of the irradiation mixture, and at 92% consumption the benzofuranol product made up 80% of the mixtuie, while 5% of the secondary photoproduct, o—hydroxybenzophenone was present. Spectral Data: 2-cyclopropyl-3-phenyl-2,3-dihydro—3-benzofuranol (both diastereomers): IR cm'l (neat): 3500(broad, -OH), 1599, 1475, 1220, 752, 702. 1H NMR (300 MHz, c505): 87.58 (dt, J-16.8, 1.6 Hz, 2H); 7.10-7.25 (m, 4H); 7.00 (t, Ji7.1 Hz, 2H); 6.80 (dt, Jh7.4, 0.9 Hz, 1H): 3.90 (d, 1H, J58.18 Hz, E isomer); 3.8 (d, 1H, J58.52 Hz, 2 isomer); 1.75 (s, 1H, broad); 1.35 (m, 1H): 0.5 (m, 1H): 0.35 (m, 23): -0.05 (m, 1H). 13c NMR (75 MHz, c505): 8130.6, 128.3, 128.2, 128.1, 128.0, 127.8, 127.7, 127.6, 127.3, 126.9, 125.7, 125.3, 121.3, 110.6, 98.9, 7.7, 2.00, 1.4. , Mass (FAB) m/z, (relative intensity): 252(M+)(30), 234(30), 223(15), 205(80), 195(100), 181(40), 165(17), 152(20), 147(20), 131(17), 121(37), 105(37), 77(30). 5. o-Isopropoxybenzophenone (44"): A 0.01 M benzene-d5 solution of o-isopropoxybenzophenone we? degassed and irradiated at >290 nm with complete conversion to 2,2-dimethyl-3-phenyl-3-benzofurano1 (45) and o-(2-propenyl)benzhydrol (47), as monitored by 1H NMR. The ketone was prepared for irradiation by passing it in a benzene solution through activated basic alumina and collecting the eluent in a base washed round bottom flask. The benzene was removed using a rotary evaporator and the oil was taken up into benzene-d5. The spectrum showed the disappearance of the signals at 57.9, (d, 2H); and 56.6, (d, S8 1H) due to the hydrogens ortho to the carbonyl on the non-substituted benzene ring and the hydrogen ortho to the phenolic ether respectively. Also seen was the disappearance of the two signals at 54.2, (septet, 1H); and 50.9, (d, 6H) from the isopropyl group were replaced by signals at 86.1, (s, 1H); 84.0, (m, 23),- 81.7, (d, am from the o-(2- propenyl)benzhydrol and 51.5, (s, 3H); 50.8, (s, 3H) from the newly formed benzofuranol. The product ratio was determined by integration of the 1H NMR spectrum to be 2:1, ratio of benzofuranol to benzhydrol. Upon addition of 2-napthalenesulfonic acid , the signals at 56.1, 54.0, and 51.7 from the o-(2-propenyl)benzhydrol disappeared and were replaced by signals at 55.8, (s, 1H); 51.6, (s, 3H); and 51.3, (s, 3H), while the signals from the benzofuranol were unaffected. The new signals were due the the acid catalyzed formation of 2,2-dimethyl-4- phenyl-1,3-benzodioxane. Again, the product ratio was determine by integration of the 1H NMR spectrum comparing the methyl signals at d 0.8 and d 1.7 corresponding to the benzofuranol 4S and the benzhydrol 47, respectively.The product ratio was found to be a 2:1 ratio of benzofuranol to benzodioxane. The photoproducts were separated by preparative TLC using a 60:40 mixture of methylene chloride/2,2,5- trimethylhexane. The 1H NMR of each photoproduct in CDC13 matched the 1H NMR spectral data reported by Lappin and Zannucci.22 Solutions of the ketone in methanol-d4 and acetonitrile-d3 with a trace of 2- napthlenesulfonic acid present were degassed and irradiated at >290 nm with complete conversion as monitored by 1H NMR. The product ratio of benzofuranol to benzodioxane was then determined by integration of the 1H NMR spectrum, comparing the areas of the methyl group of the benzofuranol 42 at 50.80 and the methyl group of the benzodioxane 46 at 51.39, to be 5:1 and 3:1 in methanol-d4 and acetonitrile-d3, respectively. Spectral Data: 2,2-dimethyl-3-phenyl-2,3-dihydro-3-benzofuranol: IR curl (heat): 3450 (broad, -OH), 3025, 3015, 2990, 2980, 1600, 1480, 1470, 1240 1H NMR (300 MHz, C5D5): 86.7-7.6 (m, 9H).- 1.52 (s, 3H).- 0.81 (s, 3H). 13c m (75 MHz, coc13): 8130.3, 127.6, 127.4, 126.9, 125.2, 120.5, 110.7, 25.2, 19.6. 59 Mass (FAB) m/z, (relative intensity): 240(M+)(60), 225(50), 207(12), 197(57), 181(100), 165(10), 152(25), 121(35), 105(27), 77(22). o-(2-propenoxy)benzhydrol: 1H NMR (300 MHz, C6D5): 8 7.8-6.7 (m, 9H); 6.07 (s, 1H, Ar- Cfl-Ar): 3.96 (dq, Ja1.5, 0.9 Hz, 1H, trans CH3-c-c-H); 3.94 (d, Jil.5 Hz, 1H, cis CH3-C-C-H). 2,2-dimethyl—4-phenyl-1,3-benzodioxane: MP. 69-71°C . IR cm.‘1 (CC14): 3025, 3015, 3000, 2975, 2935, 1600, 1550, 1490, 1450, 1400, 1280, 1260 1H NMR (300 MHz, coc13): 86.6-7.4 (m, 9H); 5.85 (s, 1H); 1.66 (s, 3H); 1.64 (s, 3H). 1H NMR (300 MHz, c605): 8 7.8- 6.7 (m, 9H); 5.75 (s, 1H, Ar-Cfl-Ar); 1.60 (S, 38); 1.39 (s, 3H). 1H NOE (300 MHz, C605): Irradiation at the 55.75 methine signal showed enhancement at the 51.39 methyl signal and no noticeable enhancement at the 51.60 methyl signal. Irradiation at the 51.39 methyl signal showed enhancement at the 55.75 methine signal. Irradiation at the 51.60 methyl signal showed enhancement at the 55.75 methine signal. 13c NMR (75 MHz, coc13): 8128.3, 128.2, 128.1, 128.0, 126.3, 119.9, 116.5, 73.1, 27.7, 21.3. Mass (FAB) m/z, (relative intensity): 240(M+)(15), 239(80), 223(100), 208(17), 197(40), 152(17), 121(20), 105(15), 77(12). 6 . o- (Isopropoxy-Z-d; ) benzophenone (44-d1) : A 0 . 0 1 u benzene-d5 solution of o-(isopropoxy-Z-d)benzophenone was degassed and irradiated at >290 nm with complete conversion to 2,2-dimethyl-3-phenyl- 3-benzofuranol (45-OD) and o-(2-propenyloxy)benzhydrol (47-OD) as monitored by 1H NMR. The spectrum was identical to that taken of the non-deuterated o-isopropoxybenzophenone. Upon addition of 2- napthalenesulfonic acid, the o-(2-propenyl)benzhydrol (47-GD) signals disappeared and were replaced by the signals from the benzodioxane 46, and again, the spectrum was identical to that taken of the non- deuterated o-isopropoxybenzophenone. 60 7. o-(Isopropoxy-l,l,l,3,3,3-d5)benzophenone (44-d‘): A 0.01 M benzene-d6 solution of o-(isopropoxy-l,1,1,3,3,3-d5)benzophenone was degassed and irradiated at >290 nm with complete consuption of the ketone as monitored by 1H NMR. The spectrum showed the disappearance of the signals at 57.9, (d, 2H); and 56.6, (d, 1H) due to the hydrogens ortho to the carbonyl on the non-substituted benzene ring and the hydrogen ortho to the phenolic ether respectively. Also seen was the disappearance of the signal at 54.1, (s, 1H) due to the single hydrogen of the isopropyl moiety. The addition of 2-napthalenesulfonic acid resulted in the appearance of a signals at 51.6 and 51.4 which came at the same chemical shift values as the methyl groups of the benzodioxane 46. Also visible were signals at 51.5 and 50.8 which were at the same chemical shift values of the methyl groups of the benzofuranol 45. The product ratio of benzofuranol 45-d5 to benzodioxane 45-d5 was determined by G.C. analysis to be 3:1. This was performed by irradiating the ketone 44-d5 to 16% conversion, then adding a catalytic amount of 2-naphthalenesulfonic acid and waiting approximately 1 hour before injecting the sample into the G.C. The areas were normalized by using the standardization factors in the appendix and the product ratio was determined. A benzene-d6 solution of 44-d‘ and anisole was degassed and irradiated at >290 nm.with complete consuption of the ketone as monitored by 1H NMR. The anisole was used as an internal standard to determine the percentage of hydrogen atoms each signal contained. The benzene-d5 solution prior to irradiation had 10% of one hydrogen atom present as impurity in the region between 50.85 and 50.65 as determined by 1H NMR (see Figure 27). The impurity of ketone 44-d5 was also determined by mass spectrum to be 16% of one hydrogen atom. After irradiation and addition of a catalytic amount of 2-naphthalenesulfonic acid, all signals in the region between 50.5 and 52.2 were integrated and normalized to the integration values prior to irradiation (see Figure 28). It was found that the 10% of one hydrogen atom could be found in the methyl group signals at 51.5 and 50.8 corresponding to the benzofuranol 45-d‘. The majority of the proton signal from the starting ketone was incorporated in the broad hydroxyl signal spanning 61 from 51.6 to 52.2. The signals assigned to the methyl groups of the 1,3-benzodioxane at 51.6 and 51.4 incorporated roughly 14% of one hydrogen atom. This amounted to 43% of the expected hydrogen atom incorporation, with the assumption that the 1,3-benzodioxane was formed as 1/3 of the total products from the starting ketone. The lack of hydrogen incorporation was likely due to the limits in the integration of the signals. Appendix Table 6 Response Factors for GC and HPLC: Acetophenone Valerophenone o-Allyloxybenzophenone 3-Phenyl-2-vinyl-2,3- dihydro-3-benzofuranol o-Hydroxybenzophenone o-Isopropoxybenzophenone 2,2-Dimethyl-3-phenyl-2,3- dihydro-B-benzofuranol 2,2-Dimethyl-4-phenyl- 1,3—Benzodioxane o-Ethoxybenzophenone 2-Methyl-3-phenyl-2,3- dihydro-3-benzofuranol o-Isopropoxybenzophenone 2,2-Dimethyl-3-phenyl-2,3- dihydro-3-benzofuranol 2,2-Dimethyl-4-phenyl- 1,3-Benzodioxane 3 HPLC, Si column, 95.5:4.5 Hexanes:BtOAc, V3. V3. V3. V3. V3. V3. V3. V3. V8. V3. V3. V3. 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I (1 JV ( g. 1 8 .o 288 838.088 fimms filrl. .IP4IrJ . me :8 er 3 l m2 3 9.6. 3 IrrrPFPLLLLLLrrPrrrPFFLLLrPrrrPPFLLLLL. \ U D D U n o o o a U rd 0 «104 O 0 IO 0 VA 9 redo 2er 8 $0 83 Table 7 Quenching of 2-Methy1-3-phenyl-2,3-dihydro-3-benzofuranol Formation from o-Ethoxybenzophenone with 2,5-Dimethyl-2,4-hexadiene in Acetonitrile at 313 nm. GC analysis with DBZlO+ column, 80°C initial column temperature, hold time-2 minutes, 180°C final column temperature, increase 10°C/min, hold 5 minutes, 230°C detector temperature, 180°C injector temperature, C15 as internal standard (5.1x10-4 M, runtl, 5.2x10-4,M, run#2), run #1 includes quencher 1.5x10'4 — 8.3x10“. iQuencherl Wm 52919 .00000 1.70 1.00 .00015 1.35 1.10 .00030 1.37 1.22 .00041 1.11 1.36 .00057 1.00 1.48 .00087 0.90 1.71 .00083 0.97 1.72 .00084 1.00 1.76 .00168 0.63 3.07 .00252 0.50 3.70 100395 0-31 5.35 [KetoneJ- 0.01994 M run#1, [Ketonel- 0.02059 u,run#2, kqx - 1135 1 y = 0.88309 + 0.11346x R42 = 0.992 0 I f I ' I V I r I 0 10 30 40 20 [Q]x10—4 84 Table 8 Quenching of 2,2-Dimethyl-3-phenyl-2,3-dihydro-3-benzofuranol Formation from o-Isopropoxybenzophenone with Naphthalene in Benzene at 365 nm GC analysis with 081+ column, 145°C column temperature, 226°C detector temperature, 180°C temperature, C15 as internal standard (4.9x10-4 u) lQuencherl AreainhotnuArealatdl 93m? .000 1.70 1.00 .001 1.42 1.18 .003 1.16 1.40 .004 1.11 1.55 .005 1.06 1.66 .007 0.98 1.87 .012 0.67 2.64 1016 0158 3-00 [Ketonel- 0.02023 M , kq'c - 127 (Do/(b 1 y = 1.0242 + 127.17x R"2 = 0.996 0 ' I fi I 0.00 0.01 0.02 [Q] 85 Table 9 Quenching of 2,2-Dimethyl-3-phenyl-2,3-dihydro-3-benzofuranol(-OD) Formation from o-(Isopropoxy-Zd)benzophenone with Naphthalene in Benzene at 365 nm GC analysis with 081+ column, 145°C column temperature, 226°C detector temperature, 180°C temperature, C15 as internal standard (5.2x10-4 M) lQuencherl iiArealphntolLArealatd) SESEP .000 2.40 1.0 .001 1.54 1.62 .002 1.28 2.03 .003 1.10 2.41 .004 0.93 2.94 .005 0.79 3.36 .006 0.65 4.02 -007 0-59 4-37 [Ketone]= 0.01948 M , kqx=- 478 y = 1.0475 + 0.4775014 R42 = 0.996 86 Table 10 Quenching of 3-Phenyl-2-viny1-2,3-dihydro-3-benzofuranol Formation from o-Allyloxybenzophenone with 2,5-Dimethyl-2,4-hexadiene in Benzene at 313 nm HPLC analysis with Si column, detector 270 nm, Ethyl benzoate used as internal standard (5.1x10-3 M) lQuencherl ArealphotoiLArealstdl SPELQL_______ .0027 0.60 1.54 .0054 0.37 2.71 .0081 0.25 3.94 -00135 0-16 6-47 [Ketone]- 0.01961 M , kqj - 458 d>ol