SPECTROSCOPIG STUDIES OF LITHIUM AND SODIUM COMPLEXES WITH THE DILACTAM OF 0222 CRYPTAND Thesis for the Degree of M. S. MECHIGAN STATE UNIVERSITY WM ROKO-HLOU HOURDAKIS 1975 ..-- w A 4.,gfl.f~._".:."_.? ' V L [3 2’3 if“? I‘ Midi??? v.31 Sf“ a- 6-23 ‘ mm; &' sous ‘1 anux mum ms. {'1 (BRARY BINDERS .—.._. 5PM on nugm 3‘“ " . 7 . A ~. . 7/ 94/ Q/ \ F‘x...‘ ABSTRACT SPECTROSCOPIC STUDIES OF LITHIUM AND SODIUM COMPLEXES WITH THE DILACTAM 0F C222 CRYPTAND By Adamantia Rokofilou Hourdakis The dilactam of the 0222 cryptand was synthesized. The complexing ability of the dilactam with lithium and sodium ion in different solvents was studied using lithium-7 and sodium-23 NMR. The addition of the dilactam to a lithium or sodium salt solution results in a definite shift of the chemical shift of the 7L1 or 23Na resonance when complexation takes place. The rate of exchange of the metal ion between the two sites, 1.3., the free ion in the bulk solution and the complex is fast compared to the NMR time scale, and in all cases only one population-average resonance was observed. The 7L1 chemical shifts were determined as a function of dilactam/Li+ mole ratios. In dimethylsulfoxide, water, methanol and dimethyl- formamide solutions there was not enough evidence that complexation is occurring because there is not enough change of the chemical shift from the position characteristic of the solvated Li+ ion in the above solvents. In the case of formamide, acetone, tetrahydrofuran, pyridine, propylene carbonate, acetonitrile and nitromethane solutions, there is a Li+—dilactam complex formed, as shown by the variation of the chemical shift. Adamantia Rokofilou Hourdakis Formation constants of the Li+-dilactam complexes were determined in pyridine, tetrahydrofuran, nitromethane and acetonitrile solutions. The values obtained were: KPy = 440 i 97, KTHF = 1327 i 263, K = 4053 i 2040 and K CHBNOZ = 1348 i 372 when LiBr was used CH3CN as the salt. The Na+-dilactam complex is very strong in the case of dimethyl— formamide solutions. In DMSO it cannot be unambiguously determined if complexation takes place or not because of the broadening of the Na resonance peak upon addition of dilactam to the sodium solution. SPECTROSCOPIC STUDIES OF LITHIUM AND SODIUM COMPLEXES WITH THE DILACTAM OF C222 CRYPTAND By Adamantia Rokofilou Hourdakis A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Chemistry 1975 ACKNOWLEDGMENTS The author wishes to express his sincere gratitude to Professor Alexander I. Popov for his interest, guidance and encouragement throughout this study. Financial aid from the Department of Chemistry, Michigan State University and National Science Foundation is gratefully acknowledged. I would like to thank all the members of the laboratory of Dr. A. Popov for their general assistance. Appreciation is extended to Frank Dennis and Wayne Burkhardt for their help with nuclear magnetic resonance instruments. Finally, my very special thanks to Dr. Christina Zioudrou of A.E.C. laboratory in Greece, for introducing me to research, and her encouragement and friendship. To her, I dedicate this thesis. ii Chapter TABLE OF CONTENTS I. HISTORICAL II. EXPERIMENTAL PART . III. SYNTHESIS OF THE DILACTAM OF THE CRYPTAND C222 . l. 2. 6. SALTS SOLVENTS SAMPLE PREPARATION INSTRUMENTAL MEASUREMENTS . Lithium-7 and Sodium-23 NMR . Infrared Spectra. . . Data Handling . . Synthesis of Starting Materials . First Cyclization . First Reduction . Second Cyclization Second Reduction. . Purification of Final Product IV. SPECTROSCOPIC STUDIES OF COMPLEXATION 0F ALKALI METAL IONS, WITH THE DILACTAM OF C222 . 1. 2. 3. Introduction. Lithium-7 NMR Study . . . Sodium-23 NMR Study . . . . . . . . . . . LITERATURE CITED iii Page 10 10 10 ll 13 13 l4 14 15 18 21 23 24 25 26 29 29 30 466 55 LIST OF TABLES Table Page I. Donor Number (DN) and Dielectric Constant (a) of Some Important Solvents . . . . . . . . . . . . . . 12 II. 7Li-NMR Study of the Dilactam of C222, Lithium Complexes in Various Solvents . . . . . . . . . . . . 32 III. 7L1 Chemical Shift as a Function of Ligand/Li+ Mole Ratio in Different Solvents . . . . . . . . . . . 34 IV. Limiting Chemical Shifts and Formation Constants of the Dil-Li+ Complex in Various Solvents . 45 V. 23Na-NMR Study of the Dilactam of C222, Sodium Complexes in DMF. . . . . . . . . . . . . . . . 47 VI. Temperature-Dependent Study of the Dilactam of C222, Sodium Complexes in DMF . . . . . . . . . . . 48 23 VII. Na-NMR Study of the Dilactam of C222, Sodium Complexes in DMSO . . . . . . . . . . . . . . . 49 iv LIST OF FIGURES Figure Page 1. Dibenzo-lB—crown-6 . . . . . . . . . . . . . . . . . . . 2 2. a) General formula of cryptands b) The dilactam of C222 . . . . . . . . . . . . . . . . 3 3. Exo-exo, endo-endo and exo-endo conformation of 222 cryptate. . . . . . . . . . . . . . . . . . . . . 5 4. Crystal structure and conformation of 3) its RbSCN cryptate and b) the free macrobicyclic ligand C222 . . . 5 5. Setup for flow synthesis . . . . . . . . . . . . . . . . 22 6. Proton NMR spectrum of the dilactam of C222 cryptand . . 28 7. Change of 7Li chemical shift with dilactam/Li+ mole ratio at constant [Li+] = 0.015 in CHBCN . . . . . 31 8. Plot of 7Li chemical shift with reference to 4.0 M aqueous LiClO ‘!§_mole ratio of dilactam to Li+ in different solvents . . . . . . . . . . . . . . 37 9. Plot of 7Li chemical shift with reference to 4.0 M aqueous LiClO vs mole ratio of dilactam to Li+ at constant fLIF] = 0.020 M in pyridine . . . . . 40 10. 7Li chemical shift with reference to 4.0 M aq eous LiClO gs mole ratio of dilactam to Li at constant [Li+] = 0.010 M_in THF . . . . . . . . . 41 11. 7L1 chemical shift with reference to 4.0 M aqueous LiClO !§_mole ratio of dilactam to Li+ at constant [Li+] = 0.015 Mlin nitromethane . . . . 42 12. 7L1 chemical shift with reference to 4.0 M aqueous LiC104 vs mole ratio of dilactam to Li+ at constant—TLi+] = 0.015 M_in CH3CN . . . . . . . . 43 LIST OF FIGURES Continued 13. 14. 15. 16. Plot of 7Li chemical shift with reference to 4.0 M aqueous LiC104 X§_mole ratio of Dil/Li+ at constant [LiBr] = 0.015 M_in CHBCN . . . . . . . . . . . 44 Plot of 23Na chemical shift with reference to 3.0 M aqueous NaCl X§_mole ratio of dilactam to Na+ at constant [Na+] = 0.1 M_in DMF at 33.: 2°C . . . . . . . 50 Plot of 23Na chemical shift with reference to 3.0 M aqueous NaCllg§_mole ratio of dilactam to Na+ at [Na+] = 0.1 M and [Na+] = 0.2 M in DMSO at 33 : 2°C . . . . . . . . . . . . . . . . . . . . 51 Infrared spectra of dilactam-sodium precipitates from a) DMF solution and b) pyridine solutions . . . . . 52 vi CHAPTER I HISTORICAL PART HISTORICAL In recent years, macrocyclic polyethers have been synthesized which are capable of forming strong complexes with the alkali and alkaline earth metal ions. Cyclic polyethers or "crown" ethers, developed by Pedersen (1) in 1967, were the first such complexing agents to appear. A typical crown is shown in Figure 1. These macrocyclic ligands form a central, two-dimensional cavity, the diameter of which can be varied by changing the number of methylene groups and/or of ether oxygens in the ring. Shortly thereafter, Lehn and coworkers (2,3) introduced a new class of complexing agents, diaza-polyoxamacrocycles called "cryptands" which form stronger complexes with alkali metal cations than do the crown ethers. The term cryptand refers to the ligand and cryptate to the complex. These ligands form a three-dimensional central cavity and often form an inclusion-type complex with the metal ion trapped inside this cavity. By changing the number of ether bridges we can vary the size of the ligand's cavity to accomodate different cations (see Fig. 2). In macrobicyclic complexes, the ligand may exist in three forms differing by the configuration of the bridgehead nitrogens: exo-exo (x-x), exo-endo (x-n) and endo-endo (n-n) (Fig. 3). These forms can easily interconvert by nitrogen inversion. Although it is not known in which conformation the free ligand exists Figure l. Dibenzo-lB-crown—6. The number 6 refers to the total number of oxygens and 18 to the total number of atoms in the polyether ring. b) a) C-211 m = 0, n = 1 Figure 2. C-221 m = l, n = 0 C-222 m = n = 1 b) The dilactam of C-222 in solution, the endo-endo form should be strongly favored in the complex since it allows both nitrogen atoms to participate in the complexation interactions. Crystal structure determination of the free ligand 0222 and of several cryptates (4-8) showed that the cation was indeed contained in the three-dimensional molecular cavity and that in all cases the ligand was in the endo-endo form. Figure 4, shows the structures of the free ligand [C—222] and of its rubidium thiocyanate cryptate. The ligand molecule is flattened and elongated when free, but becomes swollen in the complex. In the series [C-222, MS], where M+ = Na+, K+, Rb+, Cs+, a progressive opening of the molecular cavity, involving torsion of the ligand around the N.....N axis, has been observed. Since the cations are occluded in the central cavity of the ligand, the relationship between the size of the cavity and the diameter of the desolvated cation drastically affects the relative stabilities of the complexes. Formation constants of alkali—macrocyclic ligand complexes have been obtained (9,10) potentiometrically in aqueous and methanolic solutions. In the case of weaker complexes, the solvating ability of the solvent used plays an important role in the complexation reaction. The selectivity of the ligand is directly related to the strength of the complexes. The syntheses of different types of cryptands have been performed in order to better match the size of the given cation by varying the length and the nature of the bridges (11,12). Also, the alkaline earth-alkali cation complexation selectivity may be controlled by using different cryptands. Lehn, £5 31. (13), exo-exo endo-endo exo-endo Figure 3. Exo-exo, endo—endo and exo-endo conformation of 222 cryptate. Figure 4. Crystal structure and conformation of a) its RbSCN cryptate and b) the free macrobicyclic ligand 0222 (from ref. 10). 6 + + investigated the complexation selectivity for Na , K and Ba2+ in methanol and water solutions. Two comprehensive review papers, on macrocyclic ligands synthesized have been recently published (10,14). Since cryptands form strong complexes with alkali metals, while other groups of ligands, e.g., the tetrazoles which have been studied in our laboratory (15,16) do not, the study of their complexation reaction is of considerable interest. Lehn g£_§l, (17) studied the kinetics of the complexation by temperature dependent proton NMR on K+-C222 and Na+-C222 cryptates in D 0 solutions. 2 All the alkali metal ions possess at least one isotope with a magnetic nucleus, e.g., 7Li, 23Na, 39K, 87Rb, and 13303. Since alkali metal NMR, particularly sodium-23 NMR (18—26) and lithium-7 NMR (27-32) have proven to be sensitive probes of the immediate chemical environment of alkali metal ions, investigation of the complexation reaction by using NMR technique has aroused the interest of many researchers. Recent development of high resolution NMR pulse Fourier transform techniques (33-34), has made possible the investigation of nuclei with low natural abundance. A more extensive historical and theoretical discussion on 3Na NMR and 7Li NMR can be found in the Ph.D. theses of M. S. Greenberg and Y. M. Cahen (35-36). Dye and Ceraso (37) studied the exchange rates of sodium—C222 cryptate in ethylenediamine by using the sodium-23 NMR technique. They found an activation energy of 12.2 :_1.1 kcal mol-1 for the Ammv umuusempmx uwumz AmmHv amusmouvxnmuume masseuse A000 wumconumo mamaxmoum mcmcumaouufiz Hocmnumz wwwamauom Acmzov mvfixomasmamnuoaao Aezov mafiamEpowaxzumaflo mafluuwGOumo< occumu< mucm>Hom 00I<0 co mufiHHnHuamumom afiuocwmz How coauumuuoo 0cm mmfiupwaoum ucm>Hom mom .H maan 13 INSTRUMENTAL MEASUREMENTS Lithium-7 and Sodium-23 NMR Sodium-23 and lithium-7 NMR measurements were made on a Fourier transform instrument using the magnet of a Varian DA—60 NMR spectrometer equipped with a wide—band probe capable of multinuclear operation (48), and computer controlled rf pulse generation and data collection which has been described previously (49). An external 1H field lock was used to maintain field stability. A Nicolet Instrument Corporation 1082 computer was used. The computer program (49) was used to generate a single rf pulse and to collect the resultant free induction decay (FID) signal. Data treatment was performed by the Nicolet FT-NMR Program (NIC-80/S-7202-D) (50). The instrument was operated at a field of 1.4092 T and at frequencies of 15.87 MHz and 23.32 MHz for 23Na and 7L1 respectively. The references used were 4.0 M_LiClO in water for the lithium—7 4 neasurements and 3.0 M_NaCl in water and 2.5 M NaClO4 in methanol for the sodium-23 measurements. 10 mm NMR tubes were used. All the chemical shifts reported in this thesis are with respect to 4.0 M LiClO in water and 3.0 M_NaCl in water. A positive shift 4 from the reference is upfield. The chemical shifts reported are corrected for differences in bulk diamagnetic susceptibility between sample and reference according to the relationship of Live and Chan for non—superconducting spectrometers (51). 5 + 2} (X ref _ X sample corr obs 3 v v ) (1) 14 sample Where eref and Xv are the volume susceptibility of the reference and sample solutions respectively and 60 and acorr the observed and bs the corrected chemical shifts. Values of acorr were calculated on the basis of published magnetic susceptibilities of various solvents (52). The magnitude of corrections for various solvents are shown in Table I. Temperatures were measured with a digital readout calibrated thermocouple. Proton NMR measurements were made by using a Varian T—60 spectrometer. Infrared Spectra Infrared measurements in the 4000-600 cm.1 spectral region were obtained on the Perkin Elmer Model 225 Spectrophotometer. The mull samples were held between potassium bromide salt plates when the sample was not in a potassium bromide pellet form. Data Handling The CDC-6500 computer was used to trace the nmr data. Program KINFIT (53) was employed to determine complexation constants. CHAPTER III SYNTHESIS OF THE DILACTAM OF THE CRYPTAND C222 SYNTHESIS OF THE DILACTAM OF THE CRYPTAND C222 Cryptands were first synthesized by J. M. Lehn and his coworkers (2,3). Important modifications in some steps of the synthesis were made by Dye gt a1. (54). Detailed procedures for both Lehn's high dilution method, and Dye's flow mixing technique as well as procedures for the synthesis of the starting and intermediate compounds, their purification and their properties are given in the following sections. Synthesis of the Dilactam of C222 Cryptand 0 C1CH2CH20CH2CH20CH2CH201 + [:::I::G\N'K+ C/o 1,2-Bis(2—chloroethoxy ethane) potassium phthalimide 0 0 II n 1331+ GK\NCH CH OCH CH OCH CH N”’ // 2 2 2 2 2 2 \\c C H H 0 0 triethylene glycol diphthalimide (I) CQVH NHZNH2 HZNCHZCHZOCHZCHZOCHZCHZNHZ + [:::I::,/NH ————~> EtOH 1,8-Diamino-3,6-dioxaoctane CO Phthalhydrazine COC1 591—9- C1_N+H CH CH OCH CH OCH CH N+H C1- + 3 2 2 2 2 2 2 3 COC1 15 16 COONa NaOH \_ H NCH CH OCH CH OCH CH NH + _7 2 2 2 2 2 2 2 2 extract 1,8-Diamino-3,6-dioxaoctane (II) COONa HOCH CH OCH CH OCH CH OH + HNO ————+> HOCOCH OCH CH OCH OCOH 2 2 2 2 2 2 3 2 2 2 2 triethylene glycol triglycolic acid (III) (COC1) 2\ :7 C1COCH20CH2CH20CH2C0C1 triglycolyl chloride (IV) HZNCHZCHZOCHZCHZOCHZCHZNHZ + ClCOCHZOCHZCHZOCHZOCCl (II) (IV) CH CH2 OCH2 CH OCH CH 2 2 2 2\\\\\ benzene NH .77 high dilution HN\\\\\ / c- CH2 OCH 2CH OCH -C u 2 2 H O O (V) CH CH 0CH2 CH2 OCH CH N///// 2 2 2 2\\\\ H NH + AlLiH4 \\\\\fi CH OCH2 CH 2OCH 2-C////// 2 O V HZCHZOCHZCHZOCHZCH THF 2\\\\\ _____g> H /////NH \\\\\CH CH OCH CH 0CH CH2 2 2 2 2 2 VI 17 /////CH2CHZOCHZCHZOCHZCH2\\\\\ NH OCH COC1 H + ClCOCHZOCHZCH2 2 H CH OCH CH OCH CH 2 2 2 2 2 2 (IV) (VII) CH CH OCH CH OCH CH /22 22 22\ Benzene .1, ~\ N-————CH CH OCH CH OCH CH-————N high dilution 2 2 2 2 2 2 _ H 0 _ fi CHZOCHZC 2 CH2 fi 0 0 (VIII) CHZCHZOCH2CH20CH2CH2 N:::::CH2CHZOCHZCHZOCHZCHE////,N + BH3 1n THF C-CH OCH CH OCH l O 2222]? 0 (VIII) _ + + - 5} H3 BN (CHZCHZOCHZCHZOCHZCH2)3N B H3 Diborane of "2,2,2-cryptand" (IX) HCl 6Ng) _ + + - H ClN (CHZCHZOCHZCHZOCHZCH2)3N C 1H "2,2,2 cryptand" HCl salt (X) \ 18 CHZCHZOCHZCHZOCHZCHZ N————-CHZCHZOCHZCHZOCHZCHi—————N OH- anion exchange column CHZCHZOCHZCHZOCHZCHZ ion exchange Dowex 1-X8(20-80 Mesh) \/ "2,2,2 cryptand" (XI) 1. Synthesis of Starting Materials A. Preparation of (l,8-diamino-3,6-dioxaoctane) Hereafter called "Diamine" II One mole of potassium phthalimide, 1/2 mole of 1,2-(bis-(2— chloroethoxy))ethane and 1 1t of DMF are mixed in a 3-liter flask equipped with a mechanical stirrer. The solution is heated overnight with an oil bath at 95-100°C. The solution is then cooled to room temperature and poured with stirring into 2 l of ice water. A white precipitate forms. The solution is filtered and the precipitate is recrystallized from glacial acetic acid. The recrystallized product(I) is washed first with 5% Na2C03 and then with distilled water. The obtained product is suspended in m2000 ml of 95% ethanol. The ethanol solution is heated to boiling while it is mechanically stirred under reflux. Just after it is brought to boil, 102 ml of 85% hydrazine hydrate is added and refluxing is continued for two hours. Then 225 m1 of 10 N HCl are slowly added. The solution is refluxed for another 1/2 hour and most of the solvent is distilled off. Solid sodium hydroxide is added to make the solution strongly basic. This basic solution is extracted with diethyl ether for 1-2 days in a continuous liquid-liquid extractor. 19 The diethyl ether is then stripped off in a rotatory evaporator. The residue, which contains a large amount of diamine, is twice vacuum distilled to get the pure product 11. B. Preparation of Triglycolyl Chloride (hereafter called "Diacid Chloride") IV One hundred grams of nitric acid (d = 1.38) in a 500 ml conical flask, are heated in a water bath to 45°C. Four grams of triethylene glycol are added to the nitric acid. The solution is stirred continuously as the temperature is raised to 65°C. After some minutes the solution starts being colored and more and more nitrous vapors are produced. When the reaction is underway, the temperature is stabilized at 45°C. Sixteen grams of triethylene glycol are then added dropwise. The addition takes about one hour, and the temperature is kept constant at 45°C. After the addition is completed the solution is allowed to stand for 20 min at room temperature. It is heated again in a water bath at 45°C for 40 min and then at 80°C for 20 min with continuous stirring. After cooling, the solution is transferred to a 250 m1 round bottom flask and the solvent is evaporized in a rotavapor apparatus at 70°C for 3 hr. In order to dry the obtained product, 120 m1 of benzene are added to it and an azeotropic distillation of about 10 hours is performed. The product, III, crystallizes in the flask. It is recrystallized from an acetone-benzene mixture. In order to prepare the triglycolyl chloride, IV, 15 g of dry triglycolic acid, III, and 30 g of oxalyl chloride are added to 100 ml of anhydrous benzene containing three drops of pyridine, in a 250 m1 round bottom flask. The flask is topped with a tube filled with CaCl2 and the solution is stirred for 20 hours at room temperature. 20 After the end of the reaction the solution is quickly filtered, the benzene is evaporated off in a rotavapor, 100 ml of dry benzene are added twice and evaporated off. The brownish oily residue, IV, is crystallized at -70°C. It is recrystallized twice between room temperature and ~70°C from ether-petroleum ether mixtures. For the recrystallization the product IV is dissolved in minimum amount of ether at room temperature and then petroleum ether is added slowly until cloudiness appears and then brought to -70°C. A modification of the above method has been devised (55) for the synthesis of the diacid chloride. Into a 5-liter flask which contains 3150 grams of 60% nitric acid is added 5 grams of triethylene glycol and 3 grams of ammonium metavanadata (NH4V03). The solution is heated to 68-73°C and stirred with a mechanical stirrer. As soon as the brown fumes form, 745 grams of triethylene glycol is dropped into the faslk by means of a dropping funnel over a period of N4 hours. The temperature should be maintained at 68-73°C. After the addition has been completed, the solution is stirred for another hour. Then 80% of the nitric acid is removed by distillation. A green syrup is obtained after distillation. Further evaporation is carried out in an evaporating dish on a hot plate. As the temperature rises the color of the solution changes from green to brown to drak brown to purple and finally to sky—blue at about 140°C. After it is cooled it becomes a hard sky—blue colored solid. An ether Soxhlet extraction is done on the solid. A white solid, triglycolic acid, III, is recovered from the ether solution. (Because the diacid chloride is 21 unstable, large amounts of triglycolic acid can be prepared and stored for future use.) Sixty grams of triglycolic acid, III, and 180 m1 of SOCl2 (redistilled from commercially available SOClz) are dissolved in 200 ml of diethyl ether in a 1 l flask. The solution is refluxed for 4 hours. Then the diethyl ether is evaporated off in a rotatory evaporator. The yellow residue is washed twice with diethyl ether andtflunxrecrystallized in an ether-petroleum ether mixture at -50°C. Recrystallization is used instead of vacuum distillation, because triglycolyl chloride, IV, decomposes at high temperature. The recrystallized product is pumped to dryness at 15°C. The proton NMR spectrum of IV in deuterated chloroform, shows two resonance peaks, one singlet at 3.75 ppm for the -OCH CH O- protons and one 2 2 singlet of equal intensity at 4.52 ppm for the -0CH COC1 protons. 2 2. Preparation of 5,12-Dioxo-l,7,10,16-tetraoxa-4,13-diazacyclo- octadecane (lst Cyclization) The high dilution procedure requires the slow addition with vigorous stirring over a period of about 8 hours, of dilute (W0.1 M) solutions of the two reagents II and IV in benzene into a reaction flask under nitrogen atmosphere. Completion of the reaction between an amine and an acid chloride requires a base to remove the HCl formed. In this method, either a 2:1 ratio of diamine to diacid chloride is used or else a tertiary amine such as triethylamine is used to scavenge HCl. The flow technique speeds up the addition process without reducing the yields. Figure 5 shows the flow cell that is used to carry out this step. 22 9.3"“ fl. \\\Is‘\_\\‘ Figure 5. Setup for flow synthesis. 23 In a typical flow reaction, 200 m1 of 0.06 M solution of the diamine, II and 200 ml of a 0.03 M_solution of diacid chloride, IV, in dried benzene are allowed to flow through the flow cell under 3 atm pressure. Blockage of the flow tube by the precipitation of the diamine dihydrogen chloride salt can occur at higher reagent concentrations. A high polymer coating on the wall of the mixing cell, or a larger inner diameter capillary tube might help to solve this blockage problem. In the high dilution method, the by—product of the cyclization, hydrogen chloride, is removed with the diamine. The same procedure is used in the flow technique. However, the required excess of amine might either be present in the amine stock solution or it may be in the receiver flask. The diamine can be recovered from the diamine dihydrogen chloride salt with very little net loss of material. The cyclization product, the dilactam, V, is collected by evaporating the solvent in a rotatory evaporator and purified by elution through an alumina column (80-100 mesh) with benzene. The melting point of V is llO°-111°C and the proton NMR spectrum has a singlet at 3.90 ppm and a multiplet at 3.50 ppm. 3. Preparation of 1,7,10,l6-Tetraoxa-4,l3-diazacyclooctadecane (lst Reduction) Freshly distilled over sodium tetrahydrofuran, is placed in a 3 neck round bottom flask. Then 12.0 g of LiAlH are added cautiously 4 by stirring the solution. In hot THF 13.8 g of product V are dissolved, placed in a dropping funnel and added dropwise in the flask in order that the reaction temperature does not exceed 30-40°C. It is protected from humidity by covering it with a tube filled with CaClz. 24 After the end of the addition it is refluxed for 25 hours. It is cooled to room temperature and the excess of LiAlH is destroyed by 4 adding slowly at first a mixture of 20 ml H 0 with 50 ml THF, then 2 80 ml of 15% NaOH and again the mixture of H 0 with THF until no gas 2 is released. It is filtered under vacuum through a medium sintered glass funnel and the precipitate is washed with hot benzene. The filtrate and the benzene washings are combined and the solvents are evaporated off in a rotovapor apparatus. A white solid, the product V1, is obtained. It is recrystallized from benzene-petroleum ether mixture, and vacuum dried for 24 hours. The proton NMR spectrum of VI in CDCl has a singlet and a triplet.at 3.58 ppm due to the -CH 3 a triplet at 2.78 ppm due to the NCH 2-0 protons 2- protons, and a singlet at 2.25 ppm due to the —NH protons. The melting point of V1 is 115-116°C. 4. Preparation of 2,9-Dioxo-4,7,13,16,21,24—hexaoxa-l,lO-diaza- bicyclo(8,8,8)hexacosane (Dilactam of the C222 Cryptand) (2nd Cyclization) A solution of 26.2 grams of the first reduction product, VII, in 500 ml of dry benzene and a solution of 11.0 grams of diacid chloride, IV, in 500 m1 of dry benzene are added into 1 liter of dry benzene in a 5 1 flask. For the second cyclization instead of the previous high dilution method, the flow synthesis technique is also applied with similar results. The product, VIII, the dilactam of C222 cryptand is obtained which is purified by elution through an alumina column (80-100 mesh) using benzene as the eluent. The melting point of XIII is 114°C. 25 The proton NMR spectrum of XIII in deuterated chloroform has several peaks between 3.3 and 4.6 ppm. By reduction of the dilactam, VIII, and then purification, the C222 cryptand can be obtained. The detailed procedure is as follows. 5. Preparation of 2,2,2 Cryptand (2nd Reduction) Ten grams of the second cyclization product, VIII, is dissolved in 200 ml of tetrahydrofuran. One hundred fifty ml of l M solution of borane in THF is slowly added to the flask at 0°. After the addition has been completed, the solution is stirred for a half hour at this temperature and then refluxed for an additional hour. A white precipitate forms during this process. The solution is cooled to room temperature and excess reagent is decomposed by adding 50 ml of H O. (The solution must become clear after the addition of H O.) 2 2 Solvents are evaporated. Approximately 10 grams of the product (diborane adduct) IX, are formed. The diborane adduct is dissolved in 200 m1 of 6N hydrochloric acid, the solution is refluxed for an hour and then evaporated to dryness. The white crystalline solid cryptand C222‘2HC1, X, is dissolved in 100 m1 of conductance water and the solution is passed through an anion exchange column (Dowex l-X8, 20-80 mesh). The column is washed continuously with conductance water until the eluent is neutral. The solution is evaporated and further drying of the product XI, is done by using the aZeotropic mixture evaporation technique. In this case, dry benzene is added to the wet solid and evaporated. The white solid "2,2,2-crypt" so obtained is vacuum dried for a day before any further purification. The melting point of C222 XI, is 68—69°C. The proton NMR spectrum of X1 in 26 CDCl3 has a triplet at 2.65 ppm due to NCH2 3.60 due to OCH2 protons and a singlet at 3.68 due to OCHZCHZO protons, a triplet at protons. 6. Purification of Final Product Purification of the final product, X1, is carried out in three steps. The first step is n-hexane extraction. This is followed by vacuum sublimation and finally by the zone melting method (47). The compound is stored in the dark under vacuum. Synthesis Experimental Since the synthesis of the C222 dilactam was performed in collaboration with Dr. Dye's research group, it will be indicated in this section which steps were performed in this investigation, which method of the previous described ones was followed, the quantities that were used and the yield of the reactions. For the synthesis of the triglycolyl chloride IV, both methods (pp 19—20) were used. Two batches of diacid chloride were prepared. In Lehn's method the quantities used are the ones described previously. In the preparation of the diacid, III, the yield of the reaction was about 65%. The 1H NMR spectrum in D 0 gave two singlets, one at 3.70 ppm 2 for the -OCH CH O- protons and one at 4.20 ppm for the -OCH C00- 2 2 2 protons. Proton NMR shows no impurities in the spectrum which has two singlets one at 3.65 ppm and one at 4.30 ppm. The other method of the diacid chloride preparation was also followed exactly as it was described previously (pp 20-21). 27 In the purification of the first cyclization product, the dilactam, V, the yield was 82%. M.P. 113°C. 1H NMR shows no impurities. NMR spectrum has a singlet at 4.00 ppm due to -COCH2- protons and a multiplet at 3.5 ppm due to —OCH — and -NCH2- protons. 2 For the reduction of the dilactam, V, the quantities used were three times larger than the ones described on page 23. After two recrystallizations from benzene-petroleum ether the yield was 60%. The pure compound has a m.p. of ll4-ll6° and the PMR spectrum shows at 3.58 ppm (stt) l6 protons (—OCH2-), at 2.78 ppm (t) 8 protons -NCH - and at 2.10 ppm —NH. 2 For the second cyclization the flow technique was used. The yield was 90%. To purify the dilactam of C222, VIII, two recrystallizations from benzene-petroleum ether were performed but the PMR spectrum showed a small impurity from unreacted monocyclic amine. Finally it was purified by elution through an alumina column using dry benzene as an eluent. The M.P. of the compound is 113-114°C. The PMR spectrum is given in Figure 6. 28 .0cmua%uu NNNU mo amuomafiw mnu mo abuuommm mzz acuoum nv0“ ccnua O.“ .0 muswfim CHAPTER IV SPECTROSCOPIC STUDIES OF COMPLEXATION OF ALKALI METAL IONS, WITH THE DILACTAM OF C222 SPECTROSCOPIC STUDIES OF COMPLEXATION OF ALKALI METAL IONS, WITH THE DILACTAM OF C222 1. Introduction Nuclear magnetic resonance (NMR) has become a powerful tool for the investigation of complexation reactions. The chemical shifts and line widths of the nuclear resonances of alkali metal ions nuclei can give information about ion-ligand, ion-solvent and ion—ion interactions. 4 cmz), and Sodium-23 has a large quadrupole moment (0.1 e X 10-2 its chemical shift range is rather large (about 40 ppm). These two factors make 23Na nucleus a sensitive probe of the electronic environment around the nucleus as previous studies in this laboratory (19-22) and elsewhere (18,25,55) have shown. Lithium-7 nucleus is highly suitable for nuclear magnetic resonance studies because the resonance lines of Li+ ion in solutions are exceptionally narrow and chemical shifts can be measured with considerable accuracy (27). Both 23Na NMR and 7Li NMR have been found useful techniques for determination of the formation constants of weak and medium strength complexes (15,16,45). The purpose of this study is the investigation of the complexation reaction of Li+ ion and Na+ ion with the dilactam of C222 in different solvents and the determination of the formation constants, where possible. The addition of the dilactam to a lithium or sodium salt 29 30 solution results in a definite shift of the chemical shift of the 7L1 or 23Na resonance when complexation takes place. If the rate of exchange of the metal ion between the two sites, free ion in the bulk solution and the complex, is greater than /§/0Av, where Av is the difference between the characteristic resonance (in Hz) of each site, only one population-average resonance is observed. In all cases in this study only one resonance line is observed. 2. Lithium-7 NMR Stugy The 7L1 chemical shifts were determined as a function of dilactam/Li+ mole ratios. The results are shown in Table 11. Typical spectra obtained with the dilactam of C222 are shown in Figure 7. In dimethylsulfoxide, water, methanol and dimethylformamide solutions, the solvent molecules have a strong solvating ability and compete quite successfully with the ligand. There is not enough evidence that complexation is occurring because there is not enough change of the chemical shift from the position characteristic of the solvated Li+ ion in the above solvents. In the case of formamide, a solvent with a medium solvating ability, and of acetone and tetrahydro- furan with medium to low solvating ability, a lithium complex is formed, as shown by the variation of the chemical shift (Table II). In order to determine the formation constants of Li+—dilactam complexes in pyridine, tetrahydrofuran, propylene carbonate, acetonitrile and nitromethane solutions, the 7L1 chemical shifts were measured as a function of ligand/Li+ mole ratio (Table III). The exchange of Li+ ion from the bulk solution and the complex is fast compared to the NMR time scale, therefore, only the population- average chemical shift is observed, 31 nWL‘)‘ °°°° ”L” 0.56 H ”WJLm-a-W 1.99 t—i 2ppm Figure 7. Change of 7Li chemical shift Owith dilactam/Li+ mole ratio at constant [Li+] = 0.015 M in acetonitrile. 32 0H0.0 OHUMA 0H0.0 OHUHA 0H0.0 OHUHA 0H0.0 OHUfiA NH.H o wo.H o. NH.H m SH.H o oNo.o cause magaav “Seem amusemeu age H+Ha0\fiamuumfla90 Am00+aa0 samm 0cm H.mm mHSumHmQEmH ucmumcoo um mucm>Hom msowum> CH mmmeanu asfisuflq .NNNU mo Emuomafla mzu mo mvsum MZZIHA m mo mo mucuwo< mmwameuom Omzm usm>aom .HH mHQmH 33 Azufiafinfiuamomnm ofiumcwme wow wmuomuHOUV uwums CH q cause m.o.s mm Sufism Hmuaamcu nuasanuaam Hm.o- o N mH.o o H am.o m.o mk.o H o mm.o o o oHo.o cause any .36.. o .36: m mm.o- o. mm.ou m mm.ou H o mq.01 0H.0 OHUHA mic emacfiucoo HH magma 34 Table III. 7L1 Chemical Shifts as a Function of Ligand/Li+ Mole Ratio in Different Solvents at 33 : 2°C Pyridine [LiC104] = 0.020 E THF [LiClO4] = 0.010 M [Dill/ 0(ppm)a [Dil]/[Li+] 6(ppm)a [Li ] 0.00 -2.27 0.00 0.87 0.15 -1.99 0.25 0.68 0.30 -l.86 0.40 0.49 0.46 -1.68 0.64 0.22 0.61 -1.51 0.71 0.16 0.77 -1.38 1.20 -0.10 0.89 -1.26 1.33 -0.18 1.04 -1.16 1.68 -0.19 1.25 -l.ll 1.78 -0.20 1.50 -1.05 2.00 -0.24 1.69 -l.00 2.27 -0.26 2.05 -0.91 2.84 -0.26 2.25 -0.94 2.39 -0.91 PC [L1C104] = 0.011_M CH3N02 [LiClOa] = 0.015 0.00 0.80 0.00 0.18 0.21 0.55 0.20 0.02 0.35 0.35 0.27 -0.08 0.53 0.18 0.40 -0.10 0.65 —0.02 0.59 -0.24 Table III Continued Acetonitrile [LiClO4] = 0. 0. 0. .92 .20 .32 .48 .69 .85 .26 .66 .16 00 15 .31 .40 .56 .67 .77 .95 .02 .12 .30 -0.11 -0.14 -0.07 -0.05 -0.20 -0.24 -0.33 -0.35 -0.35 2.58 2.16 1.75 1.54 1.11 0.95 0.64 0.20 0.17 0.03 -0.01 015 0.92 1.13 1.33 1.47 1.67 2.04 2.40 Acetonitrile [LiBr] = 0.00 0.13 0.33 0.40 0.60 0.67 0.82 0.93 1.17 1.27 1.58 2 1. .36 .40 .56 .69 .75 .73 .79 .77 .79 .77 .77 0.015 .02 68 .22 .05 .74 .59 .27 .09 .06 .12 .16 36 Table III Continued 1.48 -0.06 2.13 -0.35 1.70 -0.08 2.37 -0.31 1.91 -0.08 3.02 -0.37 1.99 -0.14 3.58 -0.35 2 37 -O.l4 3 00 -0 18 aLithium-7 chemical shift gs 4.0 M LiClO in water (corrected for 4 magnetic susceptibility) 37 L'O Mon /MLi+ 210 Figure 8. Plot of 7L1 chemical shift with reference to 4.0 M aqueous LiClO4 y_s_ mole ratio of dilactam to Li+ at ©[Li+] = 0.02 g in 01430, Q [n+1 = 0.019 in THF, @ [1.1+] = 0.015 I! in MeOH, O [n+1 = 0.015 1.1 in H20, O[Li+] = 0.015 in formamide, D [1.1+] = 0.10 91 in DMF, 69 [Li+] = 0.015 M in acetone. 38 dobs = 6MXM + GMLXML (2) where 0 is the observed chemical shift, XM and XM are the mole o L bs fractions of the free and complexed metal ion respectively while 5 and 0 are the respective chemical shifts for the two species. M ML Assuming a 1:1 complex, we have the equilibrium M + L 3 ML (3) where L is the ligand. The formation constant of the complex, in concentration units, becomes CML CMCL where CM and CML are the equilibrium concentrations of the free ligand K (4) and the complex respectively. 2 2 /2 _ t t 2t 2t 2tt t t 1 sobs - (KCM KCL 1) :_(K CL + K CM 2K CMCL + 2KCL + 2KCM + 1) 6 - 0 M tL+5HL (5) 2KCM t L’ the total concentration of the metal ion and In eq. (5), cg and C of the ligand respectively, are known and 5M can be easily determined from measurements on solutions of lithium salts without the ligand. Eq. (5) then contains two unknowns K and 6M In the case of a rather L' strong complex 5 ML can be determined experimentally by the addition of such excess of L that essentially all of the metal is complexed. In the case of weak complexes eq. (5) is solved by the following t Ct and 6M are CM’ L procedure. The experimental parameters Gobs’ substituted into the equation, and K and 6ML are varied until the 39 calculated chemical shifts correspond to the experimental values within the error limits. The data were analyzed on a CDC-6500 computer using the FORTRAN IV program KINFIT (54). The values obtained were K = 440 i 97 in pyridine, K = 1327 i 263 f in tetrahydrofuran, Kf = 4053 i 2040 in nitromethane and Kf = 1686 i 274 in acetonitrile. In all the above cases LiClO4 was used as the lithium salt. In pyridine which has strong solvating ability the complex is weaker than in THF which has a medium to low solvating ability. In acetonitrile and nitromethane with low solvating ability the complexes are even stronger. By changing the anion from perchlorate to bromide in the case of acetonitrile we end up with a value of K = 1348 1:372 which is f essentially the same as in the case of the perchlorate anion. This is an indication that the lithium ion complexed by the dilactam is independent from the counter ion. In the case of propylene carbonate the determination of the formation constant was not possible, because it exists an anomaly, probably due to a secondary reaction. All the above values are the concentration constants. However, since the complexation reaction + + Li + Dilactam : Li - Dil (6) does not involve separation of charges, these values should represent reasonable approximations of the thermodynamic constants. 40 .muafiom Hmucmsfiummxo mum mqu can m>upo poumumamw Lofififioo ma 0:: unom .05—Cab?” ca m 0N0.0 a fad uamumcoo um +aa ou 538.30 00 oaumu mHoE.MN «OHUHA msooavm m.0.¢.0u mucoumwmu Sofia amenm Hmofiamno figs 00 uoam .m muawwm +3.04 \ 3 364 ON 0.... 0.0 41 .mucflom Hmucmswummxm mum muov 0cm m>wsu wmumpmcmwlnmusmEoU ma mafia 0HHom .mme cw m.0H0.0 u ~+wga ucmumcoo um +HA Cu Emuumfiflv mo Oflump mHoE MN «anwq msomsvm.m 0.0 Om mucmpmwmu SuwB umwnm Hmofiamsu HAN .0H mpswflm 0d 0.— 0.0 42 .mucfioa Hmucoefiwmaxw mum muow 0cm m>u=o vmumpmcmwlumusaeoo ma mafia pwaom .mcmcumEOMUflc cw m.mac.0 u H+fl4_ ucmumcou um +00 Ou Emuumafiv mo owumu wHoE.mN «Oaufiq msomsvm.m 0.0 o» mocmumwou Saws umwcm HmoHEmcu HA tsfljafl. .HH magmas 0.0 l? 43 .mucwoa HmucwEHumaxm mum muov 0cm o>usu mwumumcwwlpmupanu ma mafia 0waom .mHHpuwCOuwom :H m.mH0.0 u H+HAH ucmumcou um +flA Ou EmuumHHp 00 owumu mHoE MN «OHUMA mzomscm m.0.q cu mozwumwwp Sufi3 uwwcm HmUHEmLU HAN .NH muswwm 3., .w IF 44 .mucwom HmucmEHumaxw mew muow 0cm m>pso cmumumcmwlpmuzaaoo ma CCHH wfiaom .mfiwuuHCOuwum cw m.mao.o u HumfiaH ucmumcou um +fiq\aw0 mo ofiump wHoE.MN «OHUHA msomsvm m.0.q Cu mucoumwmu :uH3 uwwzm HmUflEmso fig 00 uoam .MH wuswwm a +38 \ :ol