A $1UDY OF HYDRO-GEN BONDING AND g _ .. 7, mmnoNAL ISOMER‘ISM LN AMLm wig, ’ 2:2 NUCLEAR MAGNETHC momma ” . .: SPECTROSCOPY 5 . g}; ; TH ES’S ..__ ___ ' LL, Q [J LIBRARY 2 MicmgaL‘L State University MICHGAN STATE UNEVERSITY EAST LANSING fx’EiCHiGAN ‘I “q _—._- . r . M‘ 1.. .. “v .‘le‘ »~ -0 Ooh-OF. Q—Q ‘... ‘1— . .. .n u r , .._ ... . I 4.+w.1nl_.‘ 1.5121,. ._ .Y .. it... Run...» 71.». 1-1. ABSTRACT A STUDY OF HYDROGEN BONDING AND ROTATIONAL ISOMERISM IN AMIDES BY NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY by Laurine Anna LaPlanche A Varian A-6O model nuclear magnetic resonance (NMR) spectrometer was used for observing the proton resonance of a series of N-monosubstituted and N,- N-disubstituted amides. The nature of the complex formation between benzene and amides was studied by observing the NMeresonance peaks of a series of sixteen symmetrically N, N-disubstituted amides upon dilution with benzene. An approximate correlation of N-alkyl peak shift in benzene with amide dipole moment and molecular volume indicates a dipole= induced dipole interaction. The decrease in the extent of peak shift with distance of the observed proton(s) from the amide nitrogen atom, as determined qualitatively by the number of intervening bonds, sug- gests that the 1r~-electrons of the benzene ring are interacting with the nitrogen atom. A study of fifteen unsymmetrically N, N-disubstituted amides was made and the‘N-alkyl resonance peaks were as signed to the respective rotational isomers on the basis of the magnitude of the long range coupling constant,- J in the formamides, and by a comparison HCONCH§ of chemical shifts in the acetamides. The preferred configuration in the formamides was found to be the isomer in which the bulkier N-alkyl substituent is trans to the carbonyl oxygen atom; however, in the acetamides the isomer in which the bulkier N-alkyl substituent is cis to Laurine Anna LaPlanche the carbonyl oxygen is preferred. The peak assignments were checked by benzene dilution studies. For four highly substituted amides, such as N-E-butyl-N-methyltrimethylac etamide, only one set of N-alkyl resonance peaks was observed in the NMR spectrum. However, two sets of resonance peaks appear in the NMR spectrum of a sulfuric acid solu- tion of the amide. Examination of the spectra of eighteen N-monosubstituted amides showed that four of these, N—methylformamide, N—ethylformamide, , N-isopropylformamide and N-t—butylformamide, exist in both the (l? andms configurations about the central C—N bond. The percentage of g isomer increases as the N—alkyl substituent becomes more bulky. In the other amides, where the carbonyl carbon substituent is larger than hydrogen, only the w configuration was found. The 2 coupling constant between the formyl and nitrogen protons more than doubles in sulfuric acid solution. In order to study the self-association of N—monosubstituted amides by NMR, a theoretical method for treating chain association which relates two equilibrium constants, K12 for monomer —‘ dimer, and _ <_._ K for n—mer + monomer ——-—“ (n + l)-mer equilibria, to the concen— (— tration of the solution, the observed chemical shift of the solute hydrogen bonding proton, and the chemical shifts of the free and bonded protons in the polymers was developed. Two special cases were used to analyze the data: the inert solvent case and the hydrogen bonding solvent case; each was programmed for use on the MISTIC Computer at Michigan State University. The equilibrium constants found for the amides in the inert solvents carbon tetrachloride and cyclohexane reveal that E >> K12, and both are much larger than the equilibrium constants found in solvents , which are capable of hydrogen bonding to the amide. In chloroform solutions of N-methylacetamide, N—isopropylacetamide and Laurine Anna LaPlanche N—t—butylacetamide, both-K12 and E decrease as the bulk of the N-alkyl substituent increases. For N-isopropylacetamide in the solvents chloroform, diethylketone and dioxane, K12 and k— remain relatively constant, with Ex 2 K12; however, in dimethylsulfoxide, both K12 and If decrease ten—fold. The chemical shift of the nitrogen proton in the N-isopropylacetamide complex was found to lower magnetic fields in the series: dioxane, diethylketone, dimethylsulfoxide, probably reflect- ing the strength of the hydrogen bond in the complex. A STUDY OF HYDROGEN BONDING AND ROTATIONAL ISOMERISM IN AMIDES BY NUCLEAR MAGNETIC RESONANCE. SPECTROSCOPY BY Laurine Anna LaPlanche A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCT OR OF PHILOSOPHY Department of Chemistry 1963 ACKNOWLEDGMENTS It is with sincere appreciation that I acknowledge the encourage- ment and counsel of Professor‘M. T. Rogers under whose direction this investigation was conducted. -I also wish to express my gratitude to Doctor H. B. Thompson, for programming the hydrogen bonding equilibria equations and contributing considerably to their development; to Doctor R. H. Schwendeman, for many helpful discus sions; to the National Institutes of Health for a fellowship; and to the National Science Foundation for grants subsidizing part of this research. I I I I I I I l I I I I I \l\’ as; Ix \ \l\ \/\t l\/ r.‘ ’|\ >'\ ’I‘ >.\ r5 q‘ l.\ “I: «x I“ >I‘ ’I‘ ii VITA Laurine Anna LaPlanche candidate for the degree of Doctor of Philosophy Dissertation: A Study of Hydrogen Bonding and Rotational Isomerism in Amides by Nuclear Magnetic Resonance Spectroscopy Outline of Studies Major: Physical Chemistry Biographical: Born, July 4, 1938, New York Undergraduate Studies: B. S. Chemistry, The University of Maryland, College Park, Maryland, 1959. Honoraries: Phi Kappa Phi Professional Affiliations: American Chemical Society The Society of Sigma Xi Sigma Delta Epsilon TABLE OF CONTENTS INTRODUCTION . . . . . . . . . . . . . HISTORICAL REVIEW . . . . . . . . THEORETICAL BACKGROUND . . . . . Energy Transitions in NMR . . . . Spin—Spin and Spin—Lattice Relaxation The Hamiltonian in NMR. ........ The Spin-Spin Coupling Constant . Spin Decoupling . . . . . . . . ..... The Chemical Shift ...... Chemical Shifts in Solution . . Page . . ...... . 1 ° 0 0 O O 3 . . . . 16 ..... . . . 16 . . l7 ...... . 19 O D O O I I 22 0 Q 0 23 . 24 The Determination of Intermolecufllar Hydrogen Bonding Equilibrium Constants for Self- Associated Species . . 34 The Special Case of the Self=Associated Solute Species in an Inert Solvent ........ . 35 The Special Case of the Self-=Associated Solute Species in a Hydrogen Bonding Solvent . . . . . 38 EXPERIMENTAL . . . . . . . . . . Determination of NMR Parameters . Preparation of Amides Purification of Solvents . . . . . . Preparation of Samples . . . . . . U 0 O O 44 9 O 44 . . . 45 . . ...... 51 52 Computation for Hydrogen Bonding Studies. . . . . . . . 53 RESULTS............ ..... ......... 57 Symmetrically N, N-Disubstituted Amides. . . . . . . . 57 N, N-Diethylformamide ............... 57 N,N-Diethylacetamide . . . N, N-Diisopropylformamide. N, N—Diisopropylacetamide . o a o N,N-Diethylchloroacetamide . . . o o 57 . . 60 . 60 . 64 TABLE OF CONTENTS — Continued N,N-=Diisopropylpropionamide . . . . . . . N, N-Diisobutylformamide . . . . . . . . . . N, N-Di—_1_'1_=propylformamide ...... . ..... N, N-Di-napropylacetamide. . . . . . . . . ‘Unsymmetrically N, N—Disubstituted Amides. . ..... N=Ethy1=-N=methylformamide ............ N—Ethyl—Nemethylacetamide . . . ..... . . . . N—Ethyl=N—methyltrimethylacetamide . . ..... N=-n=Butyl=N=methylformamide .......... N=E=Butyl=N=methylacetamide ........... N=E~ButylwN-methylisobutyramide ......... N'E' Buty1=N=methyltrimethylac etamide . . N—Cyclohexyl-Numethylformamide ......... N—Cyclohexyl=N-=methylacetamide ...... N-Isopropyla-Numethylformamide . . . . . . a a a N—Isopropyl—N=methylacetamide .......... NuFormyl- 2—methy1piperidine ........... N—Ac etyl= Z=methylpiperidine. . ....... N-Methyl==Njubutylformamide. . . . ....... N—Methyl=N=_t_== butylformamide . . . o . . N-Monosubstituted Amides ......... . . . . N-Ethylacetamide ...... . . . . . . ...... Nelsopropylacetamide . . . . ...... . . . . . N—Methylformamide . . N—Ethylformamide ........ . . . . . . ........ N—Is opropylfo rmamide ............... N—t—Butylformamide ............... . N- T5— -n Butylformamide and N-15-n«= Butyl— acetamide . . . ................ Hydrogen Bonding in N— Monosubstituted Amides. . DISCUSSION OF RESULTS . . . ...... . ......... Symmetrically N, N—Disubstituted Amides ........ Unsymmetrically N, N- Disubstituted Amides ....... N- Monosubstituted Amides . . . . . . . . . Method of Obtaining Equilibrium Constants in Hydrogen Bonding Studies . . . ...... . . . . . . . . . Results of the Hydrogen Bonding Studies ......... SUMMARY ....................... . . . . . BIBLIOGRAPHY ......................... V 105 107 119 119 120 123 125 128 130 LIST OF TABLES TABLE Page 1. Energy Barriers to Internal Rotation about the Central C=N Bond and Isomer Ratios in Some Disub— stituted Formamides. . . . . . . . . . . . . . . 6 II. Effect of Temperature on Rate of Quadrupole Relaxa- tioninAmides..................... 9 III.. Coupling Constants for N=Methylformamide . . . . o 10 IV. Thermodynamic Properties of Hydrogen Bond Form«= ation of Amides in Benzene Solution . . . . .. . .. . 11 V. Thermodynamics of Hydrogen Bond Formation of N—Methylacetamide at 25° c. . . . . 12 VI. Association Constants and Association Shifts for the Hydrogen Bonding of Chloroform to Several Bases at 0 25C............ ............ 15 VII. Method of Preparation and Boiling Points for Sym= metrically N, N-Disubstituted Amides. . . . . . . 46 VIII. Method of Preparation and Boiling Points for Unsym— metrically N, N-Disubstituted Amides. . . . . . . . . 47 IX. Method of Preparation and Boiling Points for N=Mono- substituted Amides . ..... . . . . . . . . . . . . . 48 . X. Chemical Shifts of the N-Alkyl Resonance Peaks of Symmetrically N,N-Disubstituted Amides . . . . . . 58 XI. Chemical Shifts of the N=A1ky1 Resonance'Peaks of Symmetrically N, N—Disubstituted Amides in a Five Mole Percent Benzene Solution . . . ........ 69 XII. Correlation of the Chemical Shift of the N—Alkyl Resonance in Symmetrically N, N- Disubstituted Amides in Benzene with Dipole Moment and Molecu- 1arVolume......... ........ 70 vi LIST OF TABLES = Continued TABLE XIII. XIV. XV. XVI. XVII. XVIII. XIX. XX. XXI. XXII. XXIII. Page Chemical Shifts of the N—Alkyl Resonance Peaks of Umsymmetrically N, N=Disubstituted Amides and the Percentage of the Preferred Configuration ...... 71 The Coupling Constant Between the Formyl Proton and the N—Methyl Protons in Formamides, in the Pure Liquid and in Sulfuric Acid Solution . . . . . . . . . Chemical Shifts of the N-Methyl Resonance Peaks of N—Monosubstituted Amides. . . . . . . . . . . . . . Coupling Constants in N=Monosubstituted Form= amides..................... . Concentration Dependence of the Chemical Shift of the Nitrogen Proton in N—Isopropylacetamide in Carbon Tetrachloride Solutions. . . . . ..... Concentration Dependence of the Chemical Shift of the Nitrogen Proton in N-Isopropylacetamide in Cyclohexane Solutions. . . . . . . . . . ..... Concentration Dependence of the Chemical Shift of the Nitrogen Proton in N-Methylacetamide in Chloro— form—dSolutions................... Concentration Dependence of the Chemical Shift of the Nitrogen Proton in N-lsopropylacetamide in Chloroform=_d Solutions. . . . . . . . . . . ..... Concentration Dependence of the Chemical Shift of the Nitrogen Proton in N—i—Butylacetamide in Chloro- form=£i_ Solutions ............ . . . Concentration Dependence of the Chemical Shift of the Nitrogen Proton in N—Isopropylacetamide in »DioxaneSolutions................... Concentration Dependence of the Chemical Shift of the Nitrogen Proton in N—Isopropylacetamide in Di— ethylketone Solutions . . . . . . . . . . . . . . 72 92 93 113 113 114 114 115 115 116 LIST OF TABLES - Continued TABLE XXIV. XXV. XXVI. XXVII. Page Concentration Dependence of the Chemical Shift of the Nitrogen Proton in N—Isopropylacetamide in Dimethyl-= sulfoxide Solutions. . . . . . . ........ . . . . 116 Values of K12, X, vm and Vd for N=Isopropy1aceta= mide in Carbon Tetrachloride and Cyclohexane Solutions................. ..... .. 117 Values of L12, 1:, Vm and Vd for N—Methylacetamide, N—Isopropylacetamide, and Nat «Butylacetamide in Chloroform-ug Solutions. . . .7. . . . . . ...... 117 Values of L12, E, Vc and Vd for N=Isopropy1aceta= mide in Dioxane, Diethylketone, and Dimethylsul.= foxide Solutions. . . . . . . . . . . . . ....... 117 viii FIGURE 1. 2. 10. 11. 12.. 13. LIST OF FIGURES Page Resonance in amides. . . ...... . . . ...... l Formamide...................... 3 Spin coupling constants in (a) N, N=Dimethylform= amide, (b) N—Methylformamide ........ . . . 4 The proposed association complex between an amide andbenzene....... ...... ...... 5 Resonance structures for the 0—protonated form of amides.. ..... 7 Rotational isomerism in N=monosubstituted amides 7 An approximate representation of the long range shielding effect of the carbonyl group . . . . . . . . . 25 The interatomic currents in benzene 26 Expected orientations of (a) a disk— shaped, and (b) a rod- shaped solvent molecule with respect to a spheri— cal solute molecule ..... . . ...... 28 A plo__t of S as a function of Z, with L12 — 5.0 (mf)"'1 andL=10."10(mf) ...... 42 A plot of F' as a function of 21 with Z— — 0.2.0, L12 — 5.0(mf)' ,L=10.rn0( £-)1. Diagram of the computer program used in the hydro- genbondingstudies................... Diagram of the seftion of the computer program whichcalculatesY/Y. . . . . . . . . . . . . . . . . . Diagram of_the section of the computer program which calculatesZ/Z.... ..... 43 54 55 56 ., . LIST OF FIGURES - Continued FIGURE Page 15. H1 magnetic resonance spectrum of HCON(CHZCH3)Z. . 59 16. H1 magnetic resonance spectrum of CH3CON(CH2CH3)Z 59 17. H1 magnetic resonance spectrum of CICHZCON(CHZ CH3)Z, (a) neat, (b) to (d) in benzene . . ..... . . . 61 18. H1 magnetic resonance spectrum of HCON[CH(CH3)Z]Z 63 19. H1 magnetic resonance spectrum of CH3CON[CH(CH3)Z]2 63 20. H1 magnetic resonance spectrum of CH3CHZCON [CH(CH3)Z]2........................ 65 21. H1 magnetic resonance spectrum of HCON[CH2CH (CH3)2]Z .......... . ......... . ..... 66 22. H1 magnetic resonance spectrum of HCON(CH2CH2CH3)2 67 23. H1 magnetic resonance spectrum of CH3CON(CH2CH2 CH3)2. . o ..... . . o oooooo o u ........ 67 24. H1 magnetic resonance spectrum of HCON(CH3) (CHZCH3). . . . . ........ . ....... . . . . 73 25. H1 magnetic resonance spectrum of CH3CON(CH3) (CH2CH3). u o o o o a o o n o o o o o o a o o o a o o 73 26. H1 magnetic resonance spectrum of (CH3)3CCON(CH3) (CHZCH3) .............. . . . . 76 27. H1 magnetic resonance spectrum of HCON(CH3)(CHZ CHZCHZCH3) ..... . . . . . . . . . . ........ 77 28. H1 magnetic resonance spectrum of CH3CON(CH3)(CHZ CHZCHZCH3) ....... . ........ . . . . . 77 29. H1 magnetic resonance spectrum of HCON(CH3)(CH2 CHZCHZCH3) upon dilution with benzene. . . . . . . 79 x LIST OF FIGURES— Continued FIGURE Page 30. H1 magnetic resonance spectrum of (CH3)3CCON(CH3) (CHZCHZCHZCH3). . . . . . . ..... . . . . . . 80 31. H1 magnetic resonance spectrum of HCON(CH3)(C6H11) 82 32. H1 magnetic resonance spectrum of CH3CON(CH3) (C6H11)................... ...... 82 33. H1 magnetic resonance spectrum of HCON(CH3)[CH (CH3)2] ..... . . . ................ 84 34. H1 magnetic resonance spectrum of CH3CON(CH3) [CH(CH3)2]-, (a) neat, (b) in benzene . . . . . . . . . 85 35. H1 magnetic resonance spectrum of HCON(Z—CH3— C6H16) ......... . ...... 87 36. H1 magnetic resonance spectrum of CH3CON(Z-CH3— C6H10), (a) neat, (b) in sulfuric acid ......... 87 37. H1 magnetic resonance spectrum of HCON(CH3)[C (CH3)3] ...... 89 38. H1 magnetic resonance spectrum of CH3CON(CH3) [C(CH3)3].......... .......... 90 39. H1 magnetic resonance spectrum of CH3CONHCH2CH3 94 40. H1 magnetic resonance spectrum of CH3CONHCH(CH3)Z 95 41. H1 magnetic resonance spectrum of HCONHCH3. . . 97 42. H1 magnetic resonance spectrum of HCONHCHZCH3 . 98 43. H1 magnetic resonance spectrum of HCONHCH(CH3)2 98 44. H1 magnetic resonance spectrum of N—methyl peaks in (a) HCONHCH3 (b) HCONHCHZCH3 (c) HCONHCH (CH3); ((1) HCONHC(CH3)3 ....... . . . . . . . . 99 xi LIST OF FIGURES — Continued FIGURE Page 45. H1 magnetic resonance spectrum of N—methyl peaks in (a) HCONHCH3 (b) HCONHCHZCH3 (c) HCONHCH (CH3); ((1) HCONHC(CH3)3 in benzene solution. . . . . 100 46. H1 magnetic resonance spectrum of formyl proton of HCONHCH3 in sulfuric acid. . ..... . .. . . . . . . 101 47. H1 magnetic resonance spectrum of formyl proton of HCONHCH(CH3)Z in sulfuric acid. . . . . . ...... 101 48. H1 magnetic resonance spectrum of formyl proton of HCONHCHZCH3 in sulfuric acid . . . . . . . . . . . . 103 49. H1 magnetic resonance spectrum of formyl proton of HCONHC(CH3)3 in sulfuric acid . . . . . . . . . . . . 106 50. H1 magnetic resonance spectrum of HCONISHCHZCHZ CHZCH3.......... .............. .108 51. H1 magnetic resonance spectrum of HCONISHCHZCHZ CHZCH3 in benzene solution . . ........ . . . . 108 52. Plot of 6 against mole fraction for N—isopropyl- acetamide in carbon tetrachloride and cyclohexane solutions. . . . . . . . . . . . ...... . . . . . . 109 53. Plot of 6 against mole fraction for N-methylacet— am1de, -1sopropy1acetam1de, and N—_t_-buty1acet- amide in chloroform—£1 solutions . . . . . . . . . . . 110 54. .Plot of 6 against mole fraction for N—isopropyl— acetamide 1n dioxane, diethylketone, and dimethyl- sulfoxide solutions ....... . . . . . . . . . . . . 112 55. The least squares deviation_Z (6 ~ (50)2 obtained for combinations of L12 and L used in the hydrogen bonding solvent program with data from solutions of N-_t_-buty1acetamide in chloroform-d ...... . . . .118 56. The configuration of the preferred isomer in unsym- metrically disubstituted formamides and acetamides. 121 xii INTRODUCTION The importance of the amide linkage in polypeptide chains has resulted in many investigations into the physical structure of amides. Three properties of amides are especially amenable to study by nuclear magnetic resonance (NMR): hindered rotation about the central C—N bond, configuration about this bond, and the self-association or complexation of amides by hydrogen bonding. The considerable double—bond character in the central C-=N bond of amides leads to the occurrence of two stable planar configurations. As sites A and B in Figure 1 are usually magnetically non=equiva1ent, R /R (B) R\ + R (B) Figure 1. Resonance in amides. the protons at each site will resonate at a different frequency in the NMR spectrum. This can provide a great deal of information about amide structure. The research reported in this thesis consists of the following: (1) the study of various symmetrically N,N—disubstituted amides and their interaction with the benzene molecule, (2) the investigation of unsymmetrically N, N-disubstituted formamides, acetamides and tri- methylacetamides, including the determination of preferred configur- ation and peak assignment, (3) the study of the configuration about the peptide bond in N-monosubstituted amides, especially of the C_1§. and m isomers found for monosubstituted formamides, (4) the develop- ment of equations which relate hydrogenxbonding equilibrium constants 1 for self-associated solutes to the observed NMR chemical shift, and (5) the application of these equations to the hydrogen bonding in N-monosubstituted amides in both inert and hydrogenribonding solvents. HIST ORICAL REVIEW The structure of the simplest amide, formamide, has recently been determined by microwave spectroscopy (1) by C. C. Costain and J. M. Dowling, and is shown in Figure 2. (X) H /I-1 (B) \c N / A / \H (A) Figure 2. Formamide. Although the molecule had previously been described by Kurland and Wilson (2) as completely planar, Costain and Dowling found that the HX-C—N—HB dihedral angle was 12 i 5° and the o-c-N-HA dihedral angle was 7 i 50. The central C—N bond was found to possess about 25% double—bond character. Pauling (3) has estimated that the resonance energy in amides is about 21 :kcal/mole, while Mizushima E} a}. (4) arrived at a value of 16 :kcal/mole for N-methylacetamide. Phillips (5) was the first to show that the two NMR resonance peaks obtained for N, N-dimethylacetamide and N, N—dimethylformamide were the result of the magnetic non—equivalence of the protons of the two ‘N-methyl groups. Gutowsky and Holm (6) later observed the co— alescence of these peaks as a function of temperature and determined the energy barrier to internal rotation. The dimethylamides were extensively studied by Woodbrey and Rogers (7), who were able to correlate the activation energy with the structure of the amide. Several authors (8-10) have dealt with the problem of whether, in dimethylamides, it is the resonance from the N-CH; group in a position _ci_s_ or trai to the carbonyl oxygen atom which occurs at a higher magnetic field in the NMR spectrum. Franconi (8), Kowalewski (9), and Hatton and Richards (11) have pointed out that the t_ran_s Ii-CON—CHJ coupling in dimethylformamide should be equal to the tans coupling in N-methylformamide (0. 9 cps), which has been shown to be predominately in the configuration shown in Figure 3b (4, 12, 13). J = 0.4 cps H CH3 H H ( ) \C N/ (b) \C N/ a - .. // \ // \ CH3 0 CH3 J=0.8 cps =0.9Cps Figure 3. Spin coupling constants in (a) N, N-Dimethyl— formamide, (b) N-Methylformamide. As it is the N-methyl resonance peak to higher magnetic field which is coupled to the formyl proton by 0. 9 cps, this peak has been assigned (8-11) to the group which is in a position _c_i_s to the carbonyl group. The study of the NMR spectra of amides upon dilution with benzene is in agreement with this assignment. Hatton and Richards (11) have proposed a specific association between benzene and the amide, whereby the noelectrons of the ring are attracted by the partial positive charge on the nitrogen and repelled by the partial negative charge on the carbonyl oxygen. This orientation places the ring in a plane parallel to the plane of the amide, as shown in Figure 4. In this position, the diamagnetic anisotropy of the benzene ring affects group B more than group A, and thus the protons at site B experience a larger shift to high magnetic field than do those at site A. Hatton and Richards (11) have observed R (B) \ + /C=N\ ‘ o R (A) Figure 4. The proposed association complex between an amide and benzene (11). that in N, N—dimethylformamide and N, N-dimethylacetamide, it is the N-methyl peak which is originally to lower magnetic field which "crosses over" the high~field peak and moves the greatest amount to high field upon dilution with benzene, and thusiiplriopose that this peak is associated with the protons at site B. The N—CHz-CH3 protons of N, N-diethylformamide and N, N-diethylactamide are also magnetically non- equivalent and usually appear as partially overlapping triplets in the NMR spectrum. Upon dilution of the amide with benzene, the low~ field triplet moves to high field faster than the highxfield triplet, so that the resonance peaks cross over each other. By analogy with the N, N-dimethylamides (11), it is proposed that the protons from the N-CHz—CH3 group which is in the position 2 to the carbonyl oxygen also resonate to higher magnetic field. Franconi (8) has assigned the preferred configuration in three unsymmetrically disubstituted formamides, N—methyl-N—u-phenyl— ethylformamide, N-benzyl-N-methylformamide, and N-benzhydryl-N- methylformamide, by comparing the NMR spectra of these amides with the spectra of the corresponding secondary amides. The preferred configuration in each of the tertiary amides was assigned to the rotational isomer which had the bulkier N-alkyl substituent £13113 to the carbonyl oxygen atom. The energy barriers to internal rotation were also found, as shown in Table I. Table I. Energy Barriers to Internal Rotation About the Central C=N Bond and Isomer Ratios in Some Disubstituted Formamides (8) PhCHCH3NCH3CHO PhCI—IZNCH3CHO PhZCHNCH3CHO Isomer Ratio 2.33 1.08 2.00 E(kcal/mole) 11i1.5 lziz 11i1.5 vo*(sec."1) 107 107 108 *Frequency factor The site of protonation of amides has remained in question for many years. Some authors believed that the site of protonation was the carbonyl oxygen (14, 15, 16), while others thought it to be the nitrogen atom (17). The NMR studies of Fraenkel and Niemann (15), Fraenkel and Franconi (14), and Berger (it 2:1. (16) support oxygen protonation, and Fraenkel and Franconi showed cryoscopically that amides were monoprotonated in 100% sulfuric acid. They (14) argued that nitrogen protonation would lead to free rotation about the central C—N bond in dimethylamides with a collapse of the N=methy1 doublet, which does not occur at very high acid concentrations. Further evidence against N-protonation is found by examining the NMR spectrum of a strongly acid solution of N-methylacetamide (14) where the Nemethyl resonance is a doublet, not a triplet as would be expected for the NHZCH3 group of the species protonated on nitrogen. Conclusive evidence for 0-pro- tonation has recently been found by Gillespie and Birchall (18), who report the presence of a new peak in the low temperature NMR spectra of solutions of N, N-dimethylacetamide, formamide, and N, N—dimethyl- formamide in fluorosulfuric acid, which may be definitely assigned to the proton on the carbonyl oxygen atom. Protonation of amides (Figure 5) increases the double-bond character in the central C—N bond (14), leading to an increase in the energy of activation to internal rotation. ~R R R + R \C—N/ H \C=N/ +// \ / \ H-0' R HO R Figure 5. Resonance structures for the O—protonated form of amides. The energy barrier to internal rotation was found to be 9.6 kcal/ mole for pure N, N—dimethylformamide, as contrasted to 12. 7 kcal/mole for protonated N, Nedimethylformamide (14). It may be noted, however, that Rogers and Woodbrey (7) found a value of 18.9 kcal/mole for the barrier in pure N, N-dimethylformamide. The NMR spectra of monosubstituted amides differ from that of disubstituted amides in that only one set of resonances is usually ob— served. Phillips (5) concluded that only one isomer is present in an appreciable amount in these amides. The trans configuration (Figure 6a) R H R R (B) \ / \ / /C - N\ /C - N R (A) O H (a) trans (b) E Figure 6. Rotational isomerism in N-monosubstituted amides. about the central C-N bond in N—monosubstituted amides has been shown to predominate over the E (Figure 6b) by dipole moment (4, 19, 20), dielectric constant (21), and vapor pressure measurements (22), and by ultraviolet (4, 19), infrared and Raman spectroscopy studies (12, 13, 23). Several bands in the infrared have been associated with the c_i§ isomer (24), but whether or not a predominatelytrai amide such as N-methyl— formamide contains any molecules with the _c_i_s configuration remains a point of controversy (13). The small ring lactams are in the £13 configuration (24, 25), but the girls form predominates in the larger rings. A few cyclic dimers of amides having the gs configuration have been reported, among them, >N-methy1carbamate (21) and N—methyltrichloroacetamide (22). A transi- tion from the m to the <15 configuration has been found in mono~ layers of N=_n-octadecy1acetamide (26). Both £i_s (27) and m (28) configurations about the peptide bond have been proposed for the residues of polypeptide chains, although the 3% configuration predominates, and is necessary for such protein structures as the awhelix. The nitrogen proton of monosubstituted amides exchanges quite easily upon heating (29), and causes the disappearance of the spin— spin coupling between the nitrogen proton and the N—alkyl substituent. The rate of collapse of the doublet as a function of temperature yields the activation energy for the exchange process. Saika (29) has found an activation energy of 14 i 2 kcal/mole for Namethylformamide and N-methylacetamide. Similar studies (30) show that the mean activation energy for proton exchange in N—15 formamide is 10 i 3 kcal/mole. In amides, the quadrupole relaxation of the nitrogen-l4 nucleus broadens the nitrogen proton resonance and usually "smears out" all spin- spin coupling. Roberts (31) has found that a rise in temperature will sometimes slow down the relaxation rate enough so that nitrogen- hydrogen coupling in several amides may be observed. The results are shown in Table II. A more efficient method for overcoming nitrogen quadrupole broadening is isotopic substitution of nitrogen-15 for nitrogen-14. Nitrogen-15, with its nuclear spin of 1/2, does not have a quadrupole moment. Sunners, Piette and Schneider (30) have analyzed the NMR spectra of N—l5 formamide and DCOleHZ. The proton chemical shifts at 60 mcs in formamide (Figure 2) are 6 = 12.0 cps and <5 B = —40.0 cps. AB X Table II. Effect of Temperature on Rate of Quadrupole Relaxation in Amides (31). NH observed Temp. for singlet =91: ' l t t It. at 35 mp e ran51 ion JNH Formamide broad singlet 50 :1: 100 60 i 4 cps Acetamide broad sing. at m.p. 175 1 10° 56 e 5 cps N—Methylformamide broad singlet not obs. to 2500 —————— ‘N-Methylacetamide broad singlet 225 d: 200 60 d: 5 cps ' ' z = 2. = . The sp1n coupllng constants are JAB 4 cps, JBX 2 1 cps, = l , = . = v _ : 1 ‘ ' JAX 2 9 cps, JNB 92 0 cps, JNA 88 0 cps and JNX 9 0 cps Interesting changes in several of the coupling constants in water and acetone solutions were observed. The mean value of the barrier to internal rotation in a 10% solution of formamide in acetone was found to be 18 .1: 3 kcal/mole. Sunners e_t a_1. (30) found that the two nitrogen protons were coupled differently to the nitrogen atom, .1 being 4. 0 cps larger NB than J . A possible explanation may be derived from the microwave spectri: of formamide (1), which shows that the bond length NeHB = 1.000 A0 while N-HA = 1. 012 A0. A shorter bond would be expected to lead to a larger coupling constant (32). A second explanation is that the bond angle (Figure 2) C—NwHB (120017'), being larger than the angle CiN-HA (117011‘), might lead to greater 5:. character in the N-HB bond, with a larger J (32). The none equivalence of the two N—H bonds has NB also been observed by Moritz (33) in the infrared spectra of amides. Partially.deuterated primary amides show two N—H stretching bands, 20-30 cm. '1 apart, due to the NHD group. These bands are believed to arise from the cis and trans relationship of the nitrogen—hydrogen bond to the carbonyl bond. The N—H bond stretching frequency of 10 secondary amides (33) also seems to depend on whether the nitrogen- proton bond is cis or trans to the carbonyl bond. The lactams, . in '1 which the‘ N-H and C-0 bonds are gi_s_, absorb between3420 and3440 cm."'1, while amides in the £211: configuration absorb between'3440 and 3460 cm.'1 (24). Decoupling the spin of the nitrogen nucleus by applying a second radiofrequency field at the resonance frequency of nitrogen has also been used to eliminate the broadening of the nitrogen proton. ~Piette, ~ Ray and Ogg (34) have analyzed the proton magnetic resonance spectra of HC=ONH2, DC=ONHZ, HC=ONDZ and HC= ONHD by observing the proton resonance at 40. 0011 mcs while irradiating the nitrogen nucleus at 2.8904mcs. The coupling constants found were JA = 13 cps and .1 X BX=~ 2.1 cps (Figure 2). ~Randall and Baldeschwieler (10) also used nitrogen- 14 spin decoupling to analyze the‘NMR spectrum of N—methylformamide. The coupling constants are given in Table III: Table’III. Coupling Constantsiz< for N-Methylformamide (10) (i) H H (3) \C N/ / ' \ 0/ CH3 (2) Volume percent in HZO' J13 J33 J12 100 1.8 4.9 0.9 65 2.1 4.9 0.8 33 2. 3 5.0 0.8 >1: In cps. The increase in .113 upon addition of water is attributed to the favoring of the planar form of the amide by interaction with the polar solvent. (As the dihedral angle Hl—C-N-H3 approaches zero, valence-bond theory (35) predicts that the coupling constant .113 should increase. It is well-known that amides are highly self-associated (36) by hydrogen bonding and that N-monosubstituted amides tend to form long chain polymers or cyclic dimers. The most complete study of the monomer-dimer equilibrium in amides is the vapor pressure measure- ments of Davies and Thomas (22). Selected values for the mole fraction association constants and thermodynamic constants are given in Table IV. The method of analysis used was that of Kreuzer (37), as modified by Coggeshall and Saier (38) for associative equilibria where Kn < K23 = K34 . . . = 12. Here‘Klz is for the monomer —‘ dimer equilibrium and e R is for the n-mer + monomer =——-‘ (n + 1)-—mer equilibria. ‘— Table IV. Thermodynamic Properties of Hydrogen Bond Formation of Amides in Benzene Solution (22) N-Methyl- N-Methyl— N-Methyl— N—Propyl- acetamide formamide benzamide acetamide t , c. 24.57 24.92 24.92 21.80 Km (mi)'1 6913 21345 52410.1 50 kcal ”_AHIZ me 3.45 3.49 3.57 --- ~K (mf)"1 148 1 3 218 e 4 75.0 11 52 a. 2 — k The-:11? 3.91 3.87 3.67 —-- -As,z—-=—' 3.7.10.7 1,310.5 8.840.6 --— _Enerle —As-—’-——= 2,710.5 2.410.? 3.910.? --- mole Klotz and Franzen (39) have recently completed an infrared study of the association of N-methylacetamide in various solvents. The 12 association constants and the thermodynamic constants are given in Table V. The association constant for N-methylacetamide in carbon tetrachloride (55 in mole fraction units) is quite close to the value obtained by Davies and Thomas (22) for N-methylacetamide in benzene. The values in parenthesis indicate that Kreutzer's method of analysis was used (37). The association constant was found to decrease as the competition by the solvent for the hydrogen bond increased. - Table V. Thermodynamics of Hydrogen Bond Formation of N—Methyl- acetamide at 25 K12 K12 F0 H0 s° Solvent l/m (mf)"1 kcal/mole kcal/mole E . U. /mole Carbon tetrachloride 4.7 (5.8) (55) ~0.92 -4.2 =11 Dioxane 0.52 (0.58) (9.3) 0.39 —0.8 — 4 Water 0.005 (0.005) (0.3) 3.1 0.0 -10 Using infrared and ultraviolet spectroscopy, Mizushima e_t a_l. (40) have studied the strength of hydrogen bonds formed by amides. They found that the proton donating power of the nitrogen proton in amides or diethylamine and the oxygen proton in alcohols is about the same, while the proton accepting power of the carbonyl group of N, N-dimethylacetamide is greater than that of acetone. Complete dissociation of N-methyl- acetamide polymers into monomers was found in an 0. 002 M solution in carbon tetrachloride; however, in chloroform, complete dissociation was observed in an 0. 02 M solution. Chloroform is believed to be more effective than carbon tetrachloride at breaking amide hydrogen bonds because of (1) its larger dielectric constant, and (2) the proton of the chloroform, which competes with the amide in hydrogen bonding with the carbonyl oxygen. The association constant between phenol and N,~N~dimethy1acetamide in isooctane was found to be 310' (mf)"'l at 20°C by ultraviolet spectroscopy. ~Klemperer (it a_l. (41) have studied the association of N-ethyl- acetamide, Nan-butylacetamide and 'y-butyrolactam in various solvents by infrared spectroscopy. The solvents could be separated into three classes according to the ratio em/ep: [em and ep are the apparent molal extinction coefficients of the 3450 cm. '1 (free N—H stretching frequency) and 3220 cm."1 (bonded N-H) bands, respectively] (I) CC14 and CS; (11))CH3CC13 and C6H6 (’III)CHBr3, CHC13, CHZCIZ. Amide self= association was greatest inClass I and least in Class III. The solvents in Class I have zero dipole moment and no protons, while the solvents in Classes II and III have dielectric effects, and, with the exception of benzene, which has in electrons, have protons capable of hydrogen bonding with the amide. The solvents in Class 111 have values of em/ep> 10 in... 0.04 M solutions of N—ethylacetamide, providing evidence of C-H” ' O=C hydrogen bonding. The energy of the chloroform-amide hydrogen bond was estimated to be 2 kcal/mole. The presence of a hydrogen—halogen interaction was indicated by the frequency difference of the monomeric N—H stretching band in several solvents. The lowest free'N-gH frequency was found in benzene-—indicating a considerable interaction between the N-H proton and benzene. Suzuki 3t a1. (42) have also noted a large shift (26 cm.‘1) to lower frequency of the free N—H stretching band in N-monosubstituted amides upon changing the solvent from carbon tetrachloride to benzene. The effect of hydrogen bonding upon the NMR chemical shift of proton donors was first recognized by Arnold and Packard (43) in 1951 when they observed the dependence of the chemical shift of the hydroxyl Proton in ethanol upon the temperature. Liddel and Ramsey then showed that dilution of ethanol with carbon tetrachloride has the same effect upon the chemical shift of the hydroxyl proton as raising the tempera— ture, namely, the proton resonance is shifted to higher magnetic fields as the hydrogen bonds are progressively broken (44). The observation that only a single resonance line has been found in the NMR spectrum for monomer, dimer and all higher aggregates (as contrasted to infra- red measurements) indicates that the hydrogen bonds are breaking and reforming at a rate faster than $8 103 times per second. The single resonance line then represents a weighted average of all species present in the equilibrium mixture. A number of hydrogen bonding studies by NMR have been discussed in references 36, and 45 to 47. One of the most complete of these is the study of the hydrogen bonding of ethanol by Becker, Liddel and Shoolery (48). NMR measurements were extended into the very dilute solution range (0. 03 M in carbon tetrachloride) necessary to obtain the chemical shift at infinite dilution, which is equal to the chemical shift of the monomer. The monomeradimer equilibrium constant and the chemical shift difference between the monomer proton and the bonded proton in the dimer were estimated using the limiting slope of the chemi- cal shift 2' mole fraction ethanol plot with the help of infrared data. More elaborate methods using NMR data have recently been pub— lished in which chloroform has been used as the proton donor (49=52). Chloroform is a popular choice for hydrogen bonding studies because of its small self—association and its single sharp resonance peak. Another factor is the availability of numerous other physicochemical determinations of the association constants for chloroform-base complexes with which the NMR results may be compared. Using NMR to obtain the chemical shift of the hydrogen bonded proton in various chloroform-base complexes, and literature values for the enthalpy of hydrogen bond formation for these complexes, ’Kaiser (49) was able to show that the hydrogen bond NMR chemical shift (complex—monomer) and the enthalpy increased monotonically. Creswell and Allred (50) have studied the association between chloroform and benzene and chloroform and triethylamine by NMR, and found association constants of 1. 06 i, 0. 30 and 4. 2 i 0. 2 (mf)'l, respectively, at 250 C. The chemical shift due to hydrogen bond formation was 1. 91 _+_ 0.40 ppm (parts per million) for the chloroform- benzene complex and -= 1.48 d: 0. 04 ppm for the chloroform=triethy1amine complex. Howard, Jumper and Emerson (51) have analyzed their NMR studies of the association of chloroform with various bases by fitting the data with a nonlinear least squares program. Corrections for chloroform and carbon tetrachloride self—association and for the dispersion interaction effect were made. The results are listed in Table VI. Examination of the data obtained from the two ether~=chloro- form solutions reveals that both the equilibrium constant and the chemical shift of the associated proton are strongly solvent dependent, and that the large magnetic anisotropies of acetonitrile and pyridine are reflected in the values derived for the chemical shift of the bonded proton, and thus in the value of A6 (complex-monomer). Table VI. Association Constants and Association Shifts fcpr the Hydrogen Bonding of Chloroform to Several Bases at 25 C. (51) Base Solvent K[(mf)“1] -A6 (ppm) Et3N c61412 4.70 4.0.12 1.472 40.011 EtzO c611,,2 3. 76 4 0.10 0.905 4 0.008 EtzO cc14 1.46 4 0.04 1.266 4 0.018 - [(CH3)2CH]ZO cc1, 2.06 4 0.08 1.126 4 0.019 ’ CH3CN cc14 1.14 4 0.04 0.973 4 0.019 (CH3)ZCO cc1, 2.07 4 0.05 1.419 4 0.014 C5H5N cc14 1.9040.04 2.27140.023 THEORETICAL BACKGROUND Energy Transitions in NMR Nuclear magnetic resonance is a spectroscopic phenomenon observed only for nuclei which possess a magnetic moment, H, given by —>— + +- H = Y P = 'Y 1 fi (1) —>- where ‘y is the magnetogyric ratio of the nucleus, P is the angular momentum of the nucleus, and I is the nuclear spin vector, where _9. I = I (1 + 1) . (Z) I is the spin quantum number and may be defined as the maximum observable component of the nuclear angular momentum along a fixed axis. In the presence of a uniform magnetic field, Ho’ there are 21 + 1 energy levels available to the nucleus, each corresponding to a different component of the angular momentum of value I, I—1, ..... -l+1, —I. The absorption or emission of an appropriate quantum of energy, __0_ (3) E=hV=72n 0‘ 1 ’ will enable the nucleus to make a transition from one energy level to an adjacent level. If the spinning nucleus is regarded as precessing about the H0 axis at an angle 0, the velocity of the motion is w = 7H0: 211' v, (4) where “’0 is the precessional frequency. If now a linearly polarized radio— frequency field of the correct frequency is applied, it may be regarded 16 17 as decomposable to two counter—rotating circularly polarized fields, one of which will be rotating in a plane perpendicular to HO. When equation (4) is satisfied, the precessing nucleus and the rotating magnetic field are in phase, the nucleus may absorb energy, and the angle 0 changes. The separation of energy levels of the spin states may also be written as (.1 HO/IkT, where k is the Boltzmann constant and T is the absolute temperature. In order to observe an energy transition, the populations of the energy levels must be different. For a collection of nuclei in thermal equilibrium, the relative populations are given by the Boltzmann factor 5 N+ _ (21+l)mLLHO/IkT 1. 1 ‘ e ‘ 21+1 IkT , N where m is the nuclear magnetic quantum number with values 1, 1-1, . . . . . . —I+1, -1. After the nuclei have attained this equilibrium distribution, a mechanism is needed whereby nuclei in an upper spin state may "relax" to a lower spin state so that the absorption of energy may continue. Spin—Spin and Spin- Lattice Relaxation Spin—lattice relaxation, also called longitudinal relaxation, is a process by which a nucleus in an upper spin state may give up its extra energy to the lattice (surrounding molecules) in the form of trans- lational or rotational energy. Random molecular motions of magnetic nuclei result in fluctuating magnetic fields, which may have an oscillating Component whose frequency will match the precessional frequency of the magnetic nuclei in the upper spin state. When the two are in phase, the nucleus will be able to lose its extra energy to the lattice and drop to a lower energy level. 18 The rate at which magnetic nuclei of spin I = 1/2 approach their equilibrium distribution, no, is given by (in 1 T = 7171— (no-n) (6) where T1 is the spin-lattice relaxation time, and n is the excess popu— lation of the lower energy state at time t. The magnitude of T1 depends on the magnetogyric ratio of the nucleus and on the nature of the mole— cular motions. The reciprocal of T1 gives an approximate measure of the line width (on a frequency scale) due to spin-lattice relaxation. A second type of relaxation, sometimes called transverse relaxa— tion, is by spin— spin interaction. The precession of a magnetic nucleus about the fixed axis of a uniform ma netic field, H may be resolved 0 ’ into a static component parallel to H and a rotating component in a o 3 plane perpendicular to Ho' When the rotating component is at the correct frequency, there may be an exchange of spin energy between two neighboring nuclei. Spin-spin relaxation thus results in no net change of spin state; however, it does contribute to line broadening by shortening the transversal relaxation time, T2. The linewidth is further increased by the small variation in local field at each nucleus due to the fields of neighboring nuclei. The small local magnetic fields will add to or subtract from the applied field, HO, resulting in a larger range of frequencies at which nuclei of the same type will absorb energy. Rapid rotation and tumbling, such as is found in most liquids and gases, will average the local magnetic fields so that T1 and T2 become nearly equivalent and only spin-lattice broadening remains. Thus most liquids of moderate viscosity have relatively narrow absorption lines, the width being on the order of 1/T1. Another cause of line broadening is quadrupole relaxation. Nuclei with spin I greater than 1/2 possess a nuclear quadrupole moment, 19 which means that the nuclear electric charge distribution will be non- spherical. Surrounding the nucleus is the normal asymmetric electron distribution of the molecule. When the molecule tumbles in the magnetic field, a time-variable electric torque is exerted on the quadrupole. This tends to shift the orientation of the quadrupole with respect to the magnetic field and results in a change of spin state for the nucleus. Thus the quadrupole moment provides an additional mechanism for spin- lattice relaxation of the nucleus. The appearance of the NMR spectrum of a nucleus which is coupled to a second nucleus possessing a quadrupole moment is dependent upon the rate of quadrupole relaxation. For example, the magnetic resonance line of a proton directly bonded to a nitrogen atom (I = 1) would be a triplet if the rate of quadrupole relaxation of the nitrogen were very slow. At very rapid rates of relaxation, the proton resonance line would be a singlet, due to the "averaging" of the nitrogen nuclear spin states. However, at intermediate relaxation rates, such as is usually found for the nitrogen nucleus in N-monosubstituted amides, a single broad line is found for the nitrogen proton resonance. It is often possible to remove the line broadening effects due to quadrupole relaxation by spin decoupling, a technique which will be dis- cussed in another section of this thesis. The Hamiltonian in NMR In a uniform magnetic field, the Hamiltonian for a system of nuclei which possess magnetic moments may be separated into two parts (53), O 1 1H =. it + H . (7) This treatment is applicable when the dipole-dipole interaction between the nuclear magnetic moments and the electronic magnetic moments may be neglected. If the magnetic field is taken to be in the negative 20 z direction, the first term represents the interaction of the nuclear —-> spin ‘1 with the local magnetic field Hi and is given‘(in cycles per second) by 0 1 . 1 . H=27§HH1 Iz I (1)—I 44’ = .2. J.. (j), (9) 1J 1 where I(i) and I(j) are the spin vectors of nuclei 1 and j, respectively, and Jij is a measure of the interaction between the spins. The sum is taken only over non- equivalent nuclei, because the energy of transition of a set of equivalent nuclei is independent of the coupling constant within the set. The coupling constant, Ji" is in units of cycles per second and is independent of the applied magnetic field. The matrix elements of the Hamiltonian 4..[. are given by Hmne (10) Where \‘J m and W n are orthogonal eigenfunctions of if called basis product functions or spin wave functions. It will be seen that fl 0 (equation (8)) contributes only to the diagonal elements of the matrix, while H1 (equation (9)) will also have off-=diagona1 elements. The energy eigenvalues, E, are found by solving the secular equations I 'H mn-Eamnleo, (11) Where Am is the Kronecker delta. For a system of n nuclei, n equation (11) is of order 2n; however, it may be simplified because (1) no 21 mixing occurs between functions with different values of the total spin component, and (2) no mixing occurs between functions of different symmetry. The values obtained for E from equation (11) are in terms of the relative chemical shifts of the nuclei in the system, 6 ij’ and the spin coupling constants, Jij’ between the nuclei. A transition between energy levels is observed in the NMR spectrum when the selection rule, AFZ=_+_1, (12) is satisfied, where A Fz is the difference in total spin component between the energy states. The resonance frequency of a given transition is (Em—En) and its relative intensity is given by (<0m(§IX(i)I0n>lz, (13) where the sum is taken over the x-component of the spins of equivalent nuclei and (Dm and (Dn are stationary state wave functions. Thus the chemical shifts and the coupling constants for a given system, together with their relative signs, are sufficient to describe the NMR spectrum. When the chemical shift between nuclei is large compared with the spin coupling constant, the NMR spectrum is easily interpretable. A neighboring group of equivalent nuclei will cause a splitting of the NMR peak of a given nucleus or equivalent nuclei. The multiplicity is given by (2nI + l), where n is the number of equivalent nuclei of spin I in the neighboring group. The separation between the peaks of the multiplet is a measure of the spin coupling constant, J, between the neighboring nuclei. For proton magnetic resonance spectra, the relative intensities of the multiplet are given by the binomial coefficients. 22 References (53) through (55) contain'NMR analyses of commonly occurringcomplex spin systems. Many other example-s may be found in the literature. The Spin=Spin Coupling Constant Since the spin—spin coupling constants derived from the'NMR spectra of molecules (Jij in equation (9)) measure the interaction between nuclear spins of neighboring atoms, there-(have been numerous attempts to relate the coupling constant to molecular structure parameters. Only those studies will be mentioned which are related to the work pre- sented in this thesis. Muller and Pritchard (32) have achieved some success correlating the coupling constant between c arbon-13 and directly bonded hydrogen to such parameters as the C—H bond distance, the degree of hybridization of thecarbon‘atomic orbitals, and the electronegativity and size of sub- stituents. 4 Using valence-bond theory, Karplus (35) has calculated thecoupling constants between protons on adjacent carbon atoms in ethane-like molecules as a function of dihedral angle. The coupling constant was found to be largest when the four atoms are coplanar, with the hydrogens either cis or trans to each other. ~ Similar-calculations by Karplus (35) for ethylene-type molecules, considering only the sigma electrons, yield a theoretical coupling con- stant of 6. 1 cps for0O dihedral angle, and 11. 9 cps for 1800 dihedral angle. For many molecules, the theoretical results are in good agree- ment with experimentally determined coupling constants. The “rt-electron contribution to the coupling constant has also been treated by Karplus (56) for-many types of molecular fragments contain- ing double or triple bonds. :For example, the contribution of the n‘eelectrons to the coupling between the protons in the fragments 23 ’H-C=C=-H and H=C=C-C—H is 1.5 cps and =1.7 cps, respectively. .Since the fi—electron coupling is independent of the relative configur— ations of the coupled atoms, the difference between gs; and m coupling constants in substituted ethylenes must result from the sigma electron contribution to the coupling (56). Spin Decoupling Spin decoupling, or double irradiation, has become an extremely valuable method of simplifying NMR spectra and in many cases has made possible the determination of the relative signs of spin coupling constants. It has also proved useful in the measurement of chemical shifts (57). Spin decoupling, for the case where the coupled nuclei are of different species, for example nitrogen and hydrogen, involves the application of a second radiofrequency field oscillating at the resonance frequency of the nucleus which is to be decoupled. This causes the nucleus to change spin states so rapidly that its spin vector no longer couples with the spin vectors of neighboring nuclei and multiplets due to this coupling collapse. The method has frequently been used in three-spin systems (58), where all of the coupled nuclei were protons. Irradiation at a frequency between two NMR transitions which are separated by the coupling con- stant, Jij’ has the effect of "washing out" this coupling between other transitions. Whether or not a given set of lines collapses depends upon the sign of Jij’ and thus the method may be used not only to simplify the spectra, but, in cases where the ratio J/é is not too large, it may often be used to determine the relative signs of the coupling constants. 24 The Chemical Shift —-3 The presence of a uniform applied magnetic field, Ho , will induce a secondary magnetic field at an atomic nucleus in the direction —-—> opposed to H0. The nucleus will then experience a reduction of the applied field, H1 = HO (1 — cr) (14) where 0‘ is the screening constant and is dependent upon the electronic environment of the nucleus. Since 0“ is usually positive, the applied field necessary to induce a nuclear transition will be larger for a screened nucleus than for an unscreened nucleus. The magnitude of the local field at the nucleus is 2 GHQ l H.:H..————2=——§; l 1 O 3mc i <11) (5) Where e is the—charge of the electron, r-1 is the distance of the electron from the nucleus, In is the mass of the electron and c is the velocity of light. Equating equations (14) and (15) leads to the Lamb (59) formula for atomic screening, 417 a) 0' : WOI r p (1‘) dr (16) Where p(r) is the electron density at a distance r from the nucleus. The induced magnetic field is more difficult to describe for a molecule because the spherical symmetry of the atom is lost. Ramsey (60) by a perturbation procedure for an isolated molecule developed a formula which contains a paramagnetic and a diamagnetic contribution to the screening and has been used to calculate the screening constant for molecular hydrogen. For larger molecules, however, it is more convenient to use the method of Saika and Slichter (61) in which the electron motions are separated into three components: (1) local 25 diamagnetic currents, (2) local paramagnetic currents and (3) atomic currents on neighboring atoms. A fourth contribution, which for certain molecules is quite large, is due to interatomic diamagnetic and paramagnetic currents. The local diamagnetic current contribution is given by the Lamb formula (equation (16)) and its effect is one of positive shielding for the nucleus. The local paramagnetic term may be represented as a hindrance to the diamagnetic atomic currents due to the non-spherical electron distribution, and results from the mixing of the electronic configuration of the ground state with low lying excited states. Although the electronic states of hydrogen are too high to mix, paramagnetic circulations of electrons from neighboring atoms (effect 3) may contribute to the screening constant of a proton. An example is given in Figure 7, which represents the long range shielding effect of the carbonyl group (62). The regions of paramagnetic shielding are Figure 7. An approximate representation of the long range shielding effect of the carbonyl group. The magnitude in each region increases toward the symmetry axis of the region, and towards the electrical center of gravity of the bond (62). indicated by the symbol (=), while (+) indicates a region of diamagnetic shielding. These circulations are induced by a magnetic field perpen- dicular to the plane of the sp2 hybridized carbon atom. Atoms located in this plane, for example, the formyl proton of acetaldehyde, will experience a decrease in shielding. 26 The magnitude of the neighbor=anisotropy effect on a proton H by an atom X has been estimated by Pople (63) and McConnell (64) to be Aer: —%= R"=3 (2 Xi'axi — xiii) (17) in the case where the local atomic susceptibility on the neighboring atom is anisotropic. Here R is the X—H bond length, X l is the atomic magnetic susceptibility parallel to the X-H bond and X J- and X—L* are two different atomic susceptibilities perpendicular to the X—l—I bond. Thus if X H > X J- , the proton will be shielded by atom X. The fourth contribution to nuclear shielding is found in molecules such as benzene where an interatomic current may circulate. The TI electrons of benzene may be regarded as moving in a closed loop, which induces a magnetic field parallel and opposed to the applied field, as in Figure 8. Nuclei near the six—fold axis of the ring will be shielded, 1.101 Figure 8. The interatomic currents in benzene. while those near the plane of the ring will be deshielded. By replacing the current in the ring with a charged dipole at the center of the ring and perpendicular to it, an estimate may be made (65) of the ring current Contribution to the deshielding of the benzene protons. The equation is :_ 1 4°" W ‘81 27 where e, m, and c have been previously defined, a is the radius of the ring and R is the distance of the proton from the center of the ring. Since the screening constant depends on the electronic environ— ment of the nucleus, different types of nuclei will have different values for O‘ , thus it may be seen from equation (14) that they will resonate at slightly different values of the applied magnetic field. The chemical shift of a given nucleus may then be defined as 6 (ppm): 0°07 = m . (19) where 0'1, is the screening of a reference compound and Hr is the resonant field of the reference. Chemical Shifts in Solution In addition to the atomic and interatomic contributions to the chemical shift of a nucleus, there are additional effects in liquid solu— tion. Some of the important effects of the solvent upon the chemical shift of a given proton in the solute molecule may be expressed as (66) 0=0B+6A+0W+0E+0C, (20) Where the contributions to 0 are: 6 due to the bulk diamagnetic B7 Susceptibility of the solution; due to the solvent anisotropy; 0A, 6E, due to the reaction field from a polar solute; 6W, due to van der Waals type forces; and 6 C’ due to complex formation between solute and solvent, or between two solute molecules. The bulk diamagnetic susceptibility effect results from the dif- ference between the applied magnetic field and the magnetic field inside the solution. When an external reference is used in a cylindrically shaped sample, the chemical shift of the solution is theoretically (67) 28 6:6 +—=——-(X =-X) (21) obs. 3 v, r v where” Xv, r is the volume magnetic susceptibility of the reference substance and XV, of the solution. Bothnere-By and Glick (68) have suggested that a similar equation where 211/3 is replaced by 2.6 is in better agreement with experimental results. The volume suscepti— bility is simply related through density and molecular weight to the I molar susceptibility, Xm, which, for a solution, is adequately given by Wiedemann's additivity law (69) where M1 and M2 are mole fractions. -.- + X 22 (XX‘JSOlution (X1 Mi) solute ( 2 M3) ( ) solvent The diamagnetic susceptibilities are determined experimentally, or estimated using Pascal constants (69). In practice, however, an internal reference is often added to the solution, in which case X 9 is equal to (XV) solution° The solvent anisotropy effect, which contributes to 0A, depends on the shape of the solvent molecule, its magnetic anisotropy, and its orientation with respect to both the magnetic field and the solute (66). Figure 9 shows the expected arrangement for (a) a disk- shaped and (b) a rod—shaped solvent molecule, such as (a) benzene or (b) acetylene. n CE—a (a) ‘ (b) Figure 9. Expected orientations of (a) a diskc shaped and (b) a rod-shaped solvent molecule with respect to a spherical solute molecule. Because the solvent symmetry axis is in (81), along the vector from the origin of the solvent molecule to the center of the solute molecule, 29 while in (b), is perpendicular to it, the shielding effects upon the solute protons will be different. The screening constant for symmetrical disk— shaped solvent molecules, is given by Buckingham, Schaefer and Schneider (66) as 4A: -2... (x” - xi) /3R3. (23) where XH and X-L are the magnetic susceptibilities parallel and at right angles to the symmetry axis. and R is given by R cos 0 = R ' 1 , where R is the vector from the origin of the solvent molecule to the center of the solute molecule, 1 is the unit vector along the solvent symmetry ax1s, %- 18 the angle between R and 1 , and n 18 the number of solvent molecules which are considered close enough to contribute to 0’ . A For symmetrical rod— shaped molecules, in which the largest diamagnetic susceptibility is along the axis of the rod, the screening constant is (66) = +11 (XH = 1> , (33) Where the diamagnetic shielding, é , is given by an expansion in inverse powers of the distance, r, of the electrons from the nucleus. If only the first term in equation (33) is important, a small value of r implies a large electron density and a large positive screening. However, if the second term in equation (33) should predominate, a large electron density could be associated with a large negative screening. Thus the large shift to lower magnetic fields which is associated with hydrogen bond formation may be explained in terms of a higher electron density (l/I‘ dependence of 6) or a lower electron density (electrostatic model) for the bonded proton. 34 The Determination of Intermolecular Hydrogen Bonding Equilibrium Constants for Self—Associated Species Studies of the thermodynamics of hydrogen bond formation in molecules such as the N-monosubstituted amides is complicated by the fact that these molecules are highly self—associated, resulting in complex equilibria among monomer, dimer, trimer and higher species. A theory for continuous association has been described by Redlich and Kister (85), assuming that the equilibrium constant for the reaction n-mer + monomer ”—9 (n + l)-mer (34) r...” does not depend on the value of n. Mavel (86), using similar equations, has derived a relationship whereby the equilibrium constant for continuous equilibria may be found from'NMR chemical shift data. However, other authors (22, 38, 87) have found that a single equilibrium constant is not sufficient to explain the experimental results. Coggeshall and Saier (38) analyzed their infrared data for the association of alcohols using one equilibrium con— stant (K12) for the monomer-dimer reaction, and a second general constant, I—{, for the equilibria between higher polymers. Davies and Thomas (22) followed a similar scheme and found the constants for amide association by vapor pressure lowering experiments. The de- termination of equilibrium constants for self—association has been reviewed by Rossotti and Rossotti (88). A statistical treatment of associated solutions by Sarolea-Mathot (89) predicts that K12 is less than I—{. The equation derived is P = I27K” , (35) 35 where p is the number of possible orientations of the monomer with equal energy. The difference in equilibrium constants is thus ascribed to an entropy factor, the loss of entropy when two monomer units form a dimer being greater than when only one monomer and a higher polymer unite. Coggeshall (90), on the other hand, has attributed the difference in equilibrium constants to a potential energy difference. He has calcu= lated the decrease of potential energy resulting from adding a dipole to a polymer chain of linearly hydrogen bonded hydroxyl groups and found that it increases as the chain becomes longer. The present treatmentof associative equilibria is similar to that of Redlich and Kister (85), and Mavel (86), with two important dif- ferences: (1) The theory has been modified to include two equilibrium constants, K12 and TE, and (2) the theory has been made more general by allowing the consideration of solvents which may also hydrogen bond to the self—associated species. The Special Case of the Self—Associated Solute Species in an Inert Solvent The equilibria among the solute species may be expressed as r.— for n > 1 (37) E __J Yn + Y1?— Yn+1 where Yn is the mole fraction of n—mer. The equilibrium constants are then given by: K12 = Yz/le (38) K: Yn+l/Yn Y1 forn> 1 (39) The following definitions will be used: 36 Y = z n Y (40) n n Y = Z YH (41) n where Y is the total effective mole fraction of solute. If S is the total effective mole fraction of solvent, then i?" + s = 1 (42) Substituting from equations (38) and (39), Y and Y may be expressed in terms of K12, K, and the mole fraction of monomer: Y=Y1+Y2+Y3+.... Yn _ _ _2n n+2 Y=Y,+K,ZY,Z+K,ZKY,3+... +K,ZK Y, _ _ :2 2 =11 n Y=Y,+K,,Y,Z(1+KY,+KY, +...K Y,) When (E Y,) is less than unity, this may be expressed in closed form (91): —‘ K12 Y1Z Y : Y + “—3—— 1 l E K Y, (43) Similarly, for Y: Y=Y1+ZY2+3Y3+ ccccc nYn _ __n n+2 Y=Y,+2K,z Y,2+3K,ZKY,3+.... (n+ 2) KRK Y, 2 n n __ __Z Y2Y1+K12Y12[(1+KY1+K Y1+oooK Y1)+ _ _2 z _n n (1+2KY,+3K Y, + ..... (n+l)K Y,)] When (E Y,) is less than unity, this may also be expressed in closed form (9],): 37 K12 le (2 ' E Y1) (1 "K Yflz Y=Y,+ .(44) Equations (43) and (44) were used by Davies and Thomas (22). In order to relate Y and Y to the stoichiometric concentration, a quantity C is defined, where __ stoichiometric moles of solute — stoichiometric moles of solvent (45) Or, in mole fraction units, Y Y _ W C ‘ E: " 1.= Y ' (46) Eliminating Y from equations (43) and (46), then solving for Y, and substituting Y into equation (44) results in: F = (1 - E Y,)2 [Y,(C+l)mC] + K,Z Y,Z[C(1=E Y,) + (2 - E Y,)] = 0 (47) It may be shown that equation (47) has only one real positive root for Y, within the limits 0 < EY, < 1 for the values of C, K”, and if used. The problem of finding the equilibrium constants for a given - system may be treated in the following manner: (1) Assume reasonable values of K” and R, then use equation (47) to find the value of Y, at each value of C (for each solution); (2) Use equation (43) to evaluate Y for each Y,;- (3) Relate Y, or Y to some measurable quantity of the systemiwhich is a function of the equilibrium distribution of hydrogen bonded‘species so that the correct values of K” and k- may be determined. The‘NMR chemical shift of the hydrogen bonding proton in an associated solute molecule is dependent upon the equilibrium distribution because it is equal to a weighted average of the chemical shifts of the PI‘Oton in the monomer, dimer, and higher aggregates. 38 In order to make the problem tractable, it is assumed that un— bonded protons on the ends of polymer chains will resonate at the same frequency as the free monomer proton, v and that the hydrogen m9 bonded protons within the polymer chain will resonate at the same frequency as the hydrogen bonded proton in the dimer, vd. The solute must contain only one proton capable of hydrogen bonding and the sol— vent must be inert. The observed chemical shift of this system is given by: 6 :: (Y1+Yz+....Yn) Vm+(Y2+ZY3+°°°' (n-1)Yn) vd 0 Y (48) Equation (48) may be simplified by using equations (40) and (41): Y(éO-vd) = 37 (12mm vd) (49) Rearrangement gives *3? (50 — —Y— (vm- vd) + vd . (50) A plot of 6 o as a function of Y / Y yields Vm and vid from the slope and intercept of the straight line. The best least squares fit of equation (50) to a straight line is obtained with the correct values for K12 and E0 '_I‘_he'Special Case of the Self-Associated Solute flecies in a Hydrogen Bonding Solvent When the solute species is strongly hydrogen bonded to the solvent, it may be shown (92) that each solute molecule may be considered to be hydrogen bonded to one solvent molecule. The equilibria may then be eXpressed as: 39 L12 22 ———-> 1,—— zz+s (51) T. zn+z,——-\ 2 +5 forn>l, -(52) ‘———— n+1 where Zn is the mole fraction of solvated n—mer, and S is again the total effective mole fraction of solvent. The equilibrium constants are then given by: .5" n as/ZE em IT‘I M Z +1S/ZnZ, forn>1 (54) n The following definitions will be used: 2: ZnZn (55) n z: 2 2n , .(56) n where Z is the total effective mole fraction of solute and z + s = 1 . (57) By the same summation technique as was employed in the inert solvent case, equations (53) and (54) may be used to express Z and'z in terms of Ln, E, S, and the mole fraction of solvated monomer, Z,: Z - z (141215)le 58 ‘ ‘ [1-(L/s>zli ‘ ’ Z = 21 + (LIZ/S)ZIZJ: 2" (E/S)Zl] (59) H-dflmar 40 Expressing the series in closed form requires that (I: Z,/S) be-less than unity. Since part- of the solvent molecules are hydrogenbonded to the solute, the quantity C in equation (45) in mole fraction units is Z C : : Z, (60) Rearrangement of equation (58), using equation (57), yields: s: [l—Z,+I—:Z,_+_ /[Z,(E+l)-l]Z-4L,ZZ,Z ]. (61) .1. 2 Equation (61) predicts that Z, will become very small both at high and at low solvent concentrations. The maximum value of Z,, found by setting the quantity beneath the radical in (equation (61) equal to zero is _ =1 (Zl)max. = (L + l + 2 Vle ) . (62) The sign of the radical in equation (61) is positive in dilute solutions, but as the concentration of solute is increased, (Z,)max is reached, and at higher solute concentrations the negative sign must be used. Rearrangement of equation (59) yields F' = (2 - E Z,/S)(L,7_Z,z/S)+ (z,-Z)(1-i3 z,/S)z = 0 (63) It may be shown that equation (63) has only one real positive root for Z a u n ‘u < — < 1 Within the limits 0 (L2, / S) (Zl)max.° An inverse interpolation iteration procedure‘may be used to find Z, and S using equations (61) and (63), assumed values for the equilibrium constants, and the measured quantity Z (equation-(60)). Then'Z, or Z (from equationi(58)) must be related to some measurable Quantity of the system which is a function of the equilibrium distribution 41 of hydrogen bonded species so that the correct values of Lu and I: maybe determined. Since the hydrogen bonding proton of the solute is, in this case, assumed to be bonded either with another solute molecule or with a solvent molecule, the observed NMR chemical shift of this system is given by, 6 = (Z). + Z2 + ° ° 'zn) VC + (22 + 223 + . o .(n-1)Zn)vvd O , Z (64) assuming that all solute protons which are bonded withsolvent resonate at the same frequency, Vc . Equation (64) may be simplified using equations (55) and (56): moo-yd) = 2(1),: -vd) (65) Rearrangement give s: 60: NINI (11C)- vd) + vd (66) A plot of 6 o as a function of Z/ Z yields Vc, and V91 from the slope and intercept of the straight line. The correct values: of L”, and L , when used to obtain Z / Z, will give the best least squares fit to this line. .A plot of s as a function of z, with L,, = 5. 0 (mtr1 and i = 10.0 (mf)"'l is shown in Figure 10. 1 A plot of F' as a function of z, with z = 0.20, L,z = 5. o (mf)- and I: = 10.0 (mf)’1 is shown in Figure 11. 42 Z1 Figure 10. é plot of S as a function of Z1 with Ln = 5. 0 (mf)'1, and L =10.0(m£)-‘. +. 025' F! -0.05— -0. 10— -0. 15‘ -0.ZO—i j I, I I l L 1 0.00 0.02 0.04 0.06} 0.06 0.04 0.02 0.00 (21) max. Figure ll. 12 plot of F' as a function of Z, with Z = 0.20, L12 = 5.0 (mf):1, L = 10.0 (mf)"l. EXPERIMENTAL Determination of NMR Parameters The Varian Associates A-60 model high-resolution NMR spectrom- eter was used to obtain the spectra. The chemical shift of the nitrogen proton resonance peak in the spectra of the N-monosubstituted amides was measured using a sweep width of 500 cycles and a sweep time of 250 or 500 seconds. Other proton resonance peaks were measured at a sweep width of 250 cycles and a sweep time of 250 seconds. The pre- cision of the measurements at this sweep width is abouti 0. 5 cycles per second (cps), except for the nitrogen proton peak in the NMR spectra of dilute solutions of N-monosubstituted amides where the precision is less. The probe temperature was approximately 350 C. All peaks were measured in units of cycles per second from an internal reference of one percent tetramethylsilane. The coupling constants were measured at sweep widths of 50 or 100 cycles and sweep times of 250 or 500 seconds. The precision of the measurements at these sweep widths is about i: 0. 05 cps. The integrated peak intensities were obtained using both the A-60 integrator and a planimeter. Measurements were repeated at least five times and an average value was taken. Before recording a spectrum, the homogeneity of the magnetic field was always checked by observing the NMR spectrum of the quartet Of a. thoroughly degassed sample of acetaldehyde. Narrow resonance line 5, symmetry of the multiplet and considerable ringing following each peak indicate a homogeneous field. The calibration of the sweep width used was also checked each day by observing the chemical shift difference 44 45 between the proton resonance of tetramethylsilane and chloroform in a standard sample of tetramethylsilane and chloroform in deutera-ted chloroform. Preparation of Amides The amides used in this work are listed in Table VII (symmetrically N, N-disubstituted amides), Table VIII (unsymmetrically N, N—disubstituted amides), and Table IX (N-monosubstituted amides). Boiling points or melting points observed in this laboratory, as well as the literature values, where available, are also given. The methods of preparation referred to in Tables VII, VIII and IX are described below. Method A (99)--One mole of the appropriate amine was added slowly and with stirring to a mixture of two moles of 88 % formic acid in Iii-xylene kept at about 200 C. The temperature of the mixture was gradually increased until it refluxed and then the water was continuously removed using a Barrett distilling receiver. Refluxing was continued for three hours for a primary amine and overnight for a secondary amine. After completion of the reaction, the m—xylene and excess formic acid were removed i_n vacuo and the product was fractionally distilled. Method B (122)-—A mixture of one mole of the appropriate amine hydrochloride and l. 7 moles of the primary amide were gently heated for about one hour after they melted and a precipitate of ammonium chloride was observed. After cooling, chloroform or ether was added and the ammonium chloride was removed by filtration. 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After completion of the reaction, the amide was decanted (if not water soluble) and the aqueous layer was extracted with ether. The amide layer and the ether extracts were combined and dried over anhydrous potassium carbonate. The ether was removed, and the product was recrystallized if a solid, or fractionally distilled, if a liquid. Method D (123)—-=To a solution of one mole of the appropriate acyl chloride in ether was added slowly and with stirring a solution of two moles of amine in ether. The temperature was kept below 00 C. The solution was stirred for several hours after completion of the reaction and then enough water was added to dissolve the amine hydrochloride. The ether layer was separated and washed with portions of 20% aqueous potassium carbonate until neutral. After drying over anhydrous potassium carbonate, the ether was removed by distillation and the product was fractionally distilled .133. vacuo or recrystallized. Method E—-To an aqueous mixture of one mole of the appropriate amine and one mole of sodium hydroxide was added slowly and with stirring, one mole of acyl chloride, keeping the temperature at 100 C. If the product was a liquid, the reaction mixture was treated as described in Method C. If the product was a solid, it was filtered out of the reaction mixture and recrystallized. Method F (lOO)—-—One mole of amine was added to two moles of formic acid with stirring and cooling. After refluxing for eight hours, the mixture was allowed to stand overnight, and then the product was extracted with ether. The extracts were dried over anhydrous potassium carbonate, the ether removed, and the amide fractionally distilled i_n m. A poor yield was obtained in this reaction; Method A is preferable. 50 Method G--The preparation of N-t_=butylformamide, from t_- butanol, sodium cyanide and acetic acid, given in the literature (113) ' was followed exactly. Method H--The preparation of N-E-butylacetamide, from isobutene, acetonitrile, and acetic acid, given in the literature (114) was followed exactly. N- 15-_n- Butylformamide- -N-15-Potas sium phthalimide (96 . 0% N-15), purchased from the Isomet Corporation, Palisades Park, New Jersey, was converted to N—15-2=buty1phthalimide by reaction with n-butyl bromide. Treatment of the N-lS-E—butylphthalimide with hydrazine hydrate in methanol yielded N=15-=r_i—butylamine hydrochloride. These reactions are described in detail in reference (116). Addition of aqueous sodium hydroxide to an aqueous solution of the N-lS—E—butylamine hydrochloride liberated the amine which was extracted with ether. After drying the ether extracts with anhydrous potassium carbonate and removing the ether by fractional distillation, a Iii—xylene solution of the amine was added to a mixture of formic acid and rE-xylene, following Method A, as described previously. In this way, the amine was con- verted to N-lS-g-butylformamide. After completion of the reaction, the m-xylene and excess formic acid were removed by fractional distil— lation i_n w and then the small amount of product was transferred to a molecular still with chloroform. The chloroform was removed under partial vacuum, then the still was connected to a vacuum line in which the pressure was about 20 microns. A shallow oil bath was used to heat the bottom of the still to 40-500 C. The N-lS-Li-butylformamide distilled as a colorless liquid and was collected in an A—60 sample tube to which a ground glass joint had been sealed. N-15-n-Buty1acetamide--N-lS-n-Butylamine hydrochloride, pre- pared as previously described, was converted to N-lS-n—butylacetamide 51 by reaction with acetyl chloride, according to Method C. After removal of the ether, the product was transferred to a molecular still with benzene. The benzene was removed under partial vacuum, and the still was then connected to a vacuum line in which the pressure was about 20 microns, and heated in an oil bath to 50--60o C. ' A slight yellow tinge to the liquid collected indicated that a small amount of impurity had been distilled with the N- l5—E—buty1acetamide. The amides in Tables VII, VIII and IX which are commercially available were purified by drying over anhydrous sodium sulfate and fractionally distilling 33.13222; All of the amides used were colorless liquids or white solids. The solids were recrystallized twice from hexane, except for N-methyltrichloroacetamide, for which ether was used. Purification of Solvents Benzene-—Thiophene—free C. P. grade benzene was dried over sodium and then fractionally distilled, collecting only the middle cut. Deuterated Chloroform--Chloroform-d was purchased from Merck, Sharp and Dohme of Canada Limited, Montreal, in a sealed, coated vial and was not further purified. Dioxane--Reagent grade 1, 4-dioxane, purchased from Matheson, Coleman and Bell, East Rutherford, New Jersey, was purified by refluxing with sodium oVernight, filtering, and then fractionally distil— ling, collecting only the center cut. .Diethylketone—-After drying over calcium sulfate, diethylketone, purchased from Matheson, Coleman and Bell, was fractionally distilled, the center cut being collected. 52 Dimethylsulfoxide--After drying over anhydrous sodium sulfate, dimethylsulfoxide, purchased from Eastman Organic Chemicals, was fractionally distilled, collecting only the center cut. Carbon tetrachloride--Carbon tetrachloride, C. P. grade, was dried over calcium chloride and then fractionally distilled, collecting only the center cut. Sulfuric acid--Technical grade sulfuric acid was used without purification. Deuterated sulfuric acid-—Sulfuric acid—d—Z was kindly supplied by Dr. Ching-Yong Wu who had prepared it from deuterium oxide and sulfur trioxide. Preparation of Samples The NMR spectra of the pure N, N—disubstituted amides were obtained using a sample of the amide in a capped A-60 sample tube filled to a depth of approximately four cm. The A-60 tubes are thin- walled, precision-ground, five mm. o.d. Pyrex tubes supplied by Varian Associates, Palo Alto, California. Benzene solutions of the symmetrically N, N—disubstituted amides were made up by weight, a cyclohexane internal reference added, and the solutions were transferred to thick—walled tubes. After degassing the solutions, the tubes were sealed i_n vicio. A later decision to use the A—60 spectrometer to obtain the NMR spectra necessitated opening the sealed tubes and transferring the solutions to A—60 tubes. The NMR spectra were obtained on the same day as the tubes were opened so as to minimize any change in the solution composition due to solvent evapor- ation. A tetramethylsilane internal reference was added at this time so that all chemical shifts reported in this thesis might be referred to the same standard. 53 The solutions of the N-monosubstituted amides used in the hydrogen bonding studies were made up by weight, an internal reference of tetra- methylsilane added and the solutions immediately transferred to A-60 tubes which had just been flamed out on the vacuum line to remove any contamination by water. The deuterated chloroform solutions were degassed at a pressure of about one mm. mercury with the sample tubes in an acetone—dry ice slush, and then sealed. The rest of the solutions were frozen in liquid nitrogen before degassing and sealing. The deuterated chloroform solutions were stored in the dark to avoid decompo- sition by light. Computation for Hydrogen Bonding Studies The equations described in the Theoretical Section of this thesis were programmed by Dr. H. Bradford Thompson for use on the MISTIC Computer at Michigan State University. Two separate programs were written. Figure 12 describes the general program which was used for both the inert solvent and hydrogen bonding solvent case. The calculation of Y/Y in equation (50) for solutions in inert solvents is shown in Figure 13, while Figure 14 describes the calculation of Z/Z in equation (66) for solutions in hydrogen bonding solvents. 54 . START —)[ Readrin-C's and~6"s T - =——J | 'Read'in‘K and Km, and. clue f I ‘Take Ifirst C; Setjtorage ‘ address fortfirst’Y/Y . J - ‘ ' Calculate 'Y, (max.). .Set Y, (min) a 10'6 =——L * Calculate Y/Y. .See figures 13'and 14. I 'Is this the: last C value input? I *No , 1 Yes lTake next C Fit Y/Y, .6 values to.b‘est I ' least squares straight line (Library? Rou-tine‘ K13'M) 4y Clear sum of deviations 23 A2 Take first c, Y/Y, 5 A AL Print c, Y/Y, 0 Calculate and print 6 calc. Calculate and print 6 o - 6 calc = A Square A and add to sum Is this the last c,? No i ' Yx LTake next C, Y/Y, .6 Print vm, vd’ 2 AZ, - K, Kn Check Clue 1 ' I i ‘L or F J N— l--)(Bl.Sw. )——- OFF ~ ----- ‘--- .(White‘Fetcl ‘ Figure 12. . Diagram of the computer program used in the hydrogen bonding studies. 55 IN———4 Calculate F(Y,, min), F(Y,, max) 1 .l. >l= Interpolate to find Y,‘ for which F x 0 Calculate F(Y,') F(Y1') = 0? (i 2'40) Substitute F(Y,') for Calculate Y from this Y, previously calculated F of same sign, and Y,', for corresponding Y, Calculate and store Y/Y OUT >fiPart of subroutine H-l from the ILLIAC Library, using an auxiliary subroutine prepared to calculate F for this problem. Figure 13. Diagram of the section of the computer program which calculates Y/Y. * 56 IN # Set F'(Z,) calc. for‘+ root in=S I >:< Calculate F' (2,, min), F'-(Zl, man!) J ‘F' 's of same Interpolate to find 2,! for which ~F' 'A’; O Calculate F'(Z,') F*.(zt'*).= 0-? (:1: 2‘”) /NO Y\ * Substitute F'(Z,') for previouslycalculated F’ of same sign, and 'Z,' for cor responding .Z, I Calculate-Z- = 1 - S JP- sign ? >.‘<>!= Yes LSet F',(Z,) routinefor - root ' Calculate and sto E/z , OUT re] Part of subroutine‘H- 1. from the ILLIAC library, using an auxiliary subroutine prepared tocalculate'F‘ for this problem. * This is indicated by Z, = -l on leaving H-l,. which is detected by the master programand the indicated procedure followed. Figure 14. . Diagram of the section of the computer program which calculates Z/Z. RESULTS The NMR spectra which are reproduced on the following pages were obtained using the A-6O high-resolution spectrometer and are shown with magnetic field increasing from left to right. All chemical shifts were measured in cps from an internal tetramethylsilane reference chosen as zero cps. In each case, amide resonance peaks which are labeled (A) refer to N—alkyl peaks which have been associ- ated with groups 2 to the carbonyl oxygen atom, and those labeled (B) refer to groups Ea_ns_ to the oxygen. The peak assignments are treated in the Discussion section of the thesis. Symmetrically N, N-Disubstituted Amides The chemical shifts of the N-alkyl resonance peak(s) for a series of symmetrically N, N-disubstituted amides are listed in Table X. The NMR spectra of several amides are shown in Figures 15 through 23. N, N-Diethylformamide—-The NMR spectrum of N, N-diethylform— amide is shown in Figure 15. The two triplets to high magnetic field are due to the non-equivalent N—C-CH3 groups. The peak at —69. 0 cps is due to the methyl group which is in a position tra_ns to the carbonyl oxygen atom, while the peak at -64.1 cps is due to the c_is_ methyl group. The quartet at -202.0 cps arises from the methylene protons. The formyl proton resonates at -486 cps. N, N-Diethylacetamide—-The NMR spectrum of N, N-diethylac etamide is shown in Figure 16. The broad quartet of lines at high magnetic field is composed of two partially overlapping triplets. The triplet at -69. 2 cps is due to the N-C—CH3 group which is trans to the carbonyl oxygen atom, 57 58 Table X. Chemical Shiftsa of the N-Alkyl Resonance Peaks of Symmetrically N, N-Disubstituted Amides Dimethylamides N-CH3(B) N-CH3(A) HCON(CH3)Z -180.0 —17o.o CH3CON(CH3)2 -182. 7 -172.o CH3CHZCON(CH3)2 —182.8 -173.8 CH3CH2CHZCON(CH3)Z - 182. 7 — 173. 5 ClCHzCON(CI-I3)z - 185.0 - 174. 5 Diethylamides N-CHz N-C-CH3(B) N-C-CHj(A) HCON(CH2CH3)2 -202.0 -69. 0 -64.1 CH3CON(CHZCH3)2 ~201.0 -69.Z -6Z.8 CH3CHZCON(CHZCH3)Z -202. 0 -70. 5 -63. 3 CH3CHZCHZCON(CH2CH3)Z -201.0 -68. 5 —62.2 C1CHZCON(CHZCH3)2 —202.0 (A) -72.7 -65.8 -205.0 (B) Diisopropylamides N-CH (B) N-CH (A) N-C-CH3 HCON[CH(CH3)2]Z —225.0 -239.5 -76.0 CH3CON[CH(CH3)2]Z ca. -238 ca. -212 ca. -76 CH3CH2CONICH(CH3)Z]Z —227 —227 —77.0 Di—n-propylamides N-CHZ N-C—C-CH3(B) N-C-C—CH; (A) HCON(CH2CH2CH3)Z —193.0 —51.0 —51.0 cn,c0N(CHZCH,CH,)J -194. o -53. 0 -49. 8 Diisobutllamides N-CHZ (B) N—CHL(A,) N-C-C—(CH3)2 HCON[CHZCH(CH3)Z]Z -185. 5 - 182.0 —51.1 a 0 Measured in cps from internal tetramethylsilane at approximately 35 C. mac ad: was- 56.2- . 5.2.3- _ . _ .NAmEONEO ZOOMWHO NO 8330920 oowamsom0s 30:989.” HE A: “weigh can 2 4.8.5.3- 5.8.7 3w- is... 5%.), W a 59 Alcm .NAnEONEOVZOUm mo ghoudm 00925008 0.32290”: HE .mH ohdwflh 60 while the one at —62.8 cps is due to the cis N-C-CH3 group. The acetyl protons resonate at -120. O cps, and the methylene protons at -201.0 cpS. . N, N-Diethylchloroacetamide--The NMR spectrum of N, N-diethyl- chloroacetamide is shown in Figure 17(a). The two quartets due to the methylene protons are partially overlapped, one being centered at -202. 0 cps and the other at -205.0 cps. The acetyl protons resonate at -85. 5 cps. The broad quartet of lines at higher magnetic field is composed of two partially overlapping triplets. The triplet at —65. 8 cps is due to the N-C-CH3 group which is g to the carbonyl oxygen, while the triplet at —72.7 cps is due to the m N—C-CH3. The spectrum of N, N-diethylchloroacetamide upon dilution with benzene is shown in Figures 17(b) to 17(d). In Figure 17(b), the methylene resonances over- lap or cross. The N-C-CH3 triplets start to cross inFigure 17(c), and are completely overlapping in Figure 17(d). Upon further dilution with benzene, both sets of peaks separate again, as the peaks which were originally to lower magnetic field move to high field faster in benzene than the peaks which were originally at higher field. N, N—Diisopropylformamide--The NMR spectrum of N, N-diiso— propylformamide is shown in Figure 18. The doublet at -76. 0 cps is due to the methyl protons of the isopropyl group. The nine—line multiplet at lower magnetic field is composed of two overlapping septets, centered at -225.0 cps and —239. 5 cps. The ratio of line in- tensities in a symmetrical septet is 1:6:15:20:15:6:1. However, the intensities for two septets overlapping in such a manner as to give nine lines is 1:6:16:26:30:26:16:6:1. The peak at —486 cps is due to the formyl proton. N, N-Diisopropylacetamide--The NMR spectrum of N, N-diiso- propylacetamide is shown in Figure 19. The broad doublet at -76 cps, due to the methyl protons of the isopropyl groups, is composed of two 61 1.15%? .0s0ns03 5 NAMEONEOVZOUNEOHU mo 8530220 0052800." 0.u0cw05 “2 43:2 0s5mflrm ado who: puma... .m..mwt o.~oma_o._momu . . . _ a .57 .NAmEONEDVZOONEOHU mo 55.30020 00cmCOm0s 030Gm0nfi H2 Aura 0.3..th . . u 62 & .1: 2.. .. >2 .0S0Nc0n E finmUnIOVZOONmOHO mo Esbo0mw 005050008 039»me 52 48: 085mg al on \ .0G0Nc0n g NAMEONEOVZOONEUMO m0 53.3023 00530008 030.;me .2 ASN.2 ousmau 63 o.om~- ‘ NAN- wmmu .NHNAmEUVEUBZOUmEU mo Ezuuoomm mommGOmoh 03.9%me L1H 3m; wudma o.mN_N.. m.m.vmm.. _ omw- . Alom .mmnAmIUVIOHZOUE mo SSH—oomm moCMGOmoH oflwcmma mm x: wgSm..nrA : J 64 doublets which are beginning to coalesce. - The acetyl protons resonate at- -120. 0 cps. The broad peak at lower magnetic field, due to the methine protons, is composed of two septets, which are beginning to coalesce. A One septet‘appearrs, at ; approximately -Z38 cps, the other at approximately -212 cps. -N, N-Diisopropylpropionamide--The 'NMR spectrum of N,- N-d-iiso- propylpropionamide is shown in Figure 20. The doublet at -77. O cps is due to the methyl protons of the isoprOpyl groups, while the triplet at -62.0 cps is due to the CH3-C-C-O group. The methylene protons resonate at -137. 5 cps. The broad peak at -227 cps is due to the septets from the methine protons, which are coalescing. N,- N-Diisobutylformamide--The NMR spectrum of N,- N-diisobutyl- formamide is shown in Figure 21. The doublet at --51. l cps is due to the methyl protons of the isobutyl groups. The two sets of doublets at -185. 5 cps and -182. O cps, are due to the non-equivalent N-methylene protons. The formyl proton resonates at -485 cps. The weak complex multiplet at approximately -114 cps is due to the methine protons in the isobutyl groups . ~ N, N-Di-g-prOpylformamide--The NMR spectrum of N, N-di'fl- propylformamide is shown in. Figure-22. The triplet at -51. 0 cps is due to the methyl protons in the _n-propyl group- The complex multiplet at approximately -93 cps is due to the N-C-CHz-C protons. -The'N-methy1- ene protons resonate at -l93. 0 cps. The formyl proton resonance is at «.485 cps. ~ LN, N-Digprppylacetamide--The NMR spectrum of N, N-di-B- propylacetamide is shown in Figure 23. The partially overlapping triplets at -5‘3. Ocps and -49. 8 cps are due to the non-equivalent methyl protons in the n-propyl group- The complex multiplet at approximately 6'5 mag o.Ns- m.>mn- emm- _ unu— ifzf/ .NTAmEUVEUHZOUNEUMEU mo Eduuooam ooGwQOmoH ofloamme ME .ON madman 66 30 13.. ET . 0.1%? 937. mm? . _ _ . _ _ _ _‘ . o A... m .ANAMWUVEU~EUHZOUE mo 85.30on oocchmon ofiocmme ME .HN o.domfim 67 mmo @431. o.mm.. 00.. >.w-: 04%;: n _ — j .fimIUNEONEUVZOOan mo fiauuoomm moGNCOmon 030:me mm .mm onswmh r _ q 3;. z 1:. ,2. -mmo o.dm- no- . mama“- mwv- _— « 1 .1. a s 11%.]... 11......llllll1 .NAnmUNEU~EUVZOUE mo Ednuoomm oUGNGOmOH ofiocwmg "I .mm whommh 68 '-90.cps is due to the N-C-CHz-C protons. » The acetyl protons resonate at. -118. 7 cps. The triplet at -194. O cps is due to the N-methylene groups. Table XI gives the chemical shifts of the N-alkyl resonances of the amides in Table X in‘a five ‘mole ,percent benzene solution, in which all peaks have moved to higher magnetic field. .Certain types of peaks, for example N-CH3,- N-C-CH3, cross over one another upon dilution with benzene and thus exchange their relative positions. .Certain groups resonate at almost the same magnetic field in the pure amide, for example N-CHz-C,» N-CHz-C-C, but separate upon dilution with benzene. The difference between the chemical shifts of the amide N-alkyl resonance in the pure amide (Table X) and in a five mole per cent benzene solution of the amide (Table XI) should indicate the degree of amide-benzene interaction. .For this reason, these' "benzene shifts" have been listed-in Table XII, together with the amide dipole moment and molecular volume. Unsymmetrically N, N-Disubstituted Amides The NMR spectra of the unsymmetrically'N, N-d-isubstituted amides are shown in Figures 24 to 38, and the chemical shifts of the N-alkyl substituents are listed in Table XIII. Because the“ N-alkyl groups are now different, the lifetimes of the amide in each stable planar. configur- ation will be unequal, and thus the‘ N-alkyl peak intensities in the" NMR spectrum will be different. The more intense peaks may be associated with the preferred rotational isomer. The coupling constant between the formyl proton and the N-methyl protons is given in Table XIV for the formamides. 69 .0 .omm EoH-mEMNOHQQm um odmfimfnfluoamuuou Hangmanfifioum mmo 8.” “condo-meg .m m .wm- m .3- o .2; - m .1: - fixnmovmoamoqzoom a: ”mo-o-o-z A3 MWo-o-o-z Am: ”mo-Z xi Nmo-z $282330an o .3- m .«m- N i: - w .2; - anmoumUNmovzoonmo a .3! ~13- w 4:: - o .3: - Namommoumovzoom Elmo-0-0-2 Earns-0-0-2 EV NHTS-z a: Nmo-z mmenfimaaosa-Q-S mic- mic- -I @2- m2- NEnmoEogzoosmonmo mm- 318 .03 - 2: - Afimovmouzoonmo 921 o .3- NM: - 0mm- Minamovmomzoom Am: “mo-0-2 :3 n30.0.2 a: $0.2 a: $0.2 moEEflEoEommo m .21 m .3. 3.1:- w i:- :a-mofiovzoommoa w .3- m .3- m .t: - o .N: - Nxmmonmovzoonmommonmo ---------- m .mn: - m .2: - Naroma”:zoo...mo£0 m .21 m .wm- m .37 9mm;- NAnmUNmovzoonmo 95- TB. m .34. mam:- N«frown-“0:40or Amy Miod-z :3 ”mo-o-z Am: Nro-z :3 N.mo-z 32:335sz m .34 - w .Nfl - :flovzoonoG o a? .. 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N .NN- o 62 - N .NNN - NN NNEENESNNENN.HN-2-2303822 - - o N: - N412- NN 026300N2Nfiofi-2-2NxfioNoN0-2 - - N NE - N NE - NN NBENENONNNfiofi-z2.0.2035-2 - - N .2: - N .NNN - .0-- 0283....03338223382-130-2 - - N NE - N NE - N+oN 028233825082Afism-2 - - o .NNN - N .2: .. NN 03883333824350 -2 - - N NE - N NE - 2N NEENEHofiNfimfi-z-HNNsm-z NINN- N,NN- N .oNN - N 62 - o - 0288....92.33EEKfiofi-z-NNfim-z N N? N .3. N .NNN - N .2: - 2N 03880oflNfimE-ZAEE-z N .NN- N .3. 0 NS - N NE - ON NBENENoNNNfioE-z-Efim-2 n GONfidewNN 31300-2 N $300.02 N 5120-2 N 2130-2 N L80 3:330 0284 N0 0w3200n0nm 00050N00350NQIZ .7N >NN00Nh00§E>mQD .No mvfimwnm 00G0G000m NNNVNNNNIZ 0N3 HO mu-NNNNW NMUNCQNZNU coNumhdwNmGOD 00HH0N0HnN mo 0w-00G00H00N 02-0 000NE< .HHHVA many-0H. 72 Table XIV. The Coupling Constanta Between the Formyl Proton and the N-Methyl Protons in Formamides, in the Pure Liquid and in Sulfuric Acid Solution Pure Liquid 1. 0 M in H2504 Amide J . J . trans £13 trans Cis /C-—N\ 0.9 ? 1.3 0.9b o/ CH3 H CH3 >C-o-N< 0.9 0.4 1.1 0.7 0 CH3 H CH3=CH3 2c N< 0 7 0.3 1 1 0.8 0 CH3 H\ (CH2)3‘CH3 éc N/ O 65 0.3 0 95 0 7 o \CI-l3 H CH=(CH3)2 >C—N/ 0 65 0.5 ”C "C 0 \CH3 H\ Q C-—N 0 6 0.4 0 65 7 0’ \CH3 H C-(CH3)3 \C—N/ 0 6 v 1 1 ? / \ 0 CH3 aIn cps. bMeasured in 1. O M DZSO4. c Not measured. 73 'N-Ethy‘l-N-methjlformamide—-The‘NMR spectrum of N-ethyl- N-methylformamide is shown in Figure 24. . The peaks at -.484 cps and -.480 cps are due to the formyl protons of each rotational isomer. The‘N-methyl peak at -‘179. 0 cps, which is coupled to the formyl proton by O. 3 cps, . has been assigned to the group trans to the carbonyl oxygen atom (position B), while the" N-methyl peak at -169. 5 cps, (which is coupled to the formyl proton by O. 7 cps, has been assigned tothe group 215: to the oxygen atom (position A), in the other rotational isomer. The methyl resonances of the‘N-ethyl group have been assigned similarly: The N-C-CH3 triplet at -68. 5 cps has been assigned to the group in a position t_r__an§. to the carbonyl oxygen atom, while the N-C-CH3 peak at -63. 2 cps has been assigned to the group c_'_1s to the oxygen. The N-CHZ resonance occurs at -202. 5 cps and coupling to the formyl proton is not resolvable. Upon dilution with benzene, the N-methyl peak at -179. 0 cps and the N-C-CH3 peak at ~68. 5 cps move upfield the most and cross over the corresponding peaks from the other rotational isomer. The N-methylene peaks separate in benzene solution. Comparison of the integrated intensities of the N-methyl resonances reveals that the rotational isomer in which the‘N-methyl group is £i_s_ to the carbonyl oxygen atom is preferred (60%). N-EthylnN—methylacetamide--The NMR spectrum of N-ethyl-N- methylacetamide is shown inFigure 25. The resonance peaks at -122. 0 cps and —120._5 cps are due to the CH3-CO group of each rotational isomer. The quartet at -204. 5 cps arises from the N-methylene protons. The ‘N-methyl peak at -181. 7 cps and the N-C-CH3 peak at -68. 5 cps have been assigned to the respective N-alkyl groups which are in a position 25:11.3. to the carbonyl oxygen atom, while the‘ N-methyl peak at -l71. 5 cps and the" N-C-CH3 peak at -61. Z cps have been associated with groups located Ei_s_ to the carbonyl oxygen. Upon dilution with benzene, the N-methyl peak at -181. 7 cps and the N-C—CH3 peak at ~68. 5 cps move 74 mmo is . N Jo.- m .mb: mam? 0.87 9:7 p.37 méom- P» p P P _1 d 3 , 4:1 J.1. . .A UNEOZmEUVZODmEU mo €3.50on monGOmoH 39.0:de HE .mm ohfimfih mafia _ N mo: m.wou m.ooau ORFH: m.NON1 owwu wwwa ” u u .1 A 4. _r T or .em 0.33m .AnEUNEUIMEUVZOUE A0 8530on oonGOmon 030:me Hm 75 upfield themost and cross over the corresponding resonance peaks from the other rotational isomer. The' N-methylene peaks separate in benzene solution. .Comparison of the integrated intensities of the N-methyl peaks reveals that the isomer ratio is very close to unity, but that the isomer in which the‘ N-methyl group is 9393. to the carbonyl oxygen atom is preferred (51%.). -N-Ethyl—N-methyltrimethylacetamide--The ‘NMR spectrum of N-ethyl-N-methyltrimethylac etamide is shown inFigure ‘26, and it will be noted that only one set of resonance peaks is observed for the N-alkyl protons. The‘N-methyl peak occurs at -180. 3 cps, the N-CHZ peak is at -206.1 cps, and the‘N-C-CH3 peakis at -65.4 cps. The large resonance peak at -74. 0 cps is due to the protons of the _t_-buty1 group- Dilution with benzene does not induceseparation of the peaks. However, two sets of resonance peaks, due to the two rotational isomers, are found in a 1.0M solution of the amide in 100% sulfuric acid. -N-n- Butyl-N-methylformamide--The NMR spectrum of N--_r_1_-buty1- N-methylformamide is shown inFigure 27. The formyl resonance at -481 cps is due to the overlapping of the formyl resonances from each rotational isomer. 1 The N-methyl resonance at 2168. 5 cps, , which is coupled to the formyl proton by 0. 65 cps, has been assigned to the group'which is in a position <_:i_s_to the carbonyl oxygen atom, while the N-methyl resonance at -177. 5 cps, which is coupled to the formyl proton by 0. 3 ‘cps, has been associated with the group located mm the oxygen atom. .Dilution of this amide with benzene results in a crossing over of the N-methyl resonance peaks, as shown inFigure ‘29. The'N-CHZ peaks from the E-butyl group overlap at -199. 0 cps in the pure‘amide, , but - separate upon the addition of benzene. .Spin coupling between the formyl proton and the‘N-CHZ protons is not resolvable. The high field complex multiplets are due to the N—C-CHz-CHz-CH3 protons. .Comparison of the 76 mmo $.mo1 o.w>1 — m.omH1 H.0wml .AMEUNEDIMEUVZOUUIMEUV mo €530on mosMGOmon oflocmmg am .3 oudmfim \ 77 mmo CANT. héwfloflwfin mfiom: . . _ _ . .AmmUNEUNHIHUNIOVAmEUyZODmmU mo 93.30on ooGdGOmon 3qume HI .wN mndmfih mAHU m.wn:1 mfikA: 0.00H1 Hwfin " i u " JJ 2 T or .AmmDNEDNEUNEOVAnmUVZOUE mo £5.30on ooamnommh oflocmdg am .hN Ohdmfih . rl‘l‘l v78 mmo. .. 1 1. . .. . 1 . .. .. m 1 .N .. N._mmHu H NmH N 5%; m mm: o m .M o “A: i s , g . . 1x4 . fl J. no .o mm .o me. .o 30 ~.$T 99:- 1. TNZ- mime? mg»? n u _. (e u . T or em .0 S mm .o 00 .H .oEEM coflomnm 30 E Moon node 253m swim 3 nowadays oqoo 03H. .28583 5%? :03: . coma AnmUNEUNEUumD: UVZOUE mo guuoomm monogamon on sumac: am .oN oudmfim L 79 integrated intensities of the N-methyl peaks shows that the preferred rotational isomer (61%) is the one in which the N—methyl group is located cis to the carbonyl oxygen atom. N;_n— Butyl—N-methylac etamide-—The NMR spectrum of N-n-butyl— N-methylacetamide is shown in Figure 28. The acetyl protons resonate at -121. 0 cps and the N—CHZ peaks from the _I_i_-buty1 group are over- lapped at —201.5 cps. The N-methyl peak at -171. 7 cps has been assigned to the group which is in a position 2 to the carbonyl oxygen atom, while the N-methyl peak at —181. 0 cps has been associated with the group w to the oxygen. Upon dilution with benzene, the N-methyl peaks cross and the N-methylene peaks separate. Comparison of the integrated intensities of the N—methyl peaks reveals that the preferred rotational isomer (53%) is the one in which the N-methyl group is in a position trans to the carbonyl oxygen atom. N-n-Butyl-N-methylisobutyramide——The N—methyl peaks of N—n- butyl-N-methylisobutyramide at —183. 2 cps and -17Z.0 cps partially overlap the C-methine resonance; thus the isomer ratio may not be determined from the NMR spectrum. The N-CHZ peaks of each isomer are coalesced at -2.02. 2 cps. Upon dilution with benzene, the N—methyl peaks cross and the N—CHZ peaks separate. Before the N-methyl peaks cross, it is apparent that the one to lower magnetic field (due to the isomer in which the N—methyl group is trans to the carbonyl oxygen) is the larger. N—n- Butyl-N—methjltrimethylacetamide-—The NMR spectrum of N-n-butyl-N-methyltrimethylacetamide is shown in Figure 30. Only one set of N-alkyl resonances is found for this amide. The N—methyl resonance is at -181.5 cps, the N—CHZ triplet is at -201.5 cps, and the protons from the L—butyl group resonate at -73.5 cps. The high field multiplets are due to the protons from the N—C—CHz—CHz—CH3 group. Neither the N—methyl, nor the N—methylene resonanCe peaks separate upon mmo m.ms- m.HmH- m.Ho~- 1 u p b 1.1. d - 80 .AnmSUNEUNmUNEUVAnmUVZOUnAmmUV mo ghuoomm oonGOmoH ofiocmma am .om ondmwh L 81 dilution of the amide with benzene. However, in a 1.0 M solution of the amide in 100% sulfuric acid, two sets of resonance peaks appear in the NMR spectrum due to the two rotational isomers. N-Cyclohexyl-N-methylformamide--The ’NMR spectrum. of N-cyclo— hexyl-N-methylformamide is shown in Figure 31. The N-Inethyl peak at -l65. 2 cps, which is coupled to the formyl proton by 0.60 cps, is assigned to the group which is in the positiong to the carbonyl oxygen atom, while the N—methyl peak at -172. 0 cps, which is coupled to the formyl proton by 0. 4 cps, is associated with the group 1% to the oxygen. Comparison of the integrated intensities of the N-methyl peaks reveals that the preferred rotational isomer (66%) is the one in which the N—methyl group is g to the carbonyl oxygen. Upon dilution with benzene, the N-methyl peaks cross. Weak, broad peaks at -Z43 cps and -204 cps, which may be seen upon further amplification, are due to the proton in the 1-position of the cyclohexyl ring. The larger of these peaks is at -204 cps and may thus be assigned to the isomer in which the cyclohexyl ring is c_1$ to the formyl proton. The large broad peak at higher magnetic field is due to the other cyclohexyl ring protons. The formyl protons resonate at -486 cps and —479 cps. N-Cyclohexyl-N-methylacetamide-—The NMR spectrum of N—cyclo— hexyl-N-methylacetamide is shown in Figure 32. The resonance peaks at -122. 5 cps and -119.4 cps arise from the acetyl protons of the two rotational isomers. The N-methyl peak at —164. 5 cps is assigned to the group which is in the position ci_s to the carbonyl oxygen atom, while the N-methyl resonance at —172. 0 cps is associated with the group trans to the oxygen. Upon dilution with benzene, the N-methyl peaks cross. Comparison of the integrated intensities of the N-methyl peaks reveals that the rotational isomer in which the N-methyl group is trfis to the carbonyl oxygen atom is preferred (55%). Weak broad peaks, which 82 mmo ¢.®:1..m.NN~i méofinroéhau P - n - . A . . 5 . .AZEoUXanVZOUmEU mo 5.9.50on ooddGOmon oSonmE am :9. charm mmo N.m©~.n o.NN.H.. 05... ems- I 1‘ s a 41.0mm .AZEQDZMEUVZOUE mo Edauommm ooddGOmoH 3qume "I .Hm 9%:me 83 may be seen upon further amplification, at -258 cps and -215 cps, are due to the 1-proton on the cyclohexyl ring. The more intense of these peaks is at —258 cps. The large broad peak at higher magnetic field is due to the other cyclohexyl ring protons. N-Isopropyl-N-methylformamide-—The NMR spectrum of N-iso- propyl—N-methylformamide is shown in Figure 33. The formyl proton resonances occur at —492 cps and -483 cps. The N-methyl peak at -l62.. 5 cps, which is coupled to the formyl proton by 0. 65 cps, the methine septet at -287.0 cps and the N—C—(CH3)Z doublet at -65. 7 cps have been associated with the isomer in which these groups are located c_i_s_ to the carbonyl oxygen atom, while the N-methyl peak at -l70. 0 cps, which is coupled to the formyl proton by 0. 5 cps, the methine septet at -247. 5 cps and the N-C—(CI—l3)_2 doublet at —71. 2 cps have been associ- ated with groups 1% to the oxygen. Upon dilution with benzene, the peaks which move farthest upfield are the N-methyl peak at -l70. 0 cps, the methine septet at -247. 5 cps and the N-C—(CH3)2 doublet at -7l.2 cps. The N-methyl and N-C—(CH3)2 peaks cross as benzene is added. Spin coupling between the formyl proton and the methine proton is not resolv- able. Comparison of the integrated intensities of the N-methyl peaks reveals that the preferred isomer (67%) is the one in which the N—methyl group is located cis to the carbonyl oxygen atom. N-Isopropyl-N-methylacetamide——The NMR spectrum of N-iso— propyl-N-methylacetamide is shown in Figure 34(a). The acetyl proton resonances occur at —118.7 cps and -122.0 cps. The N—C-(CH3)2 resonance peaks appear as a triplet due to partial overlapping of two doublets. The N—methyl peak at —162.0 cps, the methine septet at -Z7l. 0 cps and the N—C—(CH3)2 doublet at -62. 0 cps have been associated with the isomer in which these groups are located _CE to the carbonyl oxygen atom, while the N-methyl peak at —l69. 7 cps, the methine septet at -Z35.0 cps and the N—C-(CH3)Z doublet at —69. 0 cps have been 84 who ~3me ~45. m.NN~1 0.0:: mJJfimu 03.231 mw¢.1.mmw¢1 - q u a d a q u N T or .mxmom anion? 0:» no“ .Eo\mmo m was mxmom oGEumE paw Twang 05. H3 .§o\mmo. 0H manpodmom 9.3. .NHNAnEDvEUfinEOVZODE Ho 8550on ooddfiOmoH 0393ch mm .mm 0F 85 mmo m..mm1 0.37 06:1 odmfirofimau mfimmn mdwmu — — - - n — q a . a a a .. 1 I VJI J 1) J F 3V mmwd - .o .. . . . . . . 0“ CL 0 m. wHH1.o.NNHI 0 Ned... 5.05:1 O.mMN1 03:.NI . _. . 4 u .4 A3 690583 a: Any .30: Adv .NmmAnmUvEDHAnmUVZOUMEU mo 6.9990on oUSmGOmoH own—mama”: am .wm 09.9th L 86 associated with the isomer in which these groups are _t_1:_ar_1_s_ to the oxygen. atom. Upon dilution with benzene, the peaks which move farthest upfield are the' N-methyl peak‘at -169. 7 cps, the methine septet at -235. 0 cps and the N-C-(CH3)2 doublet at -69. Ocps. The N-methyl and‘N-C-(CH3)Z peaks cross as benzene is added,.as shown in Figure 34(b). Comparison of the integrated intensities of the N-methyl peaks reveals that the preferred isomer (58%) is the one in which the N-methyl group is located trans to the carbonyl oxygen atom. N-Formyl-Z-methylpiperidine--The‘NMR spectrum of N-.formyl'- Z-methylpiperidine is shown in Figure 35. The resonance peaks at -483 cps and -476. 5 cps are due to the formyl protons of the two rota- tional isomers. The large broad peak is due to the piperidine ring protons. The Z-methyl peaks, which are doublets due to spin coupling with the Z-proton, occur at -68. 3 cps and -75.9 cps, and appearas a triplet due to partial overlapping. The doublet at -68. 3 cps is assigned to the isomer in which the Z-methyl group is g to the carbonyl oxygen atom, while the doublet at -75. 8 cps is associated with the isomer in whi‘chthis group is t_r_ar_1_s to the carbonyl oxygen. Upon dilution with benzene, the doublets cross, the peak at —75. 8 cps moving farthest to high field. Since the Z-methyl peaks were difficult to integrate, the formyl proton peaks were used to determine the percentage of preferred configuration. For each formamide discussed in this section, the‘ NMR spectrum-reveals that the formyl peak to lower field is the more intense and may thus be associated with the preferred configuration. As Figure 35 shows, this is also the case for N-formyl-Z-methylpiperidine. By analogy with the preferred configuration found for the other form- amides, it may be said that the configuration in which the more bulky group (the Z-methyl group) is 2251—5. to the oxygen atom is the favored isomer“ (531%) in N-formyl- Z -methylpiperidine . 87 Figure 35. Hl‘magnetic resonance spectrum of HCON(2-CH3-C6Hm). Ho—9 l L . (L i u -483 -476.5 -75.8 -68.3 cps Figure 36(a). Hl magnetic resonance spectrum of CH3CON(Z-CH3-C6H10). l I -118.5 -68.0 cps Figure 36(b) H1 magnetic resonance spectrum of CH3CON(2-CH3-C6H10) in sulfuric acid. l I ‘ -56.5 -52.5 cps 88 N-Acetyl-2-methy1piperidine--The NMR spectrum of N-acetyl- Z—niethylpiperidine is shown in Figure 36(a). Only one set of resonances is foundfor this amide. The acetyl protons resonate at -118. 5 cps. The doublet at -68. 0 cps is due to the Z-methyl group, and the large broad peak is from the piperidine ring protons. Dilution of the- amide with benzene does not cause separation of the Z-methyl peaks. However, in a l. 0 M sulfuric acid solution, as shown in Figure 36(b), two separate doublets are observed for the Z-methyl protons, from the two rotational isomers. N-Methyil-N-l-butylformamide--The NMR spectrum of N-methyl- N-L-butylformamide is shown in Figure 37. The formyl proton resonance . occurs at -501. cps. The N-methyl peak at -l66. 5 cps, which is coupled to the formyl proton by 0. 60 cps, is assigned to the group which is in the position c_i_s_to the carbonyl oxygen atom, while the small N-methyl peak at -172. 5 cps, with no resolvable coupling, is associated with the group £3.25 to the oxygen. The protons from the N-L-butyl group experience a very small chemical shift difference (1. 7 cps); however, it is believed that the peak at -80. 1 may be associated with the isomer in which the L-butyl is tra___1_1_s to the carbonyl oxygen atom while the peak at -81. 8 cps may be assigned to the isomer in which the i-butyl group is gi_s_ to the oxygen. Upon dilution with benzene, the N-methyl peaks cross, and it is the' N-methyl peak at -172. 5 cps and the N-t-butyl peak at -80. l cps which move the farthest upfield. Comparison of the integrated intensities of the N-methyl peaks revealsthat the preferred isomer (89%) is the one in which the N-methyl group is cis to the carbonyl oxygen. N-Methyl-N-L-butylacetamide--TheNMR spectrum of N-methyl- N-i-butylacetamide is shown in Figure 38. AOnly one set of N—alkyl resonances is found for this amide. The acetyl protons resonate at -118. 0 cps. The N-methyl peak is at -l73. 5 cps and the N-t—butyl group 89 mmo 9 .8... 93. 98.7 WET. “ . w _ _v o .1 m C . .599? 909 ma ooddQOmoH :30an 1930M 9:. .flnAmmUvurnEUVZOUm mo 89.50on mocMGOmou 032.9me 93 .sm ma9mfim 9O mmo o.>m1 o.mHH1 m.mhfin r - .HMAMEUVUHAnEUVZOOnEU mo 59.30QO mosmCOmmp 33¢me am .3 ou9mfm 91 resonates at- -87. 0 cps. . Dilution with benzene does not induce separa- tion of the peaks. The amide decomposes in 100% sulfuric acid. All N-alkyl resonance peaks of the unsymmetricallyaN, N-disub- stituted amides in Table XIII move upfield in benzene except the lower field methine septet of the N—is0propy1amides, whichrmoves downfield. The types of peaks which cross upon dilution with benzene are the - 1 N-CH3, the N-C-CH3 and the'N-C-(CH3)Z peaks. N-Mono substituted Amide s The N-monosubstituted amides which were studied by-NMR in this work are listed in Table XV with the chemical shifts of the N-methyl substituents. Two sets of resonances, one from the e_is and one from the 1:23:93 configuration of the NH and CO about the central C-N bond, were found only for the formamides. In all of the other amides, only one set of resonances was observed in the NMR spectrum for the ‘N-alkyl substituent. The preferred configuration for all of the monosubstituted amides in Table XV is believed to be the one in which the‘ NH and C0 are 133 (Figure 6). Coupling constants in the formamides are listed in Table XVI. N-Ethylacetamide-m-The NMR spectrum of N-ethylacetamide is shown in Figure 39. The triplet at -66. 0 cps is due to the N-C-CH3 group. The acetyl protons resonate at -199 Cps. The multiplet at -194 cps arises from the methylene protons which are spincoupled to the nitrogen proton and to the N-C-CH3 protons. The broad peak at -484 cps is due to the nitrogen proton. vN-Isopropylacetamide--The 'NMR spectrum of N-isopropyl- acetamide is shown in Figure 40. The doublet at -67. 0 cps is due to the methyl protons of the isopropyl group. The acetyl protons resonate at -l 15. 0 cps. The multiplet at -Z37. 5 cps arises from the methine 92 Table xv. Chemical: Shiftsa of the N-Methyl Resonance Peaksfof N-Monosubstituted Amides N-Methylformamide -164. 5 - 172. 5 N-Methylacetamide - 164. 0 - N-Methylpropionamide -162. 5 - N-Methylisobutyramide - 162. 0 - a N-CHz-CH3(A) <5 N-CHl-CHAB) N-Ethylformamide -66. 3 -68. 5 ‘N-Ethylac etamide -66. 0 - N-Ethylpropionamide -66. 2 - N-EthylisobutyramideC -66. 0 - 5 N-CH- (CH3)2(A) 5 N-CH-a (CH3).2(B) N-Isopropylformamide -68. 5 -71. 8 N-Isopropylacetamide d -67. 0 - N-Isopropylisobutyramide -68. 0 - a N-c- (CH.).(A) a N-c- ((311.1503) - Butylformamide -81. 0 -78. 5 -Buty1acetamidee -76. 6 _ N-i N'L 3'Measured in cps from internal tetramethylsilane. The isomer in which the nitrogen alkyl substituent is cis to the car- bonyl oxygen (Fig, 61) is referred to here as A. _— An 0. 60 mole fraction carbon tetrachloride solution. An-O. 21. mole fraction carbon tetrachloride solution. An 0. 20 mole fraction carbon tetrachloride solution. 93 Table XVI. Coupling Constants in Monosubstituted Formamides Amide Solvent lea 'Jl3b Jl4b Jlsa ‘1“st J25 H\ /H Neat ? 1.8 0.9 ? 5.0 4.5 /C-N\ 33%(vol)in I-IZOC ? 2. 3 0. 8 ? 5. 0 ? 0 CH3 (1 1.0MinHzSO4 ? 5.0 1.3 0.9 5.6 ? H /H Neat ? ? $0.7 ? ? >C-N . ,, / \ 1.01nHZSO4 14 5.1 ~1.0 ? x6 0 ? O CIIHZ CH3 H\ /H Neat ? ? 951.0 ? 7.7 ? éC’N\ 1.0Min sto,e13.8 5.1 53.0.9 ? $157.7 7 O CH (CH3)2 H /H Neat ? 2.0 - - - - 2C'N\ 1 OMinHSO ”4'0 5’5) o c\ ° 7- 4' (14.4 5.0) _ - - - (CH3)3 a'The cis isomer The trans isomer (1) H\C N/R (5) (1) H\C N/H (3) é ' \ é ’ \ O H (2) O R (4) CSee reference (10). (1.11” was obtained in a 1. 0 M D2804 solution. eJM '3 0. 9 cps was obtained in a 1. 0 M DZSO4 solution. 94 0:1 17. .mmonmomzoonmo I“ we £93.3on oosmcomuom ofioawwfi ”TH .om os9mwh 95 wee o.ee- 1 o.mz9- , m.emm- _ wmvn .NAmmUVEUmZOUmmD mo 59.30on 009.95on 030:me LA .30 shipwrm 96 proton which is spin coupled to the nitrogen proton (7. 7 cps) and to the N--C-(CH3)Z protons (6. 8 tops). The broad peak at -484 cps is due to the nitrogen proton. N-Methylformamide--The‘NMR spectrum of N-methylformamide is shown inFigure 41. The more intense doublet at -164. 5 cps is due to the preferred rotational isomer, in which the‘N—methyl group is located £13 to the carbonyl oxygen atom. 1 The peak is a doublet due to spin coupling with the nitrogen proton. The small (0. 9 cps) splitting of each peak is due to coupling with the formyl proton. The less intense doublet at -172. 5 cps may be associated with the N-methyl group of the rotational isomer in which the group is 113313 to the carbonyl oxygen atom. Only approximately 8% of the amidemolecules assume this configuration. The'N-methyl peaks are amplified in Figure 44(a). 4 It is interesting to note that the coupling constant between the formyl andrN-methyl protons is equal to 5. 0 cps in the trans isomer and 4. 5 cps in the cis isomer (Table XVI). The broad peak at -485 cps in Figure 41 is due to the formyl proton. The nitrogen proton is barely observable at -474.cps. Figure 45(a) is the NMR spectrum of the‘N-methyl peaks of N-methyl- formamide in benzene. The N-methyl doublet from the less favored isomer has moved upfield farther than the N-methyl doublet from the preferred isomer, and in doing so, has crossed over the latter peak. Additional spin couplings to the formyl proton may be resolved in an .1. 0 M solution of the amide in 100% sulfuric acid, as shown in Table XVI. Figure 46 is the NMR spectrum of the formyl proton of N-methylformamide in sulfuric acid. Only the resonance from the formyl proton of the preferred rotational isomer is intense enough to be observed. ‘ The doublet of quartets is due to coupling with the nitrogen proton (5. 0 cps) and the‘ N-methyl protons (1. 3 cps). .Dissolving the amide in deuterated sulfuric acid results in almost total exchange of the nitrogen protontwith 97 mmo mJVoT. . m .Nbal _ d .MEOEZOOE mo £99.93on ooCMCOmoH 3909me 93 .3. op9wmh 98 mew.ee-w.zs- m.mv~.. owv 41cm ._ .2 14L£31<33kz _ ilIl’N .fimEOVEOZZOOE mo 83.30on 005980.»; ownosmmfi gm .2. 0.29th ma0 m .op- m .mon «on- see- Mme- . Al em _— __ _ _ ~ .anNEOEZOUE mo Enuuuomm 00995.00.” 0300me 1S :3. 0993mm wee mime- owe- mane- 3:- . _ n190597509 A3 m905092003 E 99 wee mew- mmwe- 9.1:- m.~_:- — u emofomzoom E “momzoom :3 E 3309 35.08.; We E9500mm 0 090.00g :mcwmazm .3. 0993b lOO Amfigomzoomxg :wfigmomzoomxa e.oe- o.ee- _ . upwal m.>mau _ 99%momzoomxfl o Al.m "mo 90393 a 909503 E mxmom 19:05 MmomzoomE .2 mo gsuoomm 009090909 ofiuocmmg 9TH. .mv 09.9th 101 7 mm”. VT: 0... .300 099.9390 SHNQEUVEOEZOOE mo souosm 19:0“ mo 89.500“: 009098009 0309w08 #3. .5q 099m9h P 3.1! Pi! lb: 5- b. h > x ncc d..‘ 4 1 {1“{ _“mgom m4 Tom . Tl 090 o .mlJl. .300 039390 99 nEOEZOOE mo Goponm 18.8w mo 5.99000mw 00909000n 09909w0§ 93 .30 0.39th 102 deuterium, causing collapse of all former coupling tothis proton. . Examination of the N-methyl peaks in deuterated sulfuric acid allowed determination of the long range cis coupling constant,-.1'HCONCH3 (0. 9 cpS). N-Ethylformamide--The NMR spectrum of N- ethylformamide is shown inFigure 42. The 'N-C—CH3 resonance has been amplified. in Figure 44(b). The more intense triplet at -66. 3 cps is due to the pre- ferred rotational isomer, in which the'N-C-CH3 group is located c_:_i_s to the carbonyl oxygen atom. The less intense triplet at -68. 5 cps is due to the N-C-CH3 group from the isomer in which the‘N-alkyl group is m to the carbonyl oxygen. Only approximately 12% of the amide molecules assume this configuration. The multiplet at -194 cps is due to an overlapping of the ‘N-methylene peaks from each rotational isomer. Each N-methylene proton is spin coupled to the adjacent methyl protons (7. 6 cps), to the nitrogen proton (6. 0 cps) and to the formyl proton (A), 0. 7 cps. ). The weak nitrogen proton resonance at -476 cps appears as a shoulder on the formyl proton resonance at -482 cps. .Figure\45(b) is the NMR spectrum of the N-C-CH3 peaks of N- ethylformamide in benzene. The‘N-C-CH3 triplet from the less favored isomer has moved the farthest upfield andhas crossed over the triplet from the preferred isomer. Figure 48 is the NMR spectrum of the formyl proton of N-ethylformamide in a 1. 0 M 100% sulfuric acid solution. The spectrum contains three peaks due, it is believed, to the partial overlapping of the formyl protons from the two rotational isomers. The large doublet to lower magnetic field is. due to the formyl proton of the preferred isomer. The coupling to the nitrogen proton is 5. 1 cps. -The- small peak to higher magnetic field is believed to be part of the formyl proton resonance of the less favored isomer. The rest of the doublet is buried beneath the low field half of the doublet from the preferred isomer. In this case, the coupling to the nitrogen proton is approximately 14 cps. 103 To... .300 039.390 5 MEUNEUEZOOE mo 98me 1928 mo 59.300“? 00Gmfl0moa uflvdwdg 090 «l 1- Tummo H.m W— um .wv 0H9wfih >1L 104 'All coupling to the nitrogen proton disappears in 100% deuterated sulfuric acid. ~N-IsOpropylformamide---The' NMR spectrum of N-isopropyl- formamide is shown inFigure 43. The N-C-(CH3)z,peak is amplified in-Figure 44(c'). 7 The more intense doublet at -68. 5 cps is due to the preferredrotational isomer, in which the‘N-alkyl group is'located gi_s_ to the carbonyl oxygen atom. The less intense doublet at -71.8 CpS .is due to the‘N-alkyl group from the isomer in which the‘N-alkyl group-is trans to the oxygen atom. Only approximately 12% of the amidemole- cules possess this configuration. The methine proton,. at -245. 5 cps, is coupled to the adjacent methyl protons (6.8 Cps), to the nitrogen proton (7. 7 cps) and to the formyl proton (3 1. O cps). The resonance peaks from the nitrogen and formyl protons overlap at -480 cps. Figure 45(c) is the NMR spectrum of the N-C-V(CH3)2 resonance of N-isopr0pylformamide in benzene solution. The N-C-(CH3)2 doublet from the _c_i_s isomer has moved the farthest upfield and has crossed over the doublet from the tra___11_s isomer. .Figure 47 is the NMR spectrum of the formyl proton of N-isopropylformamide in al. 0 M 100% sulfuric acid solution. , The spectrum is anapparent quartet due to the partial overlapping of the formyl resonance peaks from each rotational isomer. The more intense, inner peaks in the‘"quartet" are really members of a doublet, arising from the 5. lcps coupling of the formyl proton of the trans isomer with the nitrogen proton. A The fine structure of each inner peak reveals weak coupling (’4'; O. 9 cps) to the‘N-methine proton. The less intense, outer peaks in the “quartet" are also members of a doublet arising from the 13. 8 cps coupling of the-formyl. proton of the _c_i__s isomer with the nitrogen proton. Both doublets collapse when the amide is dis solved-in deuterated sulfuric acid. 105 EgButylformamidmehe NMR spectrum of the protons of the _t_-butyl group in N-i-butylformamide are shown inzFigure 44(d). The more intense peak at -81. O cps is due to the preferred-isomer, in which the N-.t_-butyl group is located 233 to the carbonyl oxygen atom, while the smaller peak at «=78. 5 cps is due to the N==t_-=buty1 group of the isomer in which the group is ELIE; to the oxygen. Approximately 18% of the amide molecules assume this configuration. The more intense formyl proton resonance at -475 cps, which is coupled to the nitrogen proton by Z. 0 cps, may be identified with the tsran isomer. The less intense formyl proton peak is at -475 cps. The nitrogen proton resonates at -462 cps. The NMR spectrum of the N-_t_-butyl protons in N-L-butylformamide in benzene is shown in Figure 45(d). The resonance peak from the i—butyl group of the less favored isomer has moved the farthest upfield in benzene. The NMR spectrum of the formyl proton of Nat-butylformamide in a l. O M 100% sulfuric acid solution is shown in Figure 49. In sulfuric acid, the percentage of the isomer in which the L-butyl group is located t_r_‘_a_ns to the carbonyl oxygen atom is approxi- mately 63% (compared with 18% in the pure amide), obtained by inte- gration of the L—butyl peaks. Thus, the outer pair of lines in Figure 49 is believed to be due to the formyl protons from this isomer. The pair of lines to higher field may be assigned to the formyl proton from the trans isomer. Because the peak to high field is composed of two over- lapping peaks, the coupling constants may not be accurately determined. However, the pairs 14.0 cps and 5.5 cps, or 14.4 cps and 5.0 cps for the trans and cis relationship of the formyl and nitrogen protons seem appropriate. Two formyl proton peaks remain in a l. O M solution of the amide in 100% deuterated sulfuric acid, one from each rotational isomer. N-= 15—25- Butylformamide and Na 15-_r_i- Butylacetamide--The‘ NMR spectrum of the formyl proton and nitrogen proton resonances of 106 Tom mmo .3 AL. .Eom oflhdfidm a: naanVUIZOOTH mo Goobnm TAEHOw mo gappoomw oonGomoh oflocmme ”E. .3“ “:me rm ,— -, ., ___. - < ill“ 107 N-lS-E-butylformamide are shown inFigure 50-. The two triplets at -438. 3 cps and ‘--530. 8‘cps are due to the nitrogen proton, which is coupled by- 92. 5 cps to the N-15 nucleus, and by 5.8 cps to theN—CHz protons. Each triplet is further‘split by a 2. 0 cps‘coupling to the formyl proton. The two doublets at -494. 5 cps and -479. 5 cps are due to the formyl proton, which is coupled by 15. 0 cps to the N-15 nucleus, and by '2. 0 cps to the nitrogen proton. The peaks just described are from the 133113 isomer (Figure 6). The weak multiplet, whichrmay be seen to high field of the NH peak at- -.438. 3 cps, may be due to the‘NH resonance of the c_1s_ isomer. Small sharp peaks in the formyl proton resonance region in Figure45, may be due to the formyl proton of the £13 isomer. Figure 51 shows the formyl and nitrogen proton resonances of a 0.46 mole fraction solution of N-lS-n-butylformamide in benzene. The nitrogen proton resonance has moved to higher field while the formyl proton resonance has moved slightly to lower field. The nitrogen proton in N- IS-E-butylacetamide-is coupled to the N-15 atom by 92. 0 cps and to the‘N-CHZ protons by 5. 5 cps. Hydrogen Bonding in N-Monosubstituted Amides N-Monosubstituted amides are known (4, 22, 120) to self-associate by hydrogen bonding (:N-H° ' 9 O-C:) inilinear chain-like polymers. -Adding solvent to the amide causes a breaking up of amide-amide hydrogen bonds, and, in the case of a solvent capable of hydrogen bonding, a form- ation of amide-solvent hydrogen bonds. . From a study of the changevin the observed'NMR chemical shift of the solute proton which is capable of hydrogen bonding, the equilibrium constants may be found. Figure-52 is a plot of 6 of N-isopropylacetamide against mole fraction in the NH inert. solvents carbon tetrachloride and cyclohexane. Figure 53 is a plot of 45 NH of N-methylacetamide, N-isopropylacetamide, and N-_t_-buty1- acetamide against mole fraction in the hydrogen bonding solvent, who «6.me saa-, Nwmuu ‘-N N m l T m .onoucoa E MEUNEUNEUMEUEEZOUE mo Eda mam oufidfl0moa 3qude am .Hm ohdmwh 8 0 1- who m.wm¢- m.osv- m.¢ov- w.omm- h P p p - mmz 0 m2 who who 32 o All m $2 003 mama» wads» «EvamUNEUNEUEBZOU mo 831023 moaMnOmoH oflodmme am .om opdmfim 109 -320 ' -340-» o CH3CONHCH(CH3)2 in col, B CH3CONHCH(CH3)Z in (:6le -360- 1;: (L fé :-380- (0 F4 >~ I .s o o l -420.. from internal tetrameth -440— 460— 6 NH (in cps -480— M. -500 --I I I l l I I 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Mole. fr action amide Figure 52. vPlot of 6N against molefraction for N-isoprOpylacetamide in carbon gtrachloride and cyclohexane solutions. 6 NH(cps from internal tetramethylsilane) 110 320- 340- 380- 4001 420‘ 440- .p. o o I 480.. o CH3CONHCH3 in chc13 “I; A u A o u A. n 0 o a a A o x. o I: c at o a 0 u 9 .1 o I I I I I i I I I T 0.1 0.2 0.3 0.4 ~0.5 0.6 0.7 0.8 0.9 1.0 Mole- fraction. amide Figure 53. Plot of 6 against mole fraction for‘N-methylacetamide, -N-isoprolp13¥iacetamide and N-i-butylacetamide in chloro- form-d-solutions. 111 chloroform (41). Figure 54 is a plot of,6 of N-isopropylace'tamide against mole fraction in the hydrogen bondifiig solvents, dimethyl- sulfoxide, diethylketone, and dioxane. Tables XVII through XXIV give the mole fraction of amide in each solution plotted in‘Figures 52 through 54, the observed chemical shift of the nitrogen proton, the ratio: moles amide/moles solvent (equation (45)) and the quantity. T/Y (equation (50)), or'Z/Z (equation(66)), calculated by the computer for the pair of equilibrium constants which provides the best fit of the data. ~Each set of solutions studied is listed in Tables XXV. through XXVII together with the values of K12 and R, or Lu and E, which provide the-smallest least squares deviation [ 22(6O - 6 c)2], and the values of vm or vC and vd, which are obtained from the slope and intercept of the best straight line. The chemical shift of the nitrogen proton in the pure amide, v , is also given in Table XXV for comparison. The quantity v varies fol: N-isopropylacetamide because of the small difference in the temperature of the spectrometer probe from day to day. The precision of the chemical shift measurements is approximately :1: 0. 5 cps for solutions above 0. 1 mole fraction amide, -_+. l. 0 cps for solutions between 0. 05 and 0. 10 mole fraction, and _-1-_ 1. 5 cps for solutions below 0.05 mole fraction. The values of Z (60 - 6 c)2 obtained for various combinations of L12 and I: with the data from the N-L-butylacetamide in chloroform-d solutions are shown in Figure 55. .l.\l1':l 112 -4004 -410-— -420- -430‘ -440 '- ~450— -460 a -470- -480 '- 0‘ CH3CONHCH(CH3)Z in-(CHZCHZO)z El. CH3CONHCH(CH3)7_ in~‘(CH3CHz)zCO A CH3CONHCH(CH3)2 in (CH3)ZSO T " l T l l l 1 jj 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Figure 54. Mole fraction amide Plot of 6 against mole fraction for‘N-isopropylacetamide in dioxane, diethylketone and dimethylsulfoxide solutions. 113 Table XVII. Concentration Dependence of the. Chemical Shift of the Nitrogen Proton in N-Isopropylacetamide in Carbon Tetrachloride Solutions a b — c d X c Y%Y 5NH 0.0054 0.0055 0.784 -327.0 0.0107 0.0108 0.568 -370.0 0.0165 0.0168 ---- -393.0* 0.0229 0.0235 0.351 -414.0 0.0496 0.0521 0.207 -442.0 0.0919 0.1012 0.183 —457.0 0.2501 0.3335 0.063 -472.0 0.4953 0.9813 0.033 -477.0 1.00 ---- ---- -484.0 ' Indicates that m Mole fraction amide /moles solvent on! M0138 amide See equation (50) 040 point was discarded due to a large (6 0-6 c) deviation. In cps from internal tetramethylsilane Table XVIII. Concentration Dependence of the Chemical Shift of the Nitrogen Proton in N-Isopropylacetamide‘ inCyclohexane Solution a b - c d X ‘c Y/Y 6NH 0.0114 0.0115 0.235 -449.0 0.0200 0.0204 0.148 -468.0 0.0292 0.0301 0.109 .-477.0 0.0506 0.0543 0.070 -486.0 0.0922 0.1016 0.043 -491.5 0.2039 0.2561 0.023 -496.0 0.3398 0.5146 0.014 -498.0 0.4991 0.9963 ---- -496.0ie 1.00 ---- ---- -490.5 >:< , Indicate s that m Mole fraction amide on! 9.0 Moles amide/moles solvent See equation (50) In cps from internal tetramethylsilane point was discarded due to a large (6 0-6 C) deviation. Table XIX. Concentration Dependence of the: Chemical? Shift of the 114 NitrOgeniProton int ‘N-Methylac etamide in Chlor oform-d Solution m a b — c d x c z/z 5NH 0.0195 0.0199~ 0.819 -353.0 0.0293 0.0302 0.760 -367.0 0.0395 0.0412 0.710 -376..0 0.0512 0. 0539 0. 663 -386_. 0 0.0922 0.1015 0.549 -408.0 0.1932 0. 2394 0. 400 --439. 0 0.3223 0.4756 0.297 -462.0 0.4778 0.9151 0.217 -476.0 0.7781 3.507 ---- -488.0* 1.00 ---- ---- -.492.0 'Indicates that Mole fraction amide o‘m Mole s amide/mole s s olvent 0.10 See equation (66) In cps from internal tetramethylsilane Table XX. .Conc entration Dependence of the Chemical Shift of the Nitrogen Proton in ~N-Isopropy1acetamide in-Chloroform-d point was discarded due to a large'(6 0-6 C) deviation. Solution a b -— C d 0.0124 0.0125 0.945 -330.0 0.0214 0.0219 0.906 -337.0 0.0329 0.0340 0.859 -346.0 0.0474 0.0498 0.805 -359.0 0.0617 0.0657 0.757 \-365.0 0.0791 0.0859 0.705 -375.0 0.0960 0.1062 0.661 -383.0 0.1989 0.2483 0.476 -420.0 0.3279 0.4878 0.345 -444.0 0.4994 0.9976 0.236 -465.0 0.7575 3.123 ---- -480.5* 1.00 -—-- ---- -490.0 Indicates that point was discarded due to a large (6 0-6 C) deviation. Mole fraction amide Moles amide/moles solvent ee equation (66) QaOU‘N-x- 115 Table XXI. .Concentration Dependence of the Chemical Shift of the ‘Nitrogen 'Proton in 'N-i-Alutylac etamide in Chloroform-é Solution 'a b _— c d ‘x .c z/z aNH 020123 ,0.0125 0.964 -325.0 0.0160 0.0163 0.953 1-326.5 0.0195 0.0199 0.944 ~328.0 0.0290. 0.0299 0.918 -331.0 0.0378 0.0394 0.895 4336.0 0.0463 0.0487 0.874 «340.0 0.0571 0.0607 0.848 -345.0 0.0974 0.1079 0.763 ~-358.5 0.1774 0.2156 0.630 -382.0 0.29128 0.4109 0.494 —406.0 0.4413 0.7899 0.365 -428.0 00‘5” Nlole fraction amide Moles amide/moles solvent See equation (66) In cps from internal tetramethylsilane A saturated solution (DO- ‘Table XXII. Concentration Dependence of the Chemical Shift of the ‘Nitrogen Proton in‘N-Isopropylacetamide inxDioxane Solution b —:;* d a .— C X .c z/z 5NH 0.0514 0.0542 0.799 --395.0 0.0981 0.1088 0.647 -412.5 0.1817 0.2221 10.476 -433.5 0. 33618 0.5079 0. 308 -4-53.0 0.5124 1.051 0.203 ~466.0 0.7323 2.736 0.114 -477.0 1.00 ----- ---- -485.0 00"!” CL Mole fraction amide Moles amide/moles solvent Seetequation (66) In CpS from internal tetramethylsilane 116 Table XXIII. Concentration Dependence of theChemical‘ Shift of the 'Nitrog en Proton in ‘N—‘Is-opropylacetamide in :Diethy‘lketone ‘Solution a b — c d x c z/z 5NH 0.0507 0.0535 0.808 ~4426.0 0.1039 0.1160 0.672 4436.0 0.1963 0.2442 0.518 -450.0 0.3188 0.4680 0.390 -459.0 0.5093 1.038 0.260 .470.0 10.7516 -3.026 0.140 »-480.0 1.00 ---- ---- ~485.0 0‘91 Mole fraction amide Moles amide/mole s solvent 0.10 ~ See equation '(6 6) In cps from internal tetramethylsilane Table XXIV. Concentration Dependence of the Chemical Shift of the ”Nitrogen Proton in‘N-Isopropylacetamide in Dimethyl- sulfoxide Solution . a b — C d X c z/z 5NH 0.0492 0.0517 0.966 -452.0 0.0968 0.1072 0.930 -453.0 0.2054 0.2584 0.833 -456.0 0.3533 0.5464 0.678 ‘-460.0 0.5311 1.133 0.480 1-466.0 0.7476 2.963 0.250 -472.5 1.00 -—-- ---- .-480.0 m on! 9.10 Mole fraction amide MoLes amide/moles solvent See equation (66) In cps from internal tetramethylsilane 117 Table XXV. Values of K12, 7E, pm andjvd forL:N+szopr.opy.lacetamide infCarbon Tetrachloride and Cyclohexane Solutions c a p —a, ,b b b 2 Solvent K12. K Vrn Vd VI) 2 (6 O- 6 c) CC14 l6.0:l-.2.0 150-1310 1-284 -484 --484.0 1.1 ‘C6H12 10.5:h2.0 450_+_50 -278 -.501 --490.5 0.2 a . ' . *In‘mole fraction units In cps from internal tetramethylsilane Sum—of squares of the deviations Table XXVI. Values of L... I, um and vd for N-‘Methylacetamide, N-Iso- propylac etamide and N-_t_- Butylacetamide in Chloroform-£1 Solutions _ a a b b b C , - A ~ ." _ z Amide L12 L Vm Vd VP 2 (5 C 0 C) N-‘Methylacetamide 13.0 14 0 -3.17 --521 -.492.0 6. 1 N-Isopropylacetamide 4.5 8. 0 -319 -510 -490.0 8. 6 'N-L-Butylacetamide 3.0 4 0 -318 -491 _-__ 3 2 a . . In mole fraction units In cps from internal tetramethylsilane Sum of squares of the deviations Table XXVII. Values of L12, L , .- vC and vd for' N-‘Isopropylacetamide in Dioxane, - Diethylketone and =Dimethyl sulfoxide‘Solutions a —a b b (b Solvent L12 L ”c vd vp ENG-5&2 (CHZCHZO)2 .3.5_-I;0.5 9.0.50.5 -371 -490 -485.0 0.5 '_(CH3CHZ)_ZCO 4.51 1.5 6.5.1: 0.5 .-410 -491 ~-.485.0 1.6 “(CH3)ZSO 0.65i0.10 0.90:1:0.10 -451 -480 «480.0 0.1 a . . -‘In mole fraction units In cps from internal. tetramethylsilane “Sum-of squares of the deviations Figure 55. Li. (mff 118 The least squares deviation 2(6 0-6 C)z obtained for combinations of L12 and L used in‘the hydrogen bonding solvent program with data from solutions of N-t -buty1- acetamide in chloroform-£1. The-_smallest deviation is obtained for L12 = 3.0 (mf)"l and L = 4.0(m£)-‘. L (mf)'1 3.0 3.5 4.0 4.5 5.0 2.0 43.3 22.6 13.8 2.5 15.7 9.7 5.7 4.2 5.5 3.0 7.4 4.3 3.2 4.4 8.0 3.5 10.5 8.9 9.3 11.9 16.9 4.0 20.6 19.4 20.5 23.9 29.5 DISCUSSION OF RESULTS Symmetrically N, N—Disubstituted Amides Examination of the NMR spectra of the symmetrically disub- stituted amides in Figures 15 through 23 reveals that certain N-alkyl groups are magnetically non-equivalent, and thus a chemical shift difference occurs between protons which arec_i§ and 2'32: to the carbonyl oxygen atom (Table X). Whether or not a given N=alky1 group is magnetically equivalent depends upon the rate of internal rotation about the central C-N bond, and the magnetic environment of the nuclei. Substituents on the carbonyl carbon can often alter the situation. For example, for four of the diethylamides in Table X, the'N-methylene protons are equivalent; however, the substitution of a chlorine atom in N, N—diethylchloroacetamide renders the methylene protons non— equivalent. The methylene protons in N, Nadiisobutylformamide are also non- equivalent, showing that the group adjacent to the methylene protons is also important. The two di—_I_1_=propylamides provide a second example: The N—(C-C—CH3)2 protons are equivalent in the formamide but non— equivalent in the ac etamide. The methine proton resonances in the diiso- propylamide series of Table X also show the effect of substituents on the carbonyl carbon: The formamide spectrum (Figure 18) contains two sharp methine peaks chemically shifted by 14. 5 cps. However, the methine resonances in diisopropylacetamide (Figure 19) are beginning to coalesce, and in diisopropylpropionamide (Figure 20) the peaks are over- lapping. The addition of benzene to a pure amide usually results in a con- siderable shift of the resonance peaks to high magnetic field. Hatton and Richards (11) noted that in dimethylformamide, dimethylacetamide, 119 120 diethylformamide and diethylacetamide, it was the’N-CH3 or'N-C-CH3 peak which was originally to lower -magnetic field which -moved the ‘most in benzene, and in doing so, crossed over the other-‘N-alkyl peak. On the assumption that a complex. similar to that which they propose (Figure 4) is found in2all amide-benzene solutions, the shift of the ‘N-lalkyl resonance(s) of all of the amides in Table X was-followed upon dilution-with benzene, and the peak which shifted the most to higher-field was assigned to the position (B) EELS. to thecarbonyl oxygen-atom. The chemical shifts of the amide ‘N-alkyl protons in a five mole percent' benzene solution are given in Table XI. Schneider (118) has explained the large chemical shift of the proton resonance of polar-molecules in benzene solution in terms of a dipole-induced dipoleinteraction and has shown that the shift is roughly proportional tothe quantity u/V, where u is the dipole-moment of the solute and V is its -mo1ecular volume. These quantities are given in Table XII, andan approximate-correlation is apparent. -As would be expected for the complex proposed‘(Figure 4), the greater shift-(30 to 50 cps) is observed for protons on the carbon directly bonded to the nitrogen atom. -A smaller shift (20 to ‘30 cps) occurs for protons which are three bonds removed from the'Initrogen. However, even protons four bonds removed from the nitrogen-experience a shift (16 to 17 cps) due to the largediamagnetic anisotropy of the benzene ring acting over a large distance. Unsymmetrically N, N-Disubstituted Amides The peak assignments in the unsymmetrically disubstituted-form- amides listed in Table XIII were ~made on the basis of the-magnitudeof the spin coupling c0nstants between the formyl and‘N-methyl protons of the two posmble rotational isomers. By comparison of JHCONCH3 1n N-methylformamide and dimethylformamide (Figure-3), it is generally believed (8, 9, 11) that the trans coupling constant is larger than the cis. 121 Thus, in the formamides, the“ N-methyl peak which is'coupled (most strongly to the formyl protontmay be assigned to the positionm-to the formyl proton. (Both assignments; may be checked by'b'enzene dilution studies if it is assumed that the‘peak' which -moves ~most'in ben- zene is associated-with the'N-alkyl group which is t_1_'a_1_1_s_ to the-carbonyl oxygen (Figure 4). The'NMR spectra of the formamides in Table XIII- reveal that of thetwo‘N-methyl peaks arising fromthe two rotational isomers, theone to higher‘magnetic field is always coupled more-strongly to the formyl proton. - This peak may then be associated with the‘ N-methyl group gi_s_ to the carbonyl oxygen. Since the integrated intensity of this peak is always larger than that of the 'N-methyl peak! to loweritfield, the configur- ation in which the ~N-methyl group is gig to thecarbony‘l oxygen is pre-1 ferred in all of the formamides studied. . Franconi (8),, for three formamides (Table‘l), also found that‘the bulkier group occurs _<_:_i_s_ to the formyl proton in the preferred isomer. The chemical shifts of the'N-methyl groups for the amides ‘in Table XIII are changed only slightly by replacing a formyl proton :with an acetyl group. Therefore, the peak assignments made for; each formamide maybe extended to the corresponding acetamide. - Integration of the N-methyl peaks inthe spectra shown in'Figures 25,. 28,. 32, and 34 reveals that. the preferred isomer in the acetamides is the one in which the'N-methyl [group is _t_1_'_a_._r_1_s_ to the carbonyl oxygen, as shown in Figure 56. H\ /R CH3\ N/:H3 éC—N\ O/C—\ o c H3 Figure 56. The configuration of the preferred-isomer in unsymmetrically disubstituted formamides and acetamides, R >CH3. 122 If the relative size of the substituent groups is R (alkyl) > CH3 > o .> H, then non-bonded interactions between groups on the nitrogen. atomand groups on the carbonyl carbon could lead to a‘preference» for the con- figurations shown in Figure 56,. Once the preferred configuration has been chosen, the integrated intensities of other resonance peaks from non-equivalent N-alkyl groups may be usedtfor the‘assignment of these peaks. For‘example, forethe amides in Table XIII, the protons whose resonances appear to higher magnetic field when located E_i_s_ to thecarbonyl oxygen are: ‘ N-CH3, N-C-CH3 and N-C-(CH3)2. However, peaks due to‘N-CH-C and N-C-‘(CH3)3 protons occur‘at lower magnetic field when the group is g tothe carbonyl oxygen. In every case, resonance peaks Which were assigned to the rotational isomer in which the'N-alkyl group is located trans to the carbonyl oxygen were the peaks which moved most to high field upon dilution with (benzene. The‘NMR spectra of N-ethyl-'N-methyltrimethylac etamide (Figure 24), N-E-butyl-N-methyltrimethylacetamide (Figure 30),N-methy1-N-_t_- butylac etamide, and N-Aac etyl-Ze-methylpiperidine (Figure -36(c)) differ from the spectra of the other unsymmetrically disubstituted amides in that only one set of resonances is observed. ‘ This‘may mean that (l) the chemical shifts of the two rotational isomers are ‘accidently‘ equal, (2) the rateof rotation about the C-N bond is fast enough so that the condition TA << [27217 ( VA - 0B) is fulfilled andthus only an averaging of resonance peaks is observed, or (3) only one-isomer 'is present in an appreciabl‘e‘amount. The first possibility is unlikely because of the non- equivalent N-alkyl groups of theother amides in Table XIII. The third possibility does not seem reasonable because one would not expect suchra preference for one rotational isomer 'in‘an‘amide 123 such‘as N- ethyl-N-methyltr-imethy’lacetamide in'which‘the N-Ialkyl substituents are of similar size. The second-explanationisrendered more likely by the appearance of two-rotational isomers man 1. 0 “M solution of these highly hindered amides in 100% sulfuric acid (excluding N-methyl-N-t-butylac etamide, . which decomposes). It is possible that large steric interactions in these four amides increase‘the single-bond character of the central C-N bond, leading to a less hindered rotation about this bond. . The lifetime of the' N-alkyl group at each site~may then be so small that an averaging of the NMR resonance peaks may be observed. Once the amide is protonated on the oxygen in sulfuric acid (14-16, 18), the double-bond character in the C-N bond increases‘and the rotation about the bond becomes more hindered (14). The increased lifetime in each planar configuration may be the reason .for the appear- ance of two sets of resonance peaks, from the two rotation-a1 isomers, in sulfuric acid solution. The increase in the magnitude of the long rangecoupling constant, JHCONCH3, of amides dissolved in 100% sulfuric acid (Table XIV) is consistent with an increase in the double-bond character of the C-iN bond. The belief that highly hinder ed amides possess less double-bond character in the central C-N bond than do other amides is supported by dipole moment studies (117). The smaller-dipole moment of the highly sterically hindered amides is consistent with a decrease‘in the contribu- tion of the polar resonance structure. N-Monosubstituted Amides The‘NMR spectra of N-methylformamide (Figure 41), N-ethyl- formamide (Figure 42), N-isopropylformamide'(Figure .43) and'N-i-buty-l- formamide (Figure 44(d)) reveal that both the _c_:_i_s and trans configurations of the peptide bond (Figure 6) are present. -Peak assignments -may be made by comparison of chemical shifts with the symmetrically disubstituted 124 amides (Table X) and the unsymmetrically disubstituted amides (Table XIII). The tins configuration is found to predominate in the formamides, with the percentage off-ii isomer increasing from 8% to 18% as the bulk of the N-alkyl group is increased from methyl to t-butyl. Only the _t_r_an_s configuration is found (Table XV) when the substituent on the car- bonyl carbon is larger than hydrogen, for example in N-ethylacetamide (Figure 39) or in N-isopropylacetamide (Figure 40). Previous workers (4, 12,13, 19-23) are in agreement that the tr_ans configuration predomi- nates in N-monosubstituted amides, but as far as is known, this is the first clear experimental evidence that some amide molecules exist in the e_is configuration. When the carbonyl carbon substituent is a methyl group or larger, the tie—is configuration places the alkyl groups 113% to one another, and would thus be preferred for steric reasons. However, even in the formamides, the £131}: configuration predominates. Nyquist (119) has claimed that there may be weak hydrogen bonding between the nitrogen proton and the substituent on the carbonyl carbon, which would tend to keep the amide in the leis configuration. However, this bonding would be expected to be negligible for formamides. Mizushima (120) has suggested that the strength of an amide hydrogen bond increases as each monomer is added to the polymer chain. It may be energetically favorable for the NH and CO to occur in the m configuration so that the amides can associate in linearly hydrogen bonded polymers. The chemical shift of the N—alkyl resonance peaks of the N-mono— substituted formamides in benzene solution is similar to that found in the N, N-disubstituted amides. In each case it is the smaller of the two resonance peaks which moves the most to high field upon dilution with benzene (Figure 45), indicating that this peak arises from an N—alkyl group which is in the position tra___n_s to the carbonyl oxygen atom, as indeed it is in the less favored configuration (the c__i_§ configuration of Figure 6). 125 The fact that J34 (Table XVI) is 0. 5 cps-largerthan ‘st in'Nr-methyl- formamide may be related tothe finding of Sunners gt a_l.. (30) that JNB (Figure 2) is 4. 0 cps-larger‘than‘JNA' in- N-lS-formamide.- (Re-fertothe discussion of the non-equivalence of the two‘NH bonds iniamides in the Historical Review section of this thesis.) The cis coupling constant, .I , which is equal to 1.8-cps and HCONH 2. 0 cps in pure N-methylformamide and N-i-butylformamide, respectively, increases to 5 cps. in'a 100% sulfuric acid s-olution’(Table‘XVI). The in- crease in coupling constant is attributed to an increase in the double-bond character of the central C—N bond due to protonation on the oxygen and thus a more planar ~amide.i Karplus (35) has shown that the maximum value of JHCCH in ethylene-type molecules occurs when the dihedral angle‘H-C-C—H is 00 or 1800. Extension of theargument to the‘H-Ci-N-H fragment would explain the increase in‘ JHC ONH in sulfuric acid. ~ The coupling constants found in-the'N-15 amides may b‘ecompared with the corresponding coupling constants found in N-15 formamide (30): Listing N-lS-g-butylformamide first, J = 92.5 cps, 92.0 cps; NH =1 .0 12. ;* = . , .1 . J 5 cps, 9 cps JH NH (c1s) 2 0 cps 2 cps HCON C Method of Obtaining EquilibriumeConstants in Hydrogen Bonding Studies The method used in this thesis for obtaining equilibrium constants for self-associated hydrogen bonded systems has the following require- ments: (1) the solute self-associates by forming linear, chain-like polymers, (2) the solute contains only two hydrogen bonding sites, one of which is a proton donor and the other, a protonacceptor, ~(3) intra- molecular as sociationis not present, (4) thersolvent does not self- associate, (5) either the solvent does not hydrogen bond to the solute (inert solvent case), or the solvent hydrogen bonds at only one site ~Klz, and X or'le andL,» (4) Y,n is always greater than Y 126 (hydrogen bonding solvent case). The assumptions made inthe develop- ment of thetheory are that (l) the chemical shift of the free proton in the monomer’is equal to that of the unbonded proton on the end of a polymer chain, (2) the chemical shift of theehydrogen bonded proton'in the dimeris equal to that of the bonded proton in‘a polymer chain, (3) only two equilibrium constants are necessary to describe the system, n+1»‘(for'n >1) so that by equation‘(39), - K Y1 is always less than unity, . and thus the condition necessary for summation of the series in‘order-to obtain equations (43) and (44) is always fulfilled. , For similar reasons,. Zn must always be greater than Zn+1 It is interesting to note that equation (61) predicts that the solvated monomer concentration (21) will become very, small both at high and=at low solvent concentrations (Figure 10). This behavior is expected at high solvent concentrations because the entire solute concentration becomes small; at high solute concentrations eventually. all monomers may addto the polymer chain, reducing the monomer concentration. Data for several sets of solutions were put in on both the inert solvent and the hydrogen bonding solvent programs, I and the results were‘quite similar. The reason forxthis is that, except for concentrated solutions, S approaches unity in the hydrogen bonding solvents used (becauSe the amides are so highly associated), thus equations‘ (51) to (63) reduce to equations (36) to (47). The quantity 2 (6 o - 6C)z, where 6 c is the calculated chemical shift from the least squares analysis, is an indication‘of how well the assumed equilibrium constants fit the data. Sets of equilibrium constants were fed into thecomputer until the region‘was found where thevalue of Z (6 o‘ - 6C)2,was minimized. Thenthe‘quantity (6O - 6 c) was examined for each solution-and points which deviated badly from the. straight line (more than 3 cps) were discarded and the calculations repeated. 127 In certain cases, the theory does not suffice to explain the concen- tration dependence of the chemical shift inconcentratedsolutions. For example, when‘N-isopropylacetamide is diluted with cyclohexane, the nitrogen proton resonance shifts first to lower magnetic ‘fieldand then it begins to shift to higher field. -The reason why. certain cyclo- hexane concentrations wouldfavor a greater extent of hydrogen bonding (or a different solute orientation) is not understood. The highly concen— trated chloroform solutions of N-methylacetamide and N-isopropylp acetamide (about 75 molepercent amide) also deviated-markedly from the straight line and wereconsequently discarded in the final calculation. In order to determine K12 accurately, it is necessary to-study several solutions which are dilute enough so that the monomer-dimer equilibrium is important. This condition may or'may not lie within the experimental capabilities of the NMR spectrometer, depending upon the magnitude of the equilibrium constants and upon-what type of peakis ob- served. The resonance peak of an amide nitrogen proton is very broad due to the quadrupole relaxation of the‘N-l4 nucleus, and broadens even further in dilute solutions. An 0. 005 mole fraction solution was the most dilute in which the'NH resonance could be measured. The method described appears to be generally useful for the analy- sis of linearly self-associated hydrogen bonding systems in both inert and hydrogen bonding solvents. - Further study of concentrated solutions might indicate whether or not the theory treats the entire concentration range satisfactorily. The neglect of solvent effects other-than hydrogen bondingis prob- ably ju'stified when the total chemical shift change is as large as 200 cps, as it is in the -monosubstituted amides. However, the effect of the re- action field may be considerable for these solutions, where the dipole moment of the solute is large‘(about 3. 6 D.) and where solvents with high dielectric constants were often used. - A complete analysis of hydrogen 128 bondingequ-ilibria should probably include a correction for the. chemical shift due tothe reaction field'effect. . However, there‘is' no known-way to correct forvthis effect over a. large range of concentrations. Results of the Hydrogen Bonding Studies The equilibrium constants found for'N-iso-propylacetamide in carbon tetrachloride,'- K12: 16 and-E = 150(m£)'1, and in cyclohexane, . K12 = 10. 5 and X = 450 (mf)'1, show that. monosubstituted amides are highly self-associated ininert solvents, and that thechange infree energy for the n-mer + monomer —-3 (n'+ 1)-mer equilibriumis-much larger: thanfor the monomer Viv—dimer equilibrium. ISarolea-Mathot (89) has shown statistically that E should be larger than Kn by a-factor of p, where p is the number of possible orientations of the-inonomer with equal energy. The chemical shift of the free nitrogenproton in the monomer, vm, is approximately -278 tor-284 cps, as found from the computer analysis. ~Extrapolation to infinite dilution in‘Figure 52is impossible because the slope-of the curve is still changing in the dilute solution region. The chemical shift of the hydrogen bonded proton in the dimer, vd, seems to be‘somewhat dependent upon v the chemical shift of the nitrogen proton in the'pure amide, which, ofcourse, is temperature dependent. .Studies at different temperatures 'would determine whether or not vd is really a constant for a givenamide. - The equilibrium constants found for the three‘N-monosubstituted amides in deuterated chloroform, ~N-methy1ac etamide, . L1; = 13. 0 "and I: = 14. 0 (mf)-i; N-isopropylacetamide,~ L12 = 4. 5 and I: = 8. 0‘ (mf)"l; and'N-t-butylacetamide, L12 = 3. 0 and I: = 4.. 0 (mf)"1, show that both L12 and'E decreaSe as the bulk of the'N-alkyl substituent increases. Lin'and Dannhauser (121),, studied hydrogen bonding in pure‘N-monosub- stituted amides by measuring dielectric constants and found that both ";.A‘.‘.~‘ .25 I. .. J. '.'_-.' .. I 129 the change in free energy and the change in enthalpy of hydrogen bond formation tended to decrease as the bulk of the N—alkyl substituent in— creases. Davies and Thomas (22), by vapor pressure measurements of amides in benzene solution, found that K12 and K were smaller for N-n—propylacetamide than for N-methylacetamide. The equilibrium constants for N-isopropylacetamide in deuterated chloroform are much smaller than in cyclohexane because the chloroform molecule hydrogen bonds to the amide oxygen (Cl3C-D . . . O-C ), effectively breaking up the amide-amide hydrogen bonds. - ‘(Klemperen (it 31. (41) estimate the energy of the chloroform-amide hydrogen bond to be 2 kcal/mole.) The chemical shift of the free proton for the three amides in chloroform solution is —318 i 1 Cps. That the chemical shift of the free proton is 40 cps to lower field in chloroform—d than in cyclo- hexane may be due to weak hydrogen bonding of the nitrogen proton to the chlorine atoms in chloroform—d solution. The following equilibrium constants are obtained for ‘N-isopropyl- acetamide in solvents which are capable of hydrogen bonding to the amide nitrogen proton: dioxane, K12 = 3. 5 and E = 9. 0 (mf)'1; diethyl— ketone, K12 = 4. 5 and E = 6. 5 (mf)'1; dimethylsulfoxide,- K12 = 0.65 and I(- = 0. 9 (mf)'1. These results indicate that dioxane and diethylketone compete with approximately the same efficiency as chloroform for the 1 amide hydrogen bond, but that dimethylsulfoxide is much more success- ful at breaking up‘amide self-association. The chemical shift of the bonded proton in the amide-solvent complex, -371 cps for dioxane, -410 cps for diethylketone, and -451 cps for dimethylsulfoxide, probably reflects the strength of the hydrogen bond formed, that with dimethyl- sulfoxide being the strongest. - (Kaiser (49) found a monotonic increase in the hydrogen bond NMR chemical shift (vd - vc) with the enthalpy of hydrogen bond formation.) I SUMMARY A Varian A-60 model nuclear magnetic resonance“(NMR) spectrometer was used for observing the proton resonance of a series of N-monosubstituted and N,-N-disubstituted amides. The nature of the complex formation between benzene and amides was studied by observing the‘NMR resonance peaks of a series of sixteen symmetrically N, N—disubstituted amides upon dilution with benzene. An approximate correlation of N—alkyl peak shift in benzene with amide dipole moment and molecular volume indicates a dipole—- induced dipole interaction. The decrease in the extent of peak shift with distance of the observed proton(s) from the amide nitrogen atom, as determined qualitatively by the number of intervening bonds, sug- gests that the TI’ electrons of the benzene ring are interacting with the nitrogen atom. A study of fifteen unsymmetrically N, N-disubstituted amides was made and the N—alkyl resonance peaks were assigned to the respective rotational isomers on the basis of the magnitude of the long range coupling constant, .1 in the formamides, and by a comparison HCONCH; of chemical shifts in the acetamides. The preferred configuration in the formamides was found to be the isomer in which the bulkier‘N-alkyl substituent is fins to the carbonyl oxygen atom; however, in the acetamides the isomer in which the bulkier' N—alkyl substituent is 21;: to the carbonyl oxygen is preferred. The peak assignments were checked by benzene dilution studies. For four highly substituted amides, such as N-g—butyl-N-methyltrimethylac etamide, only one set of N—alkyl resonance peaks was observed in the NMR spectrum. However, two sets of resonance peaks appear in the‘NMR spectrum of a sulfuric acid solu- tion of the amide. 130 131 ~Exam~ination of the spectra of eighteen N—monosubstituted amides showed that. four of these, ‘ N-methylformamide, N -ethylformramide, - N-isopropy‘lformamide and' N-t-butylformamide, exist in both the £23. and m. configurations about the central C-N bond. 'The percentage of_c_i_§_ isomer “increasesas the‘N-alky’l substituent becomes. more bulky. - In the other amides, wherethe carbonyl carbonsubstituent is larger than hydrogen, only the 113513 configuration was found. . The is coupling constant between the formyl and nitrogen protons-more than doubles in sulfuric acid solution. In order to study the self-association of N—monosubstituted amides by'NMR, a theoretical method for treating chain association which re- lates two equilibrium constants, Km for. monomer ———3~ dimer, and‘l? for n-mer rl- monomer -——3 (n + l)-mer equilibrYiE theconcen- ‘_____ tration of the solution, the observed chemical shift of the solute hydrogen bonding-proton, and the chemical shifts of the free-and bonded protons in the polymers was developed. Two special cases were-used tosanalyze the data: the inert solvent case‘and the hydrogen bonding solvent case; each was programmed for use on theMISTIC Computer at Michigan State University. The equilibrium constantsfound for the amides in the inert solvents carbon tetrachloride and. cyclohexane reveal that E >> K12, and both are (much larger than the equilibrium constants found in solvents 'which are capable of hydrogen bonding to theamide. 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