INFORMATION TO USERS
This reproduction was made from a copy of a document sent to us for microfilming. While the most advanced technology has been used to photograph and reproduce this document, the quality of the reproduction is heavily dependent upon the quality of the material submitted.
The following explanation of techniques is provided to help clarify markings or notations which may appear on this reproduction.
1.The sign or “target” for pages apparently lacking from the document photographed is “Missing Page(s)”. If it was possible to obtain the missing page(s) or section, they are spliced into the film along with adjacent pages. This may have necessitated cutting through an image and duplicating adjacent pages to assure complete continuity.
2. When an image on the film is obliterated with a round black mark, it is an indication of either blurred copy because of movement during exposure, duplicate copy, or copyrighted materials that should not have been filmed. For blurred pages, a good image of the page can be found in the adjacent frame. If copyrighted materials were deleted, a target note will appear listing the pages in the adjacent frame.
3. When a map, drawing or chart, etc., is part of the material being photographed, a definite method of “sectioning” the material has been followed. It is customary to begin filming at the upper left hand comer of a large sheet and to continue from left to right in equal sections with small overlaps. If necessary, sectioning is continued again-beginning below the first row and continuing on until complete.
4. For illustrations that cannot be satisfactorily reproduced by xerographic means, photographic prints can be purchased at additional cost and inserted into your xerographic copy. These prints are available upon request from the Dissertations Customer Services Department.
5. Some pages in any document may have indistinct print. In all cases the best available copy has been filmed.
Universi^ Micrwilms International aoO N .Zeeb Road Ann Arbor, Ml 48106
8513651
Wyatt, Dorothy Katharine
A STUDY OF SELECTED DIBENZOCYCLOHEPTANE AND THIOXANTHENE DERIVATIVES BY CARBON-13 NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY
The American University Ph.D. 1985
University Microfilms I nternetionelSOO N. Zeeb Road, Ann Arbor, Ml 48106
Copyright 1985 by Wyatt, Dorothy Katharine All Rights Reserved
PLEASE NOTE:
In all cases this material has been filmed in the best possible way from the available copy. Problems encountered with this document have been identified here with a check mark V
1. Glossy photographs or pages.
2. Colored illustrations, paper or print _____
3. Photographs with dark background _____
A. Illustrations are poor copy ______
5. Pages with black marks, not original copy.
6. Print shows through as there is text on both sides of page.
7. Indistinct, broken or small print on several pages
8. Print exceeds margin requirements ______
9. Tightly bound copy with print lost in spine ______
10. Computer printout pages with indistinct print.
11. P age(s) ______lacking when material received, and not available from school or author.
12. P age(s) ______seem to be missing in numbering only as text follows.
13. Two pages num bered ______. Text follows.
14. Curling and wrinkled p a g e s ______
15. O ther ______
University Microfilms International
A STUDY OF SELECTED DIBENZOCYCLOHEPTANE AND THIOXANTHENE
DERIVATIVES BY CARBON^^ NUCLEAR MAGNETIC RESONANCE
SPECTROSCOPY
by
Dorothy K. Wyatt
submitted to the
Faculty of the College of Arts and Sciences
of The American University
in Partial Fulfillment of
the Requirements for the Degree
o f
Doctor of Philosophy
in
C hem i s t r y
Signatures of Committee;
Chairman: — *
\ ^ ^_C y^-L L-gL ' 4 Dean of the Co 11 eg
Da t
1985 The American University l e 4 4 l Washington, D.C. 20016
•JÏ5E AKMHI C M UHIVEltSITY LIBRARY COPYRIGHT
BY
DOROTHY K. WYATT
1985
ALL RIGHTS RESERVED A STUDY OF SELECTED DIBENZOCYCLOHEPTANE AND THIOXANTHENE
DERIVATIVES BY CARBON^^ NUCLEAR MAGNETIC RESONANCE
SPECTROSCOPY
by
Dorothy K. Wyatt
ABSTRACT
Carbon^^ nuclear magnetic resonance (NMR) chemical shift assignments are reported for Z~ and ^-doxepin hydrochloride (N,N,-dimethyl-dibenz[b,e]oxepin-de1ta-
11(6H), gamma-propylamine hydrochloride), Z- and E- dothiepin hydrochloride ( N , N-d ime thy Id i benzo[ b , e ] th ie- pin-delta-ll(6H), gamma-propylami ne hydrochloride), Z- and E- thiothixene (N ,N-dimethy 1-9-[3-(4-methy 1-1-piper- aziny1)propy1 idene]thioxanthene-2-su Ifonamide), Z- and
E- chlorprothixene (1-propanamine, 3-(2-chloro-9H- thioxanthen-9-ylidene)-N,N-dimethyl), amitriptyline hydrochloride (1-propanamine, 3-(10,11-dihydro-5H-diben- zo[a,d]cyclohepten-5-ylidene)-N,N-dimethyl-hydrochlor- ide), and nortriptyline hydrochloride (1-propanamine, 3-
(10,11-d ihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-
N ,N-diraethyl-hydrochloride). In addition to these latter pharmaceuticals, precursors and model compounds such as 5-methy 1ene-5H-dibenzo[a,d]eyeloheptane and 6H-
ii d ibenzothiepin-11-one were also studied.
The pharmaceuticals under study are used in the treatment of anxiety, depression, and schizophrenia.
They are believed to act by preventing reuptake inacti vation of biogenic amines at the nerve endings thereby potentiating the amine action at postsynaptic receptors.
Conformational variations between isomers in solution and predictably at the biogenic amine uptake jump may explain the greater biological activity of the 7^- iso mer. Conformation studies of non isomer ic drugs such as amitriptyline may also explain the biological activity of these dibenzocycloheptane derivatives.
Current studies indicate that doxepin isomers differ in dibenz[b,e]oxepin ring conformation and that the a Iky 1 amino o 1e f in ic group is oriented above the most adjacent aromatic ring as in analogous studies of d ib enzoc yc lo hep tane derivatives. Carbon^^ NMR studies of dothiepin indicate similar conclusions. The thio- xanthene derivatives, thiothixene and chlorprothixene, do not differ in isomer ring conformation. Alkylamino o 1e f in ic group orientation agrees with previously re ported X-ray crystallography data. This group is fully extended away from the thioxanthene ring. IQ Carbon NMR shift assignments for these compounds
111 were made by comparison of model compound chemical shifts, off-resonance data, spin lattice relaxation time
(Tj) determinations, homo - and heteronuc1 ear shift- correlated 2D NMR spectroscopy, proton NMR, selective decoupling, and selective INEPT experiments.
iv ACKNOWLEDGEMENTS
I wish to express deepest appreciation to my advisors without whose encouragement and support this work would not have been possible. I wish to especially thank Dr. Nina M. Roscher whose untiring encouragement and assistance made possible the completion of this effort. She not only provided the financing necessary for access to the more sophisticated NMR instrumentation as well as necessary chemicals and supplies, but gave extensively of her time to provide encouragement as well as assistance in planning and organizing access to these instruments. I wish to thank Dr. Lee T. Grady, who suggested this topic and who encouraged me throughout this project as well as gave me the opportunity to develop and grow as a research chemist and later, as a supervisor under his direction, for the use of the
Varian FT 80-A NMR spectrometer which has been used extensively throughout this endeavor, for providing drug samples for analysis, and for providing the introduc tions necessary for the acquisition of the dothiepin samples. I also wish to thank Dr. Mary Aldridge without whose encouragement I would not have entered and con tinued my graduate school efforts at American University which resulted in the completion of this Ph.D. In addition, I wish to acknowledge the support of the U.S.
Department of Education under the Graduate and Profes sional Opportunities Fellows program.
I wish to express great appreciation to Dr. Mike
Geek 1e and Bruker Instruments, Inc., Billerica, Massachu setts for their assistance and the use of their Bruker
AM-400 NMR spectrometer and instruction in the use of 2D
NMR techniques. I wish also to thank Dr. Ad Bax of the
National Institutes of Health for use of the Nicolet NT-
270 NMR spectrometer and instruction in the use of selective INEPT experiments. I wish to also acknowledge the support of the NSF Northeast Regional NMR Facility at Yale University, which was funded by Grant Number
CHE-7916210, from the Chemistry Division of NSF.
I wish to further acknowledge the assistance of
Dr. Ann Turner of Howard University who provided use of a Nicole t NT-200 NMR spectrometer as well as Dr. Cecil
Dubrowski of the University of Delaware who provided use of their Bruker AM-250 NMR spectrometer.
I wish to thank Mr. Johnny Johnson and Dr. Islam of the British Pharmacopoeia as well as Dr. Spooner of
Boots Chemical Co. for their assistance and courtesy and for providing dothiepin hydrochloride and 6H-d ibenzo-
VI [ b , e ] th i epln-11-one reference standards and E^- and dothlepln hydrochloride samples, respectively, that were
used in this analysis. Their kindness and generosity while visiting their laboratory facilities in England will always be remembered. I wish also to thank Dr. Y .
Segal1 of the Israeli Institute for Biological Research
for providing the 5-methy1ene-5H-dibenzo[a,d]eyelohep
tane sample used in the analysis.
I wish to especially thank my husband, William K.
Wyatt who not only encouraged and supported me in this endeavor but shared my travails as his own. He not only kept the same erratic schedule necessitated by my off-hour use of NMR instrumentation but also travelled with me whenever possible to remote NMR locations. I wish also to thank my dear friend Mrs. Ann Ferguson who not only endeavored to assist and encourage me whenever possible on this effort but who frequently gave of her own time toward that end.
V I 1 TABLE OF CONTENTS
ABSTRACT ...... 11
ACKNOWLEDGMENTS ...... v
LIST OF TABLES ...... ix
LIST OF ILLUSTRATIONS ...... xi
INTRODUCTION ...... 1
TECHNIQUES OF ANALYSIS ...... 10
MODEL COMPOUNDS ...... 16
NUCLEAR MAGNETIC RESONANCE ANALYSIS OF DIBENZOCYCLO
HEPTANE DERIVATIVES ...... 76
Carbon^^ NMR of Z- and Doxepin Hydrochlor
ide (76) -- Z- and Dothiepin Hydrochloride
(106) -- 6H-Dibenzothiepin-ll-one (135) --
Amitriptyline Hydrochloride (150) -- Nortript
yline Hydrochloride (168) -- 5-Methylene-5H-
dibenzoCa,d]eyeloheptane (180) -- Dibenzo-
suberone (196)
NUCLEAR MAGNETIC RESONANCE ANALYSIS OF THIOXANTHENE
DERIVATIVES ...... 203 13 Carbon NMR of Z- and Thiothixene (203) --
Z- and E- Chlorprothixene (230)
EXPERIMENTAL ...... 258
REFERENCES ...... 260
V I 11 LIST OF TABLES
1. Benzophenone ...... 21
2. BenzyImercaptan ...... 29
3. BenzyIphenylether ...... 36
4. Benzylphenylsulfide ...... 42
5. Ch lorobenzene ...... 46
6. Dibenzyl ...... 49
7. N,N-Dimethy1-2"toluenesulfonamide ...... 54
8. 1,1-Diphenylethylene ...... 58
9. DiphenyImethane ...... 65
10. Diphenylsulfide ...... 69
11. N-Methy 1-£-toluenesu Ifonamide ...... 75
12. Doxepin Hydrochloride Alkyl Carbon Assignments ... 80
13. ^-Doxepin Hydrochloride Aromatic and Olefinic
Carbon Assignments ...... 81
14. ^-Doxepin Hydrochloride Aromatic and Olefinic
Carbon Assignments ...... 82
15. Dothiepin Hydrochloride Alkyl Carbon Assignments . 110
16. ^-Dothiepin Hydrochloride Aromatic and Olefinic
Carbon Assignments ...... Ill
17. Z-Dothiepin Hydrochloride Aromatic and Olefinic
Carbon Assignments ..... 112
18. 6H-Dibenzo[b,e]thiepin-11-one Carbon Assignments . 136
IX 19. Amitriptyline Hydrochloride Alkyl Carbon Assign
ments ...... 153
20. Amitriptyline Hydrochloride Aromatic and Olefinic
Carbon Assignments ...... 154
21. Nortriptyline Hydrochloride Alkyl Carbon Assign
ments ...... 169
22. Nortriptyline Hydrochloride Aromatic and Olefinic
Carbon Assignments ...... 170
23. 5-Methylene-5H-Dibenzo[a,dIcycloheptane Carbon
Assignments ...... 181
24. Dibenzosuberone Carbon Assignments ...... 192
25. 10,11-Dihydro-5H-dibenzo[a,d]eyeloheptane Carbon
Assignments ...... 198
26. Thiothixene Alkyl Carbon Assignments ...... 206
27. ^-Thiothixene Aromatic and Olefinic Carbon
Assignments ...... 207
28. ^-Thiothixene Aromatic and Olefinic Carbon
Assignments ...... 208
29. Chlorprothixene Alkyl Carbon Assignments ...... 233
30. ^-Chloprothixene Aromatic and Olefinic Carbon
Assignments ...... 234
31. ^-Chlorprothixene Aromatic and Olefinic Carbon
Assignments ...... 235 LIST OF ILLUSTRATIONS
1. Dibenzocycloheptane Derivatives ...... 2
2. Thioxanthene Derivatives ...... 6
3. NMR Pulse Sequences ...... 14
4. Model Compounds ...... 17
5. Benzophenone Carbon^^ NMR Off-Resonance Decoupled
Spectrum ...... 19
6. Benzophenone Carbon^^ NMR Off-Resonance Decoupled
Spectrum: Downfield Signals ...... 20
7. Benzophenone Carbon^^ NMR Spectrum ...... 22 13 8. Benzophenone Carbon NMR Spectrum: Downfield
Signals ...... 23
9. Benzyl Mercaptan Carbon^^ NMR Off-Resonance
Decoupled Spectrum ...... 24 13 10. Benzyl Mercaptan Carbon NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 25 13 11. Benzyl Mercaptan Carbon NMR Spectrum ...... 27
12. Benzyl Mercaptan Carbon^^ NMR Spectrum: Downfield
Signals ...... 28 13 13. Benzylphenylether Carbon NMR Off-Resonance
Decoupled Spectrum ...... 31
XI 13 14. BenzyIphenylether Carbon NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 32
15. Benzylphenylether Carbon^^ NMR Spectrum ...... 34 13 16. Benzylphenylether Carbon NMR Spectrum : Down
field Signals ...... 35 13 17. Benzylphenylsulfide Carbon NMR Off-Resonance
Decoupled Spectrum ...... 37 13 18. BenzyIpheny1sulfide Carbon NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 38 13 19. Benzylphenylsulfide Carbon NMR Spectrum ...... 40 13 20. Benzy1pheny1 su If ide Carbon NMR Spectrum: Down
field Signals ...... 41
21. Chlorobenzene Carbon^^ NMR Spectrum ...... 44
22. Chlorobenzene Carbon^^ NMR Spectrum: Downfield
Signals ...... 45 13 23. Dibenzyl Carbon NMR Spectrum ...... 47 13 24. Dibenzyl Carbon NMR Spectrum: Downfield
Signals ...... 48 13 25. N ,N-Dimethyl-£-to luenesulfonamide Carbon NMR
Spectrum ...... 52
26. N ,N-Dimethy1-£-toluenesu Ifonamide Carbon^^ NMR
Spectrum: Downfield Signals ...... 53 13 27. 1,1-Diphenylethylene Carbon NMR Off-Resonance
Decoupled Spectrum ...... 55
Xll 13 28. 1,1-Dlphenylethylene Carbon NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 56
29. 1,1-Diphenylethylene Carbon^^ NMR Spectrum ...... 59
30. 1,1-Diphenylethylene Carbon^^ NMR Spectrum: Down
field Signals ...... 60 13 31. DiphenyImethane Carbon NMR Off-Resonance
Decoupled Spectrum ...... 61
32. DiphenyImethane Carbon^^ NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 62 13 33. DiphenyImethane Carbon NMR Spectrum ...... 63 13 34. DiphenyImethane Carbon NMR Spectrum: Downfield
Signals ...... 64
35. Dipheny1 su If ide Carbon^^ NMR Spectrum ...... 67 13 36. Dipheny1 su 1fide Carbon NMR Spectrum: Downfield
Signals ...... 68
37. N-Methyl-£-toiuenesuIfonamid e Carbon^^ NMR Of f-
Resonance Decoupled Spectrum ...... 70 13 38. N-Methyl-£-toluenesuIfonamide Carbon NMR Off-
Resonance Decoupled Spectrum: Downfield
Signals ...... 71
39. N-Methyl-£-toluenesulfonamide Carbon^^ NMR
Spectrum ...... 73 13 40. N-Methy1-£-toluenesulfonamide Carbon NMR
Spectrum: Downfield Signals ...... 74
Xlll 41. Conformations of the Dibenz[b,e]oxepin Ring ...... 77
42. Conformation of Doxepin Isomers ...... 79 13 43. ^-Doxepin Hydrochloride Carbon NMR Off-Resonance
Decoupled Spectrum ...... 83 13 44. ^-Doxepin Hydrochloride Carbon NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 84 13 45. ^-Doxepin Hydrochloride Carbon NMR Off-Resonance
Decoupled Spectrum ...... 85
46. ^-Doxepin Hydrochloride Carbon^^ NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 86
47. ^-Doxepin Hydrochloride Homonuc1 ear Shift-
Correlated 2D NMR...... 87
48. ^-Doxepin Hydrochloride Homonuc1 ear Shift-
Correlated 2D NMR : Expanded Plot ...... 88
49. E-Doxepin Hydrochloride Homonuclear Shift-
Correlated 2D NMR...... 89
50. ^-Doxepin Hydrochloride Homonuc1 ear Shift-
Correlated 2D NMR : Expanded Plot ...... 90
51. ^-Doxepin Hydrochloride Heteronuclear Shift-
Correlated 2D NMR ...... 91
52. ^-Doxepin Hydrochloride Heteronuclear Shift-
Correlated 2D NMR: Expanded Plot ...... 92
53. ^-Doxepin Hydrochloride Heteronuclear Shift-
Correlated 2D NMR ...... 93
XIV 54. E-Doxepln Hydrochloride Heteronuclear Shift-
Correlated 2d NMR: Expanded Plot ...... 94 13 55. Doxepin Hydrochloride Carbon NMR Spectra ...... 95
56. Doxepin Hyd rochor id e Carbon^^ NMR Spectra:
Downfield Signals ...... 96
57. Doxepin Hydrochloride Proton NMR Spectra ...... 97
58. Doxepin Hydrochloride Proton NMR Spectra : Down
field Signals ...... 98
59. Doxepin Hydrochloride Proton NMR Spectra: Expanded
Region ...... 99
60. Conformations of the Dibenz[b ,e]thiepin Ring .... 107
61. Conformation of Dothiepin Isomers ...... 109 13 62. ^-Dothiepin Hydrochloride Carbon NMR Off-
Resonance Decoupled Spectrum ...... 113 13 63. ^-Dothiepin Hydrochloride Carbon NMR Off-
Resonance Decoupled Spectrum: Downfield
Signals ...... 114 13 64. ^-Dothiepin Hydrochloride Carbon NMR Off-
Resonance Decoupled Spectrum ...... 115
65. Z-Dothiepin Hydrochloride Carbon^^ NMR Off-
Resonance Decoupled Spectrum: Downfield
Signals ...... 116
66. ^-Dothiepin Hydrochloride Homonuclear Shift-
Correlated 2d NMR ...... 117
XV 67. ^-Dothiepin Hydrochloride Homonuclear Shift-
Correlated 2d NMR: Expanded Plot ...... 118
68. ^-Dothiepin Hydrochloride Homonuclear Shift-
Correlated 2D NMR ...... 119
69. ^-Dothiepin Hydrochloride Homonuclear Shift-
Correlated 2d NMR : Expanded Plot ...... 120
70. ^-Dothiepin Hydrochloride Heteronuclear Shift-
Correlated 2D NMR ...... 121
71. ^-Dothiepin Hydrochloride Heteronuclear Shift-
Correlated 2d NMR : Expanded Plot ...... 122
72. lE-Dothiepin Hydrochloride Heteronuclear Shift-
Correlated 2d NMR ...... 123 13 73. Dothiepin Hydrochloride Carbon NMR Spectra ..... 124 13 74. Dothiepin hyd rochor id e Carbon NMR Spectra:
Downfield Signals ...... 125
75. Dothiepin hyd rochor id e Carbon^^ NMR Spectra :
Upfield Signals ...... 126
76. Dothiepin hydrochloride Proton NMR Spectra ...... 127
77. Dothiepin hydrochloride Proton NMR Spectra: Down
field Signals ...... 128
78. Dothiepin hydrochloride Proton NMR Spectra:
Expanded Region ...... 129
79. 6H-DibenzoCb,e]thiepin-11-one Carbon^^ NMR Off-
Resonance Decoupled Spectrum ...... 137
XVI 13 80. 6H-Dibenzo[b ,e]thiepin-ll-one Carbon NMR Off-
Resonance Decoupled Spectrum: Downfield
Signals ...... 138
81. 6H-Dibenzo[b,e]thiepin-11-one Homonuclear Shift-
Correlated 2D NMR ...... 139
82. 6H-DibenzoCb,e]thiepin-11-one Homonuclear Shift-
Correlated 2D NMR: Expanded Plot ...... 140
83. 6H-Dibenzo[b,e]thiepin-11-one Heteronuclear Shift-
Correlated 2D NMR ...... 141
84. 6H-Dibenzo[b,e]thiepin-ll-one Heteronuclear Shift-
Correlated 2D NMR : Expanded Plot ...... 142 13 85. 6H-Dibenzo[b,e]thiepin-11-one Carbon NMR
Spectrum ...... 143 13 86. 6H-Dibenzo[b,e]thiepin-11-one Carbon NMR
Spectrum: Downfield Signals ...... 144
87. 6H-Dibenzo[b,e]thiepin-11-one Proton NMR
Spectrum ...... 145
88. 6H-Dibenzo[b,e]thiepin-11-one Proton NMR Spectrum:
Downfield Signals ...... 146
89. Conformation of 6H-dibenzCb,e]thiepin-ll-one .... 148
90. Conformation of Amitriptyline ...... 151 1 3 91. Amitriptyline hydrochloride Carbon NMR Off-
Resonance Decoupled Spectrum ...... 155
xvii 92. Amitriptyline hydrochloride Carbon^^ NMR Off-
Resonance Decoupled Spectrum: Downfield
Signals ...... 156
93. Amitriptyline Hydrochloride Homonuc1 ear Shift-
Correlated 2D NMR ...... 157
94. Amitriptyline Hydrochloride Homonuclear Shift-
Correlated 2d NMR : Expanded Plot ...... 158
95. Amitriptyline Hydrochloride Heteronuclear Shift-
Correlated 2d NMR ...... 159
96. Amitriptyline Hydrochloride Heteronuclear Shift-
Correlated 2d NMR : Expanded Plot ...... 160 13 97. Amitriptyline Hydrochloride Carbon NMR
Spectrum ...... 161
98. Amitriptyline Hyd rochor id e Carbon^^ NMR Spectrum:
Downfield Signals ...... 162
99. Amitriptyline Hydrochloride Proton NMR Spectrum .. 163
100. Amitriptyline Hydrochloride Proton NMR Spectrum:
Downfield Signals ...... 164
101. Nortriptyline Hydrochloride Carbon^^ NMR Off-
Resonance Decoupled Spectrum ...... 171
102. Nortriptyline Hydrochloride Carbon^^ NMR Off-
Resonance Decoupled Spectrum: Downfield
Signals ...... 172
X V I 11 103. Homonuclear Shift-Correlated 2D NMR of Nortrip
tyline hydrochloride ...... 173
104. Nortriptyline Hydrochloride Carbon^^ NMR
Spectrum ...... 174
105. Nortriptyline Hydrochloride Carbon^^ NMR Spectrum:
Downfield Signals ...... 175
106. Nortriptyline Hydrochloride Proton NMR Spectrum:
Downfield Signals ...... 177
107. Conformation of Nortriptyline ...... 178 13 108. 5-Methylene-5H-Dibenzo[a,d]cycloheptane Carbon
NMR Off-Resonance Decoupled Spectrum ...... 182 13 109. 5-Methylene-5H-Dibenzo[a,dDcycloheptane Carbon
NMR Off-Resonance Decoupled Spectrum: Downfield
Signals ...... 183
110. He teronuc1 ear Shift-Correlated 2D NMR of 5-Meth-
ylene-5H-Dibenzo[a ,d]-eyeloheptane ...... 184 13 111. 5-Methylene-5H-Dibenzo[a,d]cycloheptane Carbon
NMR Spectrum ...... 185 13 112. 5-Methylene-5H-Dibenzo[a,d]cycloheptane Carbon
NMR Spectrum: Downfield Signals ...... 186
113. 5-Methylene-5H-Dibenzo[a,d]eyeloheptane Proton NMR
Spectrum ...... 187
114. 5-Methylene-5H-Dibenzo[a,d]cycloheptane Proton NMR
Spectrum Downfield Signals ...... 188
XIX 13 115. Dlbenzosuberone Carbon NMR Spectrum ...... 193
116. Dlbenzosuberone Carbon^^ NMR Spectrum; Downfield
Signals ...... 194
117. Dlbenzosuberone Proton NMR Spectrum ...... 195
118. Conformation of 10,11-Dihydro-5H-Dibenzo[a,d]cy-
cloheptane ...... 199
119. 10,11-Dihydro-5H-Dibenzo[a,d]eyeloheptane Carbon^^
NMR Spectra ...... 200 13 120. 10,11-Dihydro-5H-Dibenzo[a,d]eyeloheptane Carbon
NMR Spectra: Downfield Signals ...... 201
121. Conformation of Thiothixene Isomers ...... 204 13 122. E-Thiothixene Carbon NMR Off-Resonance
Decoupled Spectrum...... 209
123. JE-Thiothixene Carbon^^ NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 210
124. Z-Thiothixene Carbon^^ NMR Off-Resonance
Decoupled Spectrum ...... 211 13 125. ^-Thiothixene Carbon NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 212
126. Z-Thiothixene Homonuclear Shift-Correlated 2D
NMR ...... 213
127. ^-Thiothixene Homonuclear Shift-Correlated 2D
NMR ...... 214
XX 128. ^-Thiothixene Heteronuclear Shift-Correlated 2D
NMR ...... 215
129. Z-Thiothixene Heteronuclear Shift-Correlated 2D
NMR: Expanded Plot ...... 216
130. ^-Thiothixene Heteronuclear Shift-Correlated 2D
NMR ...... 217
131. E-Thiothixene Heteronuclear Shift-Correlated 2D
NMR: Expanded Plot ...... 218 13 132. Thiothixene Carbon NMR Spectra ...... 219
133. Thiothixene Carbon^^ NMR Spectra: Downfield
Signals ...... 220 13 134. Thiothixene Carbon NMR Spectra: Upfield
Signals ...... 221
135. Thiothixene Proton NMR Spectra ...... 222
136. Thiothixene Proton NMR Spectra: Downfield
Signals ...... 223
137. Thiothixene Proton NMR Spectra: Upfield Signals .. 224
138. Conformation of Chlorprothixene Isomers ...... 231 13 139. ^-Chlorprothixene Carbon NMR Off-Resonance
Decoupled Spectrum ...... 236
140. ^-Chlorprothixene Carbon^^ NMR Off-Resonance
Decoupled Spectrum: Downfield Signals ...... 237 13 141. ^-Chlorprothixene Carbon NMR Off-Resonance
Decoupled Spectrum ...... 238
XXI 13 142. ^-Chlorprothixene Carbon NMR Of£-Resonance
Decoupled Spectrum: Downfield Signals ...... 239
143. ^-Chlorprothixene Homonuclear Shift-Correlated 2D
NMR ...... 240
144. ^-Chlorprothixene Homonuclear Shift-Correlated 2D
NMR: Expanded Plot ...... 241
145. E-Chlorprothixene Homonuclear Shift-Correlated 2D
NMR ...... 242
146. ^-Chlorprothixene Homonuclear Shift-Correlated 2D
NMR: Expanded Plot ...... 243
147. ^-Chlorprothixene Heteronuclear Shift-Correlated
2D NMR ...... 244
148. ^-Chlorprothixene Heteronuclear Shift-Correlated
2D NMR ...... 245
149. Chlorprothixene Carbon^^ NMR Spectra ...... 247
150. Chlorprothixene Carbon^^ NMR Spectra: Downfield
Signals ...... 248
151. Chlorprothixene Carbon^^ NMR Spectra: Upfield
Signals ...... 249
152. Chlorprothixene Proton NMR Spectra ...... 250
153. Chlorprothixene Proton NMR Spectra: Downfield
Signals ...... 251
154. Chlorprothixene Proton NMR Spectra: Upfield
Signals ...... 252
X X I 1 INTRODUCTION
Carbon^^ nuclear magnetic resonance (NMR) data
are presented for various dibenzoxepin, dibenzothiepin,
dibenzocycloheptane, and thioxanthene derivatives of
pharmaceutical interest. These materials are mood al
tering drugs used in the treatment of schizophrenia,
depression and/or anxiety, and other related psychotic
disorders. The c is- (Z-) isomer is usually the more
biologically active moiety. Therefore, improved char
acterization of isomer contents is useful to define drug
efficacy. Where applicable, NMR data is presented for both i some r s.
Dibenzocvcloheptane Dérivât ives
Amitriptyline and nortriptyline are dibenzo[a,d]- cycloheptane derivatives. Doxepin is a dibenz[b,e]oxe- pin tricyclic derivative similar in structure to ami triptyline. In dothiepin, the oxygen of the oxepin ring
is replaced by sulfur. Figure 1. Both E^- and isomers are presented. Amitriptyline and nortriptyline are nonisomeric. Doxepin is marketed as a mixture of approximately 15% Z^- and 85% isomer ^ ‘ ^ Dothie pin has been reported mainly as the E^- isomer^ and as 5% 16 16 HCCH,CH,N(CHO (CHjijNCHiCHzpH
Z-Doxcpin E-Doxcpin
CHgCHgNKH;); (CHglzNCHgCHzRH 2
Z-DothIcpIn E-Dothiepin
HCCH,CH,N(CHJ; CH3(H)NCH,CH2CH
S' ------4 Amitriptyline Nortriptyline
6H-Dibenzo[b,e]thicpin-ll-one Dibenzoeuberone
5-Methylene-5H- 10,ll-Dihydro-5H- dibenzo[a,d]cycIoheptane dibenzo[a,d]cycloheptane
Figure 1. Dibenzocycloheptane devlatlvea Z_- and 95% isomer^. The ^-isomers of both doxe-
pin^’^*^’® and dothiepin^’^ have been shown to be the
more biologically active. Both the Z^- and ^-doxepin
isomers are formed during synthesis as a result of acid
catalyzed equilibration on the final synthesis step^’^®.
In v.ilL2. conversion of the ^-isomer to the ^-isomer has 7 8 also been postulated » . Irradiation of both doxepin and dothiepin samples causes an increase in ^-isomer content; however, these compounds more readily decompose during irradiation^.
These drugs are used in the treatment of depres sion and/or anxiety^ ^ ^ ^ . Amitriptyline and nortrip tyline (an active metabolite of amitriptyline) are more effective in endogenous depression than in other de pressive states^. Amitriptyline is also effective in the management of depression accompanied by anxiety 2 .
Nortriptyline has been found to cause excitement or increased agitation is some patients and to have seda- 2 tive effects in others . Doxepin has been shown to 12 have anticonvulsant but not muscle relaxant activity
It is also used in neurosis involving tension, somatic symptoms, insomnia, guilt, lack of energy, fear, appre- hens ion, and worry 1 3 . Doxepin also antagonizes the central depressant effects of reserpine and tetrabena- zine to suppress conditioned avoidance behavior in rats^^ and spontaneous motility^^. Doxepin possesses
tranquillizing effects similar to the benzodiazepines^^.
Both doxepin and dothiepin show peripheral and central anticholinergic ac t i v it y ^ ^ ^ Doxepin increases cor onary blood flow in the isolated cat heart and inhibits cat nictitating membrane response to adrenaline and to both pre- and postganglionic electrical stimulation of the cervical sympathetic chain . Doxepin reduced blood pressure, reduced pressor effects of adrenaline in cats and dogs, and increased the effects of noradrenaline in cats and reduced total peripheral resistance and cardiac output in dogs when administered intravenously^^.
The mechanism of action of each drug is not known.
It has been suggested that doxepin may potentiate the central and peripheral action of adrenergic agents by blocking the reuptake of no rephinephr ine at the adrener- 1 3 g ic neurons . Dothiepin has been shown to inhibit the uptake of serotonin into platelets^^. Both drugs have been shown to block muscarinic acetylcholine recep- tors^^'l^. Doxepin may block both acetylcholine stimu lated guanylate cyclase activity and dopamine stimulated adenylate cyclase activity^^. Doxepin has been shown to increase levels of homovanillic acid (HVA) and to a lesser extent dihydrophenylacetic acid (DOPAC) in the corpus striatum, nucleus accumbens, and the tuberculum olfactorium . Nortriptyline has been shown to inhibit the activity of histamine, 5-hydroxytryptamine, and acetylcholine. It also increases the pressor effect of norepinephrine but blocks the pressor response of phen- ethylamine^. Determination of the exact mode and loca tion of action of each drug awaits additional study.
Thioxanthene Derivatives
Thioxanthenes are similar in structure to the phenothiazines, a major class of tranquillizer drugs.
Chlorprothixene, Figure 2, the thioxanthene analog of chlorpromazine, was first introduced in 1959^^. Thio thixene, the analog of thioproperazine was introduced six years later^^’^®. Both thiothixene and chlorprothi xene exist in two isomeric forms. Both isomers are formed during synthesis and either isomer is readily converted into the other. Thiothixene exists as a ther mal equilibrium mixture of 37% ^ - i s o m e r ^ ^ ^ ^ ^ al though it is marketed as 100% Z-isomer. Chlorprothixene is approximately 100% ^-isomer Conversion of isomers of either drug has been accomplished by irradia tion of the or isomer which has been stored under nitrogen^. Either isomer can be dissolved in 2N hydro- (M lO X Ü z
(M lO
« e
■ H « I > U| « >
» •C •o « I c «I O £ C lO lO X X X o Ü Ü CM £ lO H X Z N0 3 CM « V C « 9 K eo « CM e « K O b fr
X u I N | chloric acid and heated for four hours to produce an equilibrium mixture . Iii vi.vo_ conversion of thiothi- xene isomers has also been reported 2 3 . However, only the ^-isomer of thiothixene^ ^ ^ ^ and of chlorpro- t hixene ^ ^ is biologically active.
Thiothixene is used mainly in the treatment of both acute and chronic schizophrenia. It has also been effective in anxious depressed patients . It is es pecially active in disorders of perception, thought content and processes, insight and judgement 2 8
Improvement in hallucinatory behavior or irritability, social competence and personal neatness has also been shown 2 9 . Symptoms such as mannerisms, suspiciousness, tension, withdrawal, hostility, and disorientation also 2 9 were considerably decreased . Chlorprothixene is used in the control of anxiety, agitation,and the tension of psychotic states^. It also has sedative, antihistami- nic, anti-emetic, anticholinergic, and alpha-adrenergic blocking properties^. Chlorprothixene has also been used in the treatment of schizophrenia^.
Thiothixene disrupts conditioned avoidance be havior in rats at low doses^ ^ ^ ^ and monkeys^^. It blocks apomorphine induced emesis in dogs^®*^^. Thio- thixene blocks hyperactivity 2 9 * 3 0 , stereotyped symptoms, and mortality caused by amphetamines in mice and rats
It exhibits only very weak anticholinergic, antihist-
aminic, hypotensive, hypothermic^®’^^, and sedative
properties in animaIs^l. It is very weak in disrupting
escape behavior in rats, in potentiating hexobarbital or
ethanol induced loss of righting reflex, and in eli
citing flaccidity in rats . Thiothixene also induced
catalepsy in rats and both catalepsy and tremors in dogs q 0 ”19 and monkeys ’
Thioxanthenes are believed to act at four anatomi cal sites: the reticular activating system of the mid brain, the amygdala and the hippocampus of the limbic system, the hypothalamus, and the globus pallidus and corpus striatum . The exact biochemical mechanism of action is unknown. However, thioxanthenes are believed to act by directly inhibiting the dopamine receptor or by inhibiting the post synaptic action of a dopamine sensitive adenylate eye 1 ase^®’
Neuroleptic drugs have been shown to be active inhibitors of the dopamine sensitive adenylate cyc- lase^^’^^. In addition, structural similarity to dop amine has been postulated for the neuroleptics^^'^^.
Receptor blockage by a dopamine-1 ike drug might lead to a compensatory increase in activity of the dopaminergic cells by a neuronal feedback mechanism^^Thiothi
xene has been shown to increase synthesis and turnover
of dopamine resulting in an elevation of dopamine meta- O C bolites in the brain and in the cerebrospinal fluid .
This increase in synthesis is in approximate proportion O £. to clinical potency . Increased brain concentration of dihydroxypheny1 acetic acid (DOPAC) and homovanillic
(HVA) has been observed in the striatum of rodents^^.
Increased homovanillic acid concentration has been ob served after treatment with neuro 1eptics^^. The O C O Q elevation of prolactin concentration in serum ’ and O Q in cerebrospinal fluid has also been observed. This is believed to be mediated by blockage of hypothalamic and/or pituitary dopamine receptor by neuroleptics and specifically thiothixene and chlorprothixene. TECHNIQUES OF ANALYSIS
Chemical shift assignments were made using off-
resonance and selective decoupling, inversion-recovery
(Tj) measurements, homo- and hetero- nuclear shift-
correlated two dimensional nuclear magnetic resonance
(2D NMR), and selective insensitive nucleus enhancement
by polarization transfer (selective INEPT) techniques.
Chemical shifts were also defined by comparison to model 1 3 compound data run concurrently. Carbon chemical shift
values, off-resonance decoupled spectra, and model com
pound data were obtained on a Varian FT 80-A NMR. Pro
ton NMR, homo- and hetero-nuc1 ear shift correlated 2D
NMR, and selective decoupling experiments were obtained on Bruker AM-400 or WM-500 instruments. Selective INEPT experiments were accomplished on Nicolet NT-270 or
Bruker WM-500 instruments. All experiments were con ducted using deuterochloroform and tetramethylsilane
(TMS) as internal standard.
Off-resonance decoupling experiments allow assess ment of C-H coupling. These signals are normally de coupled by a field whose frequency matches the Larmor frequency of the coupling protons. In broadband de coupling, the decoupler frequency (02 and DO) corres-
10 11
ponds to approximately 4.5-5 ppm in the proton spectrum.
All C-H coupling down- or upfield of this frequency are
normally not observed. In off-resonance decoupling, the
decoupler position is shifted approximately 800 Hz.
either up- or downfield of this central (4.5-5 ppm)
location. Decoupler power may be lowered or noise modu
lation eliminated. This shifting and power reduction or
elimination of noise modulation allows observation of
residual C-H coupling. The multiplets obtained are
characteristic of the number of protons to which the
carbon is attached. This characterization of the degree
of protonation allows assessment of nonprotonated car
bons as singlets, monoprotonated carbons as doublets,
and di- and tri-protonated carbons as triplets and
quartets.
Selective decoupling experiments are accomplished
by determining the proton frequency of interest by ob
taining a proton spectrum. The decoupler power is then
significantly lowered and the decoupler is set to the
predetermined proton frequency. This selective decoup
ling will result in a sharp singlet for any carbon
directly bonded to protons resonating at that frequency.
All other signals will be coupled. The spectrum ob
tained can be compared to the normal decoupled spectrum 12
and the ppm value of the enhanced signal obtained.
Inversion-recovery measurements determine spin-
lattice relaxation time (Tj). Two spin alignments are
allowed for either or This alignment is either
with the static magnetic field and lower in energy or
against this field and higher in energy. At equili
brium, these nuclear magnetic energy levels are popu
lated according to the Boltzmann distribution which
favors the lower energy state. At resonance, the ap
plied radio frequency field causes a spin transfer from
the lower to the upper energy level and the equilibrium
distribution of the spins in the static magnetic field
is disturbed. The nuclear spins then relax back to
their initial equilibrium positions. This is a first
order process of rate constant 1/Tj which is character
istic of each kind of nuclei. Rigid nonprotonated nu
clei tend to have longer Tj. A typical experiment
consists of a 180 deeree-tau-90 degree pulse sequence in
which the time, tau. is varied either geometrically or
arithmetically and a curve or linear fit is used to
calculate Tj from a plot of peak intensity versus tau.
A relaxation delay of three to five times the estimated
T^ is used throughout the experiment.
Homo- and hetero-nuc1 ear shift-correlated 2D NMR 13
are magnetization transfer experiments in which data are
collected as a function of two independent time domains
followed by a double Fourier transformation. The spec trum that is obtained consists of two frequency axes and one intensity axis. Homonuclear shift-correlated 2D NMR
is a proton NMR experiment used to determine proton coupling. An initial 90 degree pulse, Figure 3, gener ates x-y magnetization which evolves during time, t, according to chemical shifts and coupling. An addi tional 45 or 90 degree mixing pulse transfers mag netization among the various transitions of a coupled spin system. When the transfer occurs between transi tions for the same nucleus, the corresponding peaks fall on approximately the diagonal of the 2-D matrix. Off- diagonal peaks are observed when magnetization transfer occurs between transitions for two different but coupled spins. The 45 degree pulse is favored where a supres- sion of signals at or near the diagonal is desirable.
Heteronuclear shift-correlated 2D NMR allows correlation of carbon and proton chemical shifts. An initial proton 90 degree pulse. Figure 3, is followed by a time, tj, in which the proton chemical shift informa tion evolves. C-H coupling is removed by a 180 degree carbon pulse. Polarization transfer occurs in time. 14
O O o o Z z z z < ü 32 CD ÔL (D|i o . O =) 33 < O O O Q iioc UJ oc LU t r Sae s (D a u. GQ O U. ü. (D a g : qd g S I g : A eu o (S Q o es 'O 00 0) 'O JJ eu cd 4J1—4 cd (U I—I w 'H CD H o u O M P h p O M M m 0) Ç3 'H 0) (0 O 4J (0 w M U rH a d) O g > 4J 1-4 0 PL g Q) 0) co O œ i ! 00 S I % (d ^
o; M ;3 üO •H o k o o
rOO 15
t au . following a second 90 degree proton puise. A
simultaneous carbon 90 degree puise is followed by a
refocusing time, taun. which allows the carbon multip
lets to acquire a net magnetization which can be ob
served in a broadband decoupled free induction decay
(f i d ) collect ion.
Selective INEPT experiments determine three and two bond couplings. An initial proton 90 degree pulse.
Figure 3, followed by time, tj, in which proton magneti zation evolves is followed by simultaneous 180 degree carbon and proton pulses and by time, tj. A second simultaneous 90 degree proton and carbon pulse is fol lowed by a second delay, 12 , for refocussing as above.
Data is then acquired with the decoupler on. Proton pulses are approximately 25 Hz. MODEL COMPOUNDS
A series of model compounds which included substi
tuted aromatic and olefinic compounds, dibenzocyclohep-
tanes, and thioxanthenes were evaluated and ppm correc
tion values were obtained. Literature referen-
ces^^for these compounds frequently
indicated chemical shift and assignment discrepancies.
Hence, all model compounds were analyzed concurrently on
the same instrument (Varian FT 80-A) as the compounds of
interest and chemical shift assignments were verified.
Where possible data were compared to Ewing^^ confidence
classes A and B. Calculations were made based on mono
substitution of individual functional groups and, of
necessity, do not address isomeric or geometric differ
ences between these samples and the compounds of in
terest. Calculations of this nature also do not take
into account the steric interactions and neighboring
group anisotropy which contribute significantly to the
shielding of ortho carbons. All samples were analyzed
in deuterochloroform using tetramethylsilane (TMS) as
the internal standard. Dibenzocycloheptane and thio xanthene derivatives are discussed in subsequent chapters.
Chemical shift data for benzophenone. Figure 4,
16 1 7
R= -OCHg, anlsole
-Cl, chlorobenzene
-SCgHj, dIphenylsulfIde
S« -(C*0)CgHj, benzophenone
-CHgSH, benzylmercaptan
-CHgCHgC^Hg, dibenzyl
-CHgC^Hg, diphenylmethane
u. -CgHj, 1,1-diphenylethylene
X* -0-, benzylphenylether
-S-, benzy1pheny1 su 1fide
(Cfî^VSO^N ' eu.
Tm 1, N-methy1-£-toluenesulfonamide
2, N ,N-d ime thyl-£-toluene su 1f onam id e
Figure 4. Model compounds. 18
varied by about 1 ppm between sources for Cl and C 2
carbons. Assignments were verified by off-resonance
decoupling and by comparison to chemical shift and cor
rection tables^^»^® and existing literature data^‘ ‘ for benzophenone, butyrophenone, and benzil references. Off-resonance decoupled spectra.
Figures 5 and 6, indicated the positions of the nonpro tonated carbons as singlets. Three nonprotonated sig nals are observed for this compound. The extreme down field signal can be identified as C=0 by chemical shift table comparison^^»^® as well as comparison to benzil, butyrophenone, and benzophenone references. Table 1. The remaining signals can also be predicted by comparison to the above compounds and correction factors found in
Breitmaier tables^®. Typical spectra obtained are given in Figures 7 and 8. Correction values used for assign ment are in Table 1.
Literature references were not found for the assignment of benzyl mercaptan. Figure 4. Assignment was made by comparison to benzyl disulfide, dibenzylsul- fide, d ipheny 1 su 1 f id e, me thy Ipheny 1 su 1 f id e (Figure 4), and Breitmaier correction tables^®. Off-resonance de coupled spectra. Figures 9 and 10, indicated a chemical shift singlet at 141.1 ppm corresponding to the nonpro- 19
B 0 U 4J U O Qa co
Q> *—4 Cu O O o Q) na 0) o a co C 0 (0 0) M 1
c o w co U Qj 0 O 0 Q) 04 O N 0 (U m
Q) u 0 60 • H Pt4 20
t) Q) CL 0 O O Q) TJ OA X X fi O w Cd o o IIN (0 fi Q) fQ vO fi 3 Table 1. Benzophenone Assignments, ppm and correction values, and theoretical calculations. carbon number 1 2 3 4 5 reference ppm 137.62 129.95 128.24 132.32 196.38 spectra # of carbons 2 4 4 2 1 CDC13 ppm 137.6 130.0 128.3 132.3 196.4 correction 9.1 1.5 -.2 3.8 40 ppm 137.9 130.2 128.3 132.1 correction 9.4 1.7 -.2 3.6 39 ppm 137.6 129.8 128.2 132.2 196.1 41 correction 9.1 1.3 -.3 3.7 CDCL3 ppm 137.8 130.1 128.2 132.2 44 correction 9.3 1.6 -.3 3.7 CDC13 ppm 138.5 130.8 129.2 133.3 196.2 50 correction 10 2.3 .7 4.8 unknown 128.5 128.5 128.5 128.5 base Similar Compounds BUTYROPHENONE, C6H5(C=0)CH2CH2CH2CH3 PPM VALUE 137.1 127.9 128.4 132.7 199.8 42 BENZIL, C6H5-(C=0)2-C6H5 PPM VALUE 133 129.7 128.9 134.7 94.3 42 BENZOPHENONE correction values 9.12 1.45 -.26 3.82 (196.4) spectra carbon number 1 2 3 4 5 22 6 o u 4J o d) ÇU U3 Od X z 0 o X i u cd Ü Q) 0 o 0 0) *£2 04 O N 0 0) PQ (d a ûO •H CO -Ü Q) 0 O 8 3 U O 0) o« co ai % z en i-H a o M cd o 0) 0 O 0 Q) 04 O N 0 d) ta 00 OJ w 0 00 'H 24 O a> A. « O 3 3 3 0 M 3 3 1 AS % g en 3 o .A 3 3 O 3 3 A A. 3 O 3 3 N 3 3 3) d\ 3 3 3 60 A, 2 5 0) A 0 O o 0) *0 0) U 0 0 0 0 0 0) 1 *w u-i o od % z m fH 0 O Xi u 0 o 0 0 4J A 0 O u Q> e 0 f-l 0 « N dO S « "•o r4 • 0 o 'H 3 > 3 O 9 TJ 60 • H • • 04 B V40 4J O 0 A 0 2 6 tonated Cl carbon and an upfield triplet at 28.9 ppm corresponding to the -CH2 SH carbon. The remaining off- resonance decoupled signals are unresolved doublets corresponding to the monoprotonated carbons. Of these carbons, a 2:2:1 abundance should be approximately ob served for C 2,6 :C3 , 5 :C4. Hence, C 4 is assigned to the signal at 127.0 ppm which is of significantly lower intensity. This assignment also agrees with that given for the equivalent carbon in dibenzylsulfide and benzyl disulfide as well as diphenyl- and methyIpheny1 su 1fide models. Assignments of C2,6 and €3,5 at 128.0 and 128.6 ppm, respectively, were made by comparison with Breit- maier tables^® for dibenzylsulfide and methyIpheny 1- sulfide as well as by comparison to data for dibenzyl sulfide obtained from Sadtler^^. Literature references for benzyl disulfide found in the Atlas of Carbon-13 NMR Data^^ and values found in Breitmaier^® for di- phenyIsuIfide differ in assignment of C2,6 and C3,5. Spectra for benzyl mercaptan are given in Figures 11 and 12. Correction values and assignment data are given in Table 2. Benzy1pheny1ether, Figure 4, was assigned by off- resonance decoupling and by comparison to Breitmaier correction tables^® and existing literature for butyl- 2 7 G 0 U u o 0 04 0 ca % z 0 O «û u 0 o 0 0 u 04 0 O k 0 8 N 0 0 PQ 0 W 0 60 2 8 0 0 60 •H 0 T) «—» 0 •W 44 0 0 O 73 8 0 M W O 0 04 0 04 Z z 0 o M 0 O 0 0 4J 04 0 O M 0 B >s N 0 0 ta CM 0 M 0 60 04 2 9 Table 2. Benzyl Mercaptan Assignments, ppm, and correction values, and theoretical calculations. Carbon number 1 2 3 4 5 reference ppm value 141.14 128.0 128.62 126.98 28.91 spectra number of carbons 1 2 2 1 1 CDC13 128.5 128.5 128.5 128.5 base Similar Compounds BENZYL DISULFIDE (C6H5CH2S-)2 ppm value 137.2 129.2 128.2 127.2 43.1 42 DIBENZYLSULFIDE (C6H5CH2-S-CH2C6H5) ppm value 137.3 128.4 129.3 127.3 43.2 41 ppm value 139.0 128.8 129.4 127.0 37 40 Theoretical Calculations DIBENZYLSULFIDE 10.5 .3 .9 -1.5 40 Theorl, ppm values 139 128.8 129.4 127 43.2 METHYLPHENYLSULFIDE 10.1 -1.7 .3 -3.5 40 theor2, ppm values 138.6 126.8 128.8 125 BENZYLMERCAPTAN correction values 12.64 -.5 .12 -1.52 (28.91) spectra carbon number 1 2 3 4 5 30 phenyl- and benzy1 ethyI-ether, anisole, dibenzy1 ether, and dipheny1 et her. Off-resonance decoupled spectra, Figures 13 and 14, indicate the presence of two down- field singlets corresponding to two nonprotonated car bons, Cl and C5. Cl, which is attached to oxygen, is assigned to the most downfield location at 158.9 ppm by comparison to Breitmaier correction tables^® and anisole o g and dipheny1 et her values obtained from Wehrli and Breitmaier^®. The equivalent carbon for the latter compounds is found at 157.7-159.9 ppm. The remaining nonprotonated carbon, C 5 is assigned the signal at 137.2 ppm by elimination and by comparison to dibenzyl- and benzylethyl- ether data obtained from Sadtler and Breit maier sources. For these compounds, this carbon is assigned to a chemical shift of about 139 ppm. An off- resonance decoupled triplet is observed upfield at about 69.9 ppm corresponding to -CH2 O. The remaining signals are unresolved off-resonance decoupled doublets. Of these carbons, an approximately 2 :2 : 1 abundance should be observed for C2,6:C3,5:C4 and C6 ,10 : C 7 ,9 :C8 . Two signals are of lower intensity at 121.0 and 127.9 ppm. Comparison to model compounds indicated a chemical shift range of 120.6-123.5 ppm for C4 and 127.5-128 ppm for C8 . C4 has, thus been assigned to the signal at 121.0 31 8 0 U u u Q) P4 na Q) r—4 a 3 O O 0) 'O 0) u c CO c co0 0> u 1 s g: co m4 0 O U co U kl (U >> a 0) Æ CL rH > , N C Q) PQ 0) D to pL 32 73 (U CL 0 O ü 0) T3 0) Ü C Cd C 0 co Q) U 1 C o u cd o kl > > a > N C Q) CQ and C8 to that at 127.9 ppm. The remaining signals at 1 14.9, 129.5, 1 27.4, and 128.5 ppm corresponding to €2,6, €3,5, €6,10, and €7,9 were assigned by comparison to the appropriate model compounds. The €2,6 upfield carbon signal at 114.9 ppm corresponds to model compound data of 114.1-119.5 ppm. €3,5 values of 129.4-130.5 correspond to the assigned 129.5 ppm value. €6,10 and €7,9 model compound values are 127.5-128 and 128.4-129 ppm, respectively. These correspond to assignments of 127.4 and 128.5 ppm for these carbons, respectively. Spectra are given in Figures 15 and 16; assignments and correction values are reported in Table 3. Benzy1pheny1su1fide, Figure 4, was assigned by off-resonance decoupling and by comparison to benzyl disulfide, dibenzylsulfide, benzyl mercaptan, and dipheny1 su 1fide data as well as by comparison to Breit maier tables^® and Sadtler^^ spectra. Off-resonance decoupling. Figures 17 and 18, reveals two nonprotonated downfield singlets corresponding to €1 and €5 at 136.5 and 137.5 ppm, respectively. Model compound comparisons for €1 are 135.7-138.6 ppm and for €5, 137.2-141.1 ppm. € 1 values tend to be slightly more upfield; therefore, € 1 has been assigned to 136.5 ppm whereas €5 values tend to be more downfield (137.5 ppm). An upfield triplet at 34 0 d u 4 J U (U a co od S % (3 O U cd u k 0) 43 X (3 OJ 43 Cu 1-4 N C 0) P3 0) M d 60 35 CO a 60 •H (0 6 D W w o OJ A CO S R CO #—I q o x> M q o M 0) 4J 0) r-( % q 0) ^q q. r-4 >> N q 0) CQ VO Table 3, Benzylphenylether Assignments, ppm and correction values, and theoretical calculations carbon number 1 2 3 4 5 6 7 8 9 reference ppm 158.89 114.93 129.46 120.96 137.19 127.43 128.54 127.87 69.93 spectra tof carbons 1 2 2 1 1 2 2 1 1 CDC13 128.5 128.5 128.5 128.5 128.5 128.5 128.5 128.5 base Similar Compounds DIBENZYLETHER, C6H5CH2-0-CH2C6H5 ppm 139.0 128.0 129.0 128.0 72.5 40 BENZYLETHYLETHER, C6H5CH2-0-CH2CH3 ppm 138.9 127.5 128.4 127.5 72.6 41 DIPHENYLETHER, C6H5-0-C5H6 ppm 157.7 119.1 129.9 123.1 40 ppm 157.5 119.5 130.5 123.5 39 «ETHYLPHENYLETHER, C6H5-0-CH3 ppm 159.9 114.1 129.5 120.7 40 159.9 114.1 129.5 120.8 39 BUTYLPHENYLETHER, C6H5-Q-CH2CH2CH2CH3 ppm 159.4 114.7 129.4 120.6 67.6 41 THEORETICAL CALCULATIONS C6H5CH2-0-CH2C6H5 10.5 -.5 .5 -.5 40 Theorl, ppm 139 128 129 128 C6H5-0-C6H5 29.2 -9.4 1.4 -5.3 40 Theorl, ppm 157.7 119.1 129.9 123.2 C6H5-0-CH3 31.4 -14.4 1 -7.8 40 Theor2, ppm 159.9 114.1 129.5 120.7 C6H5-0-C6H5 29 -9 2 -5 39 Theor3, ppm 157.5 119.5 130.5 123.5 C6H5-0CH3 31.4 -14.4 1 -7.7 39 Theorl, ppm 159.9 114.1 129.5 120.8 BENZYLPHENYLETHER correction values 30.39 -13.57 .96 -7.54 8.69 -1.07 .04 -.63 (69.93) SPECTRA carbon number 1 2 3 4 5 6 7 8 9 37 Q) O fl (0 a 0 CQ 0) M 1 ed %; % m q o ,q #4 q o q tt q 0) .q A rH {►> N a a « . 8 . 0 r» a •-I 4J O 0) 0) w o. 0 m 60 •H "O h « r“4 ÇU q o o 0) •d 3 8 4) O a « a 0 co 41 k 1 Ck| "44 O 04 5 % q o A U q u q . •q w •H i-t **4 q r-4 q q 60 «Q•iH w q *o q 0) m!î 8 • q 00 M f-4 4J U Q) 0) M CL q «0 60 •H *0 PL 0) f-4 pq q o o 0) •d 3 9 about 39.1 ppm corresponds to -CH2 S-. Signals at 126.3 and 127.1 ppm are of approximately equal abundance and of lower height than remaining, nonoverlapping mono protonated signals. These more upfield signals corres pond to model compound ranges of 125-127 ppm and 127- 127.3 ppm for C4 and C8 , respectively. Therefore, C4 is assigned to the more upfield signal at 126.3 ppm and C8 to the signal at 127.1 ppm. The C2 carbon is assigned to the signal at 129.9 ppm based on model compound comparisons of 130.8-131.1 ppm as well as comparison to Sadtler^^ data. C3, C6 , and C7 have theoretical values of 128.9-129.1, 128-128.4, and 128.6-129.4 ppm, res pectively following d ipheny 1 su 1 f id e, dibenzylsulfide, and benzyImercaptan models. Peak assignments for C6 and C7 carbons are reversed in benzyl disulfide. C6 is assigned to the slightly more upfield signal at 128.4 ppm following these model compound comparisons and Sad- tler^^ assignment and C3 and C7 are assigned to the overlapping signal at 128.8 ppm. Spectra are shown in Figures 19 and 20 and data is reported in Table 4. Chlorobenzene, Figure 4, was evaluated by compari son to existing literature values found in Breitmaier^®, Wehrli^*, and Ewing^^. Peaks were found to differ by about 0.5 ppm for Cl assignment at 134.4 ppm. This 4 0 G a u u o Q) eu CO od s % c O u CQ U 0> na 3 co 1-4 >% C 0) 43 A r4 >» N 0 r4 'O 8 3 M 4J Ü 0) A CO Pd 35 Z 3 O 43 M CO a 0) ' 3 3 CO r4 >y 0 0 ) r4P* N 0 O N 0) M 3 00 •H 42 Table 4, BenrylphenylsuHide Assignments, ppm and correction values, and theoretical calculations carbon number 1 2 3 4 5 6 7 8 9 reference ppm value 136.48 129.87 128.8 126.29 137.51 128.44 128.8 127.12 39.06 spectra number of carbons 1 2 2 1 1 2 2 1 1 CDC13 ppm value 136.5 129.5 128.7 126 137.3 128.3 128.7 126.9 38.7 41 correction value 8 1 .2 -2.5 8.8 -.2 .2 -1.6 CDC13 128.5 128.5 128.5 128.5 128.5 128.5 128.5 128.5 base Similar Compounds BENZYL DISULFIDE C6H5CH2S-SCH2C6H5 ppm value 137.2 129.2 128.2 127.2 43.1 42 DIBENZYLSULFIDE C6H5CH2-S-CH2C6H5 ppm value 137.3 128.4 129.3 127.3 43.2 41 ppm value 139.0 128.8 129.4 127.0 37.0 40 BENZYL MERCAPTAN HS-CH2C6H5 ppm value 141.1 128.0 128.6 127.0 28.9 spectra DIPHENYLSULFIDE C6H5-S-C6H5 ppm value 135.9 131.1 129.2 127.0 spectra ppm value 135.7 130.8 128.9 126.8 41 ppm value 135.8 130.9 129.1 126.9 40 Theoretical Calculations DIBENZYLSULFIDE 10.5 .3 .9 -1.5 40 Theorl, ppm value 139 128.8 129.4 127 C6H5-SC6H5 7.4 2.6 .7 -1.5 spectra Theorl, ppm value 135.9 131.1 129.2 127.0 C6H5-SCH3 10.1 -1.7 .3 -3.5 40 Theor2, ppm value 138.6 126.8 128.8 125 BENZYLPHENYLSULFIDE correction values 7.98 1.37 .3 -2.21 9.01 -.06 .3 -1.38 (39.06) spectra carbon number 1 2 3 4 5 6 7 8 9 43 signal also exhibits the smaller height usual for non protonated carbons of longer Tj. The peak observed at 126.4 ppm is in an approximately 1:2:2 with the re maining peaks and is thus assigned to the C4 carbon. The remaining signals are assigned based on literature comparisons. Spectra are given in Figures 21 and 22. Peak assignments are given in Table 5. Dibenzyl, Figure 4, has been assigned by compari son to Sadtler^^ spectra, Ewing^^ data, and ethyl- and n-propy1 -benzene as well as data obtained on concur rently run diphenyImethane. The upfield signal corres ponding to -CH2 CH2 - can be assigned by comparison to chemical shift tables^^»^® at 37.9 ppm. Cl, the nonpro tonated carbon, is assigned the downfield signal at 141.76 ppm. This signal is of significantly smaller height and probable longer Tj. C4 is assigned to the signal at 125.9 ppm since it is in an approximately 1 :2 : 2 ratio with the remaining monoprotonated signals. These latter signals are observed at 128.3 and 128.4 ppm. Sadtler does not give clear assignment. Following literature assignments for diphenyImethane, as well as Ewing^^ confidence class B data, 02 is assigned to the slightly downfield signal. Spectra are given is Figures 23 and 24. Data is presented in Table 6 . 4 4 G 0 u 4J O Q) CL (0 Cd X z co m4 g O ,o M Cd u Q) 0 0) N 0 Q) Xi O M O r4 43 ü cd a 60 (0 0 o 8 0 U u D o Q) 04 (0 Pd X X 0 o 43 U cd o 0) 0 0) N 0 0) *o O O 43 O c s CM 0 u 0 • 60H 4 6 Table 5. Chlorobenzene Assignments, ppm and correction values, and theoretical calculations carbon number 1 2 3 4 reference ppm 134.41 128.66 129.72 126.42 spectra # of carbons 1 2 2 1 CDC13 ppm 134.9 128.7 129.5 126.5 40 correction 6.4 .2 1 -2 CDC13 ppm 134.7 128.9 129.8 126.6 39 correction 6.2 .4 1.3 -1.9 unknown ppm 134.B 128.54 129.9 126.6 44 correction 6.3 .04 1.4 -1.9 CDC13 128.5 128.5 128.5 128.5 base CHLOROBENZENE correction values 5.91 .16 1.22 -2.08 spectra carbon number 1 2 3 4 47 B o 4J O Q) O. (A Od S % a o u cd o >> N 0 0> *r4 Q 00 CM 0) M 0 60 4 8 (d 0 50 T3 1-4 0> 0 > O 03 a 0 ÀJU u Q) 04 CO 03 X X 0 O rÛ U 0 o N QJ0 CS Q) U 0 50 4 9 Table 6. Dibenzyl Assignments, ppm and correction values, and theoretical calculations carbon number 1 2 3 4 5 reference ppm 141.76 128.44 128.31 125.91 37.92 spectra # of carbons 2 4 4 2 2 CDC13 ppm 141.7 128.5 128.3 125.9 44 correction 13.2 0 -.2 -2.6 CDC13 ppm 141.6 128.3? 128.2? 125.8 (37.9) 41 correction 13.1 -.2 -.3 -2.7 CDC13 128.5 128.5 128.5 128.5 base Similar Compounds DIPHENYLMETHANE, C6H5-CH2-C6H5 ppm 141.07 128.91 128.41 126.02 41.93 spectra N-PROPYLBENZENE, C6H5CH2CH2CH3 ppm 142.6 128.3 128.6 125.8 40 ETHYLBENZENE, C6H5CH2CH3 ppm 144.1 128.1 128.5 125.9 39 DIBENZYL correction values 13.26 -.06 -.19 -2.59 (37.92) spectra carbon number 1 2 3 4 5 50 N,N-Dimet hy 1-2 .“to luenesu 1 f onamid e. Figure 4, was assigned by comparison to existing literature data found in Sadtler^^, Breitmaier, and Ewing^^ references for N-substitu t ed-£.-to luenesulfonamides, benzenesulfonamide, and benzenesu1 fonic acid as well as concurrently run spectra. The spectra of toluene was run concurrently to obtain correction values for the N,N-dimethy1 su 1fonamide group. The upfield signals at 37.9 and 21.5 ppm corres pond to N,N-dimethyl and methyl carbons. The signal at 37.9 ppm is approximately double the abundance of the other upfield signal. Because of this significant size differential, the signal at 37.9 ppm can be readily assigned to the N,N-dimethyl carbons. The other signal at 21.5 ppm is assigned to the methyl carbon. This assignment also agrees with the value obtained for the toluene methyl. Cl and C4 are assigned to downfield signals of significantly less abundance according to Sadtler comparisons. C4 is assigned to 143.5 ppm where as Cl is assigned to 132.66 ppm. This latter peak is of the significantly shorter height and probable longer T^ that would be associated with a nonprotonated carbon bound to the sulfonamide function. The remaining sig nals at 127.8 and 129.8 ppm are assigned to C2 and C3 carbons, respectively following comparisons to existing 51 literature data. Spectra are given in Figures 25 and 26; data is presented in Table 7. The chemical shifts of 1,1-Dipheny1 ethy1ene, Figure 4, were assigned by off-resonance decoupling and by comparison to existing Sadtler^^ literature values as well as by comparison to Breitmaier^®, Wehrli^*, and Bruker^^ references for styrene. Olefinic carbon as signments were made by theoretical calculations using Breitmaier^® values and aIpha-methvIstvrene. styrene, and 2-ethy1-1-butene models. Off-resonance decoupling. Figures 27 and 28, reveals two nonprotonated carbon singlets corresponding to C5, the nonprotonated olefinic carbon, and Cl, the nonprotonated aromatic carbon. C 5 is assigned the most downfield signal at 150.1 ppm. Whereas, Cl is assigned to the signal at 141.6 ppm. The off-resonance decoupled triplet corresponding to -CH2 - is assigned to the only corresponding carbon C6 at 114.2 ppm. This also agrees with model data. The remaining off-resonance decoupled signals are unresolved doublets. The signal of less intensity corresponding to these doublets is assigned to the C4 carbon at 127.7 ppm. This signal should be of approximately a 1:2:2 abundance with the remaining monoprotonated carbon signals. C2 and C3 at 128.2 and 128.3 ppm are assigned based on 52 X z m 0 O XU i 0 o 0 '0 •r4 B 0 0 O 0 0 0 0 0 rH0 0 u 1 1-4 xs 4J 0) B •H Q I & lA CS 0) w 0 50 •»4 • 04 G 0 u u o 0 04 0 53 0 o *0 u 0 o J 0 •i4 8 0 0 O r4 0 0 0 0 0 0 0| I f—I ►. 4 J •i4 A I . m W z __ • 0 \0 CS U4 0 0 ^ U o 0 *0 50 •H •• k G 0 U u o 0 0# 0 54 Table 7. N,N-Dimethyl-g-toluenesulfonamide Assignments, ppm and correction values, and theoretical calculations carbon number 1 2 3 4 5 6&7 reference ppm 132.66 127.78 129.66 143.50 21.46 37.92 spectra # of carbons 1 2 2 1 1 2 CDC13 ppm 132.6 127.7 129.7 143.4 21.4 37.9 41 correction 7 -.8 .4 5.6 CDC13 TOLUENE ppm 125.45 128.35 129.16 137.97 21.5 spectra correction -3.05 -.15 .66 9.47 CDC13 ppm 125.6 128.5 129.3 137.8 21.4 39 correction -2.9 0 .8 9.3 CDC13 128.5 128.5 128.5 128.5 123.5 123.5 base Similar Compounds N-HETHYL-p-TOLUENESULFONAHIDE, C6H5S02NHCH3 ppm 136.4 127.1 129.6 143 21.3 29 41 BENZENESULFONAMIDE, C6H5S02NH2 ppm 143.5 125.7 128.7 131.9 41 N-ETHYL-p-TOLUENESULFONAMIDE, C6H5S02NHCH2CH3 ppm 143.2 127.2 129.6 137.3 21.5 38.2 41 N'BUTYL-p-TOLUENESULFONAHIDE, C6H5S02NHCH2CH2CH2CH3 ppm 137.6 127.1 129.6 143.1 21.4 43 41 N.N-DIHETHYL-p-TOLUENESULFONAMIDE correction values 7.21 -.57 .5 5.53 21.46 37.92 spectra carbon number 1 2 3 4 5 6&7 55 0 o q 0 0 0 0 0 N 1 S z 0 O A 0 U 0 0 0 I—I X 0 X 04 G • 0 es u o 0 0 u 0 4 0 0 • 5H 0 *0 P4 0 r4 0 4 0 O O 0 *0 56 0 o c 0 0 0 0 0 u 1 <44 <44 O X z en «-4 0 O Xi U 0 U 0 0 • 0 0 r4 -E II 8 . 0 00 u CS 44 u 0 0 u 04 0 0 60 • i4 k 0 i“4 04 0 O O 0 •0 57 literature comparisons. Data are reported in Table 8 . Spectra are shown in Figures 29 and 30. Dipheny Imethane. Figure 4, is assigned by compari son with literature references as well as by off-reson ance decoupled spectra. Figures 31 and 32. Spectra are given in Figures 33 and 34. The upfield off-resonance decoupled triplet corresponds to -CH2 - and can thus, be assigned to the chemical shift at 41.9 ppm. The off- resonance decoupled singlet, a nonprotonated carbon, is assigned to Cl at 141.1 ppm. The remaining unresolved signals, off-resonance decoupled doublets correspond to C2,6 , C3,5, and C4 carbons. A comparison of peak inten sities allows estimation of C4 at 126.0 ppm which is the nonprotonated carbon signal of lowest intensity. Liter ature references differ significantly in assignment of the remaining carbons. Table 9. Assignment of C2,6 and C3,5 at 128.9 and 128.4 ppm, respectively, follows literature references a and b. Table 9. Dipheny1 su 1fide. Figure 4, was identified by com parison to existing literature data found in Breit- maier^® and Sadtler^^ references. Chemical shift differences of 0 . 2 ppm or less are observed between references. Assignment for C4 at 127.0 ppm agrees with the 2:2:1 abundance ratio for C2,6:C3,5:C4. A signifi- 58 Table 8. 1,1-Diphenyl ethylene Assignments, ppm and correction values, and theoretical calculations carbon number 1 2 3 4 5 6 reference ppm value 141.6 128.17 128.3 127.71 150.18 114.17 spectra number of carbons 2 4 4 2 1 1 CDC13 ppm value 141.6 127.7 128.2 128.2 150.1 114.1 41 correction value 13.1 -.8 -.3 -.3 26.6 -9.4 CDC13 128.5 128.5 128.5 128.5 123.5 123.5 base Similar Compounds STYRENE, C6H5CH=CH2 ppm value 137.6 126.1 128.3 127.6 147.5 101.5 40 ppm value 138.0 126.5 128.7 128.0 47.3 101.3 39 ppm value 137.6 126.1 128.3 127.6 137.1 113.3 43 alpha-METHYLSTYRENE, C6H5(CH3-)C=CH2 ppm value 141.4 125.6 128.2 127.4 143.4 112.3 41 2-ETHYL-l-BUTENE ppm value 150.2 105.2 40 Theoretical calculations STYRENE,C6H5-CH=CH2 9.1 -2.4 -.2 -.9 40 Theorl, ppm values 137.6 126.1 128.3 127.6 147.5 101.5 STYRENE,C6H5-CH=CH2 9.5 -2 .2 -.5 39 Theor2, ppm values 138.0 126.5 128.7 128.0 147.3 101.3 1,1-DIPHENYLETHYLENE correction values 13.1 -.33 -.2 -.79 26.68 -9.33 spectra carbon number 1 2 3 4 5 6 59 G 9 M U O Q) 04 0 Od X z en 4—4 0 o x> u 0 o 0 0 0 I— I > ^ X i 0 0 rC 04 •rl p I ON N 0 U 0 50 •rH tu 6 0 0 a 60 •H J 0 -0 0 • iH LW O> *0 G 0 w 4 J o 0 04 0 Pd S z 0 o ,0 u 0 o 0 0 0 i-H > > ,0 > > 0 0 XP •H0 4 P I O m 0 U 0 50 • i-( i k G1 G U0 u o 0 04 0 TJ 0 1-4 0 4 0 O o 0 *0 0 U 0 0 0 0 0 0 U 1 X z 0 O Xi 0 U 0 0 0 ,0 4J 0 G 1— 1 a (U Æ A ai u 3 OD •H 6 2 '0 0 04 0 O u 0 *0 0 O 0 0 0 0 0 0 H <441 co m4 0 O rO M 0 O 0 0 0 U 0 ; 0 4 •H 0 P « 0 es *H G 0 U 4J 0 0 04 0 Pi X z co 1 0 O M 0 O 0 0 0 Xi u 0 r4G >% 0 0 XS •l-l04 P CO co 0 u 0 • 50i-l k 6 4 0 a 50 'tj 1-4 0 •H <44 a > o 13 8 0 U 4J O 0 0 4 0 03 S z CO 1-4 0 O XU i 0 O 0 0 0 XS u 0 8 1-4 >. 0 0 X i •H0 4 P CO 0 u 0 50 •r4 65 Table 9. Diphenyliethane Assignments, ppm and correction values, and theoretical calculations carbon number 1 2 3 4 5 reference ppm 141.07 128.91 128.41 126.02 41.93 spectra # of carbons 2 4 4 2 1 CDC13 ppm 141.3 130.0 128.5 126.2 44 correction 12.8 1.5 0 -2.3 CDC13 ppm 140.8 128.7 128.3 125.7 42.0 42 correction 12.3 .2 -.2 -2.8 CDC13 ppm 140.4 128.4 127.9 125.6 41.7 42 correction 11.9 -.1 -.6 -2.9 CCI 4 ppm 141.3 129.0 128.5? 126.2 42.0 50 correction 12.8 .5 0 -2.3 CDC13 ppm 141.0 128.4? 128.9? 126.0 41.9 50 correction 12.5 -.1 .4 -2.5 CDC13 ppm 142.3 129.2 129.9 126.9 42.6 50 correction 13.8 .7 1.4 -1.6 THF ppm 141.0 128.8? 129.3? 125.9 41.9 41 correction 12.5 .3 .8 -2.6 CDCI3 128.5 128.5 128.5 128.5 base Similar Compounds N-PROPYLBENZENE,, C6H5CH2CH2CH3 ppm 142.6 128.3 128.6 125.8 40 ETHYLBENZENE, C6H5CH2CH3 ppm 144.1 128.1 128.5 125.9 39 ETHYLBENZENE ppm 143.4 127.2 127.8 125.2 43 DIPHENYLMETHANE correction values 12.57 .41 -.09 -2.48 41.93 spectra carbon number 1 2 3 4 5 6 6 c an t 1 y smaller peak is observed downfield at 135.9 ppm. Nonprotonated carbons tend to have longer Tj and there fore smaller heights. This chemical shift is assigned to the nonprotonated Cl. The 02,6 and 03,5 carbons are assigned by comparison with literature values and comparison to methyIpheny1 su 1 f ide and an iso 1 e and dipheny1 ether correction values found in Breitmaier tables^®. Spectra are given in Figures 35 and 36. Chemical shifts are reported in Table 10. N-Me t hy 1 -p.-t o luenesu 1 f onam id e , Figure 4, was assigned by off-resonance decoupling. Figures 37 and 38, and by comparison to existing literature data found in Sadtler^^, Breitmaier^®, and Ewing^^ references for N- subst itu t ed-£.-t o luenesulfonamides, benzenesulfonamide, and benzenesu1 fonic acid as well as concurrently run spectra. The upfield signals, off-resonance decoupled quartets, at 29.2 a n d 21.5 ppm correspond to N-methy1 and methyl carbons. The signal at 21.5 ppm is assigned to the methyl carbon. This chemical shift agrees with the value obtained for the toluene methyl. The re maining upfield signal at 29.2 ppm is assigned to the N- methyl carbon. This can be verified by comparison to chemical shift tables^® and Sadtler data^^. 01 and 04 are assigned to downfield off-resonance decoupled sing- 67 G 3 U 4J U 0 a 0 Pi X z m 1-4 C o X i u 0 o 0 •H <44 1-4 0 0 1-4 >1 O 0 Æ 0m m en 0 u 0 50 •H 6 8 0 0 •f-t50 0 -0 1-4 0 G 0 U O 0 0m 0 04 Z z 0 o Xi U 0 Ü 0 •0 •r4 0 0 r4 >> 0 0 0 m • |4 p V0 m 0 u 0 50 • H b 6 9 Table 10. Diphenylsulfide Assignments, ppm and correction values, and theoretical calculations. Carbon number 1 2 3 4 reference ppm 135.89 131.07 129.17 127.02 spectra # of carbons 2 2 2 2 CDC13 ppm 135.8 130.9 129.1 126.9 40 correction 7.3 2.4 .6 -1.6 CDC13 ppm 135.7 130.8 128.9 126.8 41 correction 7.2 2.3 .4 -1.7 CDC13 128.5 128.5 128.5 128.5 base Similar Compounds «ETHYLPHENYLSULF1DE , C6H5-S-CH3 ppm 138.6 126.8 128.8 125 40 DIPHENYLSULFIDE correction values 7.39 2.57 .67 -1.48 spectra carbon number 1 2 3 4 70 oi X Z CO 0 O 10U 0 O 0 •l-t e 0 0 O <44 1-4 0 0 0 0 0 0 r4 o B 4J 0 1 U ol 4J 1 u 1-4 0 >» CL 10 0 4J 0 0 z 0m z 0 o o 0 fO *v 0 0 w u 0 0 60 0 •H 0 P4 O 0 0 W I MH 71 % z c o 0 O X i U 0 0 O «-4 0 0 0 *0 60 .H ••4 e 0 0 0 -O o f-4 W4 0 i“H • H 0 <44 0 0 0 > 0 O 0 *o 0 1-4 O B w 0 1 U 0 l 1 o 1-4 0 > > CL 10 0 U 0 *0 0 Z r4 CL z 0 O o 00 0 m 'O 0 0 u o 0 0 60 0 •H C k O 0 0 U I M4 O 7 2 lets. C4 is assigned to 143.4 ppm whereas Cl is assign ed to 135.9 ppm. This latter peak is of the shorter height and probable longer Tj that would be associated with a nonprotonated carbon bound to the sulfonamide function. The remaining off-resonance decoupled doub lets correspond to signals at 127.3 and 129.7 ppm. These are assigned to C2 and C3 carbons, respectively following comparisons to existing literature data. Spectra are given in Figures 39 and 40. Data is presented in Table 11. 73 a o Xi u CO o Q) 'O •p-J e CO c o 3 (0 3 N I 43 (U X I 2 o \ cn ai S Z 0 O fO u co u 0) r0 •H B cd 0 o M-l f—4 CO ■u o 0) CL 75 Table 11. N-Methyl-g-toluenesulfonamide Assignments, ppm and correction values, and theoretical calculations carbon number 1 2 3 4 5 6 reference ppm 135.85 127.28 129.73 143.44 21.46 29.22 spectra # of carbons 1 2 2 1 1 2 CDC13 ppm 136.4 127.1 129.6 143.0 21.4 29.0 41 correction 10.8 -1.4 .3 5.2 CDC13 TOLUENE ppm 125.45 128.35 129.16 137.97 21.5 spectra correction -3.05 -.15 .66 9.47 CDC13 ppm 125.6 128.5 129.3 137.8 21.4 39 correction -2.9 0 .8 9.3 CDC13 128.5 128.5 128.5 128.5 123.5 123.5 base Similar Compounds N,N-DIHETHYL-p-TGLUENESULFONAHIDE, C6H5S02N(CH3)2 ppm 132.6 127.7 129.7 143.4 21.4 37.9 41 BEN2ENESULFÜNAKIDE, C6H5SD2NH2 ppm 143.5 125.7 128.7 131.9 41 N-ETHYL-p-TOLUENESULFONAHIDE, C6H5S02NHCH2CH3 ppm 143.2 127.2 129.6 137.3 21.5 38.2 41 N-BUTYL-p-TOLUENESULFONANIDE, C6H5S02NHCH2CH2CH2CH3 ppm 137.6 127.1 129.6 143.1 21.4 43.0 41 N.N-DlMETHYL-p-TOLUENESULFONAHIDE correction values 10.4 -1.07 .57 5.47 21.46 29.22 spectra carbon number 1 2 3 4 5 6 NUCLEAR MAGNETIC RESONANCE ANALYSIS OF DIBENZOCYCLOHEPTANE DERIVATIVES Carbon-^ NMR of. Z- and E-Doxepin Hydrochloride 1 1 Carbon NMR data is presented for and E^- doxe- pin hydrochloride. Figure 1. The commercial product is a mixture of approximately 85% E^- and 13% 7^- isomer. Since this drug is believed to act by preventing reup take inactivation of biogenic amines at the nerve end ings thereby potentiating the amine action at post- synaptic receptors , conformational variations between doxepin isomers in solution and predictably at the bio genic amine uptake jump may explain the greater biologi cal activity of the Z^-isomer ^ » 7,8 Previous proton NMR of E.-doxepin indicates that the d ib enz [ b , e ] ox ep in ring exists in, two thermally dependent conformations^^, Figure 41. While X-ray structure determinations of similar dibenzo[a,d]eyeloheptane derivatives yield a crystalline stucture in which the olefinic substituent is fully extended away from the ring^®, in solution the alkylamino olefinic group of these latter drugs is oriented above the most adjacent aromatic ring^®. Analogous studies have not been conducted with doxepin isomers. Current NMR studies indicate differing dibenz- 76 77 00 c "p4 X k e -#4 a 01 X O 0 01 JO N e / 01 u JC 44 O « C C C o "H **4 *t4 0« 44 0> u O • • o Oi k 9 00 nJ 78 [b,e]oxepin ring conformations for each isomer as well as olefinic substituent orientation above the most adja cent aromatic ring, Figure 42. 13 Carbon NMR shift assignments (Tables 12, 13, and 14) for these compounds were made by comparison of model compound chemical shifts, off-resonance data (Figures 43,44,45,46) inversion-recovery (T^) determinations, homo- and he teronuc1 ear shift-correlated 2D NMR spectro scopy (Figures 4 7,48,49,50,51,52,53,54) and selective decoupling and INEPT experiments. Bruker AM-400, WM- 500, and Varian FT-80A spectrometers were used for the analysis. Carbon^^ NMR spectra are given in Figures 55 and 56. Proton NMR spectra are given in Figures 57, 58, and 59. All spectra were obtained using deuterochloro- form solutions and tetramethylsilane (TMS) as internal standard . Alkyl Carbon Assignments 13 The carbon shifts. Figure 55, for the alkyl car bons can be predicted using known substituent chemical 39 40 shift tables ’ and off-resonance data. The intense upfield signal, an off-resonance decoupled quartet, can readily be attributed to the N,N-dimethyl carbons. The remaining less intense signals, off-resonance decoupled 79 03 U 03 B 0 80 C fi a 03 X 0 ■ o VM o C C c 0 • H M a CL 4 J q j q , « X X E 0 0 k , 7 3 - o O 1 1 1*4 M | N | 0 , . ü (d ^ CNI 03 U 3 0 0 8 0 Table 12. Doxepin Hydrochloride Alkyl Carbon Assignments. (CH312N- -CH2N- -CH2- -CH20- Z-doxepin HCl 42.8 57.1 24.7 70.8 E-doxepin HCl 42.6 56.8 24.4 70.00 Spectra were obtained using a Varian FT 80-A spectrometer, 100 mg/ml CDCI3 solutions and tetramethylsi lane as internal standard. 81 1 h^ o I D h a u a O O CO ^ 4" C-J K > o ~ *cu - •¥ u a CM •** 1 «** O' M 3 M 3 5 O *1 1 M a CM <=> 0 3 4 4 h - h*. OO h a 1 C M ", 1 r— • Ch" O ' Ol CO *D 1 c > h ô a . * o 1 C M h a ^ 4 k. CM 1 C M CMID r - CM MO MO 2 S 1 O O ID CM OOOJ 1 1 K > O ID 1 CM ^ GO Zî CN 1 CM CM S 4-> 1 ID o - . SJ3 O 1 h O CM OCM CM OO CM CM r o I D ID 1 O T 4 0 0 M 3 1 CM o ô Ch. 1 C O M 3 ID 1 C M CMCM K > I D K > 4-4 "i 1 h O I D o o 4 4 c > O O 4 ; O O * 1 C M 0 0 h a OJ "1 R u a u a * 8 ,- 1 C M CM CM a * o 1 h ^ CD 4 4 h a h - 1 M 3 Ü") —• 1 '■a cr* Ol u“T CO rô OO 1 C M C M 4 4 CM 1 ü*a M 3 - a -DO 4 4 p o OO < s O O CM ID Ol u a OO 0 3 M 3 CM 3 1 • f CO CO o ~ M 3 ~ o h-*. < c h-s 1 C M M 3 CD 0 3 * o 1 C D C D 0 3 1 C**J CM CM h-a CM t r-. h*a - 4 r a C 3 u a h** CO 1 > D M 3 *o j M 3 i CD 0 3 o ~ r-*. 1 C M C M C M h a 5 : 4 4 1 rD , o > 4 4 4*. OO ^ t if) CM OJCM u a h*. 8 '■ 1 C M C M h a -* r - o u a o s O C M 1 * D CO 1 fD 1 -, - - C > I cr* h a 1 C O h a 1 M 3 h â 1 -, - 1 -D h a u a 1 ID I D C 4 h a 1 0 3 ID 8 r 1 ID Ü-3 u a 1 UI ►— A . c a . A o CO w A CM M 3 1 e k. -, ID m IT* U OM HI Ol o ra 1 ac 3: z: fo —. nj 4 4 •a .JO ^ sO U CM l_i irt Ol o 03 e U C_1 CJ 3= -r-i 1 a O 01 > a k_ 03 ^ 4-» LJ 44 a c c 4-> a a OK-OC IIZrCMfc-CNbD o o rd w k. s U 3 LU I— OJCMC-IZ O 3: =C t a j a O M 3 D Ol 03 g L. z : - 4 m z c a c J o i c j c j i t Ol Ol m I z:njtJ'^*-'j='-‘0 m LJ 03 03 a ui U“i <3C xa •"■ I I *— I I nS CD 3 = X s 8 2 3 = 1 r a o M 3 r a 0 3 0 3 #1 C J 1 r*. CM m " « M 3 u a CM CM o - 5 CM 2 : — CM o «*• r*. r a l~. 0 3 r a 1 CM X# CJ 1 r*. o CM O'. “oj ? 4* «# A - O K > #« 4* 4» 1 £ j 1 r a CM c C M o O'* CM - CM i o CM r a • 0 3 4* 1 0 0 r*Z CM 4* 1 C M CM CM 4* 4* 1 1 m P*. : 1 C M M 3 o CM o - s O 03 u a C 3 1 OO u a O'* O' o! S 4* 1 r à o A u a u a 4» 1 C M CM £ 4« 1 x c 1 r a o - r*s • o 0 3 - u a < o 4* C 3 1 CM o o r a *CU C M u a u a - £ 1 r-s M 3 4 0 r a 1 C M C 4 CM g X C 3 1 r a o * o r a u a r - 4« 1 u a M 3 4* o 0 3 O ^ CM 4* r a 4* 4» 1 £ < o 4* C 3 0-. r.*. O'. u a 4» > O O £ 1 -Ô C M 1 4* ^ 4* 1 4, 1 r-*. C 3 i 1 u a u a 4* O'. 4< t O O o ^ ID CM 4* t u a u a u a 4t 4* I £ £ c a m in - 1 h— C M A e 1 ÛL. A o a ° \ C M 4* O c. J 3 I m ra C k. U. ' £ 1 Ol Ol OJ O ra 1 ra 1 * o r-m ^ u m S S S 'ro ^ 1 k. m UI O Ol g 4« 1 a o a u. a 3 3 g C A « OJ CM a xa V g 8 : 8 hc o < r S §■> o 1 a X 3 O = 3 Ol Ol Ol 1 OJ CU r — ■“■=^3 8 S 5 S J = •n » M = CO Ol Ol a 2 - I 4, 1 ►— r - «cr c n = c a c 8 3 oeS Z Z 0 o M 0 o 0) 'O •i-i u o *0 o o u *0 >» .si I!0) • *—I cn çt4 9 o Q> o u o> 9 *9 60 .H Of O 0 0 0 O CO Q) 8 4 I MM MM O C4 Z Z 0 O • X i 00 U i-M 0 0 O 0 60 0 • iM 0) •H W *9 O i-M rM (U Z •H ü M4 o 0 M O •9 -9 Z 0 6 •H 0 w 0 4 9 4M X Ü O 0) A 0 4 1 CO w l »9 Q) i-M 'd' 0 4 0 O 0) ü k 0 0 *9 60 •tM 9 k Ü 0 0 0 O 03 0) U 85 8 6 MM O Z z z m C o A (0 u rM 0 0 o 0 60 a 'O . 0 0 B • H 0 0 4 W Q) 4M X O O 0 A Ou 1 CO toi 0 5 0 rM v O 0 4 0 O OJ o »M Q) 0 0 3 60 • H 0 P4 U 0 0 0 O (0 Q) U 87 0 Figure 47. ^-Doxepin hydrochloride homonuclear shift-correlated 2D NMR. 88 jiAa #• #• o* ê» 00» • • 0O»ê • Figure 48. ^-Doxepin hydrochloride homonuclear shift-correlated 2D NMR; expanded plot. 8 9 Figure 49. E^-Doxepin hydrochloride homonuclear shift-correlated 2D NMR. 90 % ii Figure 50. ^-Doxepin hydrochloride homo- nuclear shift-correlated 2D NMR: expanded plot. 91 M Figure 51. ^-Doxepin hydrochloride hetero nuclear shift-correlated 2D NMR. 92 Figure 52. ^-Doxepin hydrochloride hetero- nuclear shift-correlated 2D NMR: expanded plot. 93 Ji__ JL Figure 53. ^-Doxepin hydrochloride hetero- nuclear shift-correlated 2D NMR. 94 Figure 54. ^-Doxepin hydrochloride hetero- nuclear shift-correlated 2D NMR: expanded plot. 95 X Z cn C o Xi m V U TD T3 cd •H »H o U W O o X jC •H U u w o o o W *4 1-4 •o 'X3 x: V Æ X: o u c c •o f* «f4 X CL O. X: 0^ Q> X X o o •o -o a t I 4) U}N| X o p in m o; w D 00 •H • pbt on z Z m c 0 0) 01 w •O •o (0 •H •H ü k4 M 0 0 0) r—1 •o JS X •H u o w 0 0 o M tri 1—4 •O •o z >% X VÆ j : 0 M C c T3 •H riri a a Z D V CD XX c f—4 0 0 H-l cO •V •o a e 1 1 o> 00 M | N | X •H o CD Q td "O f-i • 0) vO f-4 m c 0) > M 0 3 00 •H u« CD u « a (0 97 Figure 57. Doxepin hydrochloride proton NMR spectra a. Z-Doxepin hydrochloride b. E-Doxepin hydrochloride 9 8 o r-l <0 c eo •H QD -o r-4 Of •H U-l c > 0 1 3 cd u 4 J O 0) a to Z Z c 0 4J « 0) 0 X) T) u ■H ■k PL k k O O 0> ^4 fk x: J= •H u u u o 0 0 k k ^4 •o TJ u x: X: 0 u c e T 3 •H • k > , a O. 01 01 XX e 0 0 •H A o a 1 1 « W N l X o o 0) X) 00 S eo 99 c 0 •H eo w TJo; T3 c (0 a X 4J 9) y s •a (0 o M k a U OJ 0—4 a <0 m t 4 Ü a! L4 Z d) z e 6 c 0 0 o 4J V 0 •o •V •• u •H •k 0) CL u k -o 0 0 0) fk w •o x: x: 0 •H y y m-4 u 0 0 X: 0 k k y •o •o o X: k u X: X: •o o >s k c c M •o •k •k >» a (X C X: y V v4 X X a c 0 0 « •f4 ca o X a 1 1 o 01 N | U | 0 X o o a X3 y O' m Of u o eo 100 triplets, can be attributed to methylene (24-25 ppm), N- methylene (57 ppm), and 0-methylene (70-71 ppm) carbons by comparison to model compounds and use of chemical shift tables. Results are presented in Table 12. A chemical shift difference between isomers of 0.7 ppm is obtained for the 0-methylene carbon while alkyl- amino carbons exhibit only a 0.2 to 0.3 ppm difference. The 0.7 ppm difference between isomers for the 0- methylene carbon shift observed here indicates that a different conformation may be favored for each isomer. Proton NMR of and doxepin. Figure 58, also indi cate differences in orientation for the -CH2- protons of the oxepin ring. Two broad peaks are observed at 4.8 and 5.5 ppm for E^doxepin whereas a single broad peak at 5.2 ppm is observed for the ^-isomer. Spectra of the commercial product which is 85% E.- and doxepin indi cates the presence of all three broad peaks. Figure 59. Two thermally dependent conformations have been shown to exist for ^-doxepin hydrochloride^^. Figure 41. The ^- and Z^- isomers appear to favor conformation A and B, respectively. A low barrier to interconversion between conformations was reported (delta = 13.8 kcal/ mole)^^. The broadness of the peaks observed for the -OCH2- protons may be indicative of this low barrier to 101 interconversion and may reflect some flexing of the dibenzoxepin ring. All spectra were accumulated at 298 and 303 degrees Kelvin which is above the postulated coalescence temperature (283 degrees Kelvin)^^. The £- isomer was still found to favor conformation A. This conformational difference between isomers for the 0- methylene carbon shift observed here may also be re levant to the greater biological activity reported for the ^-isomer 5,6,7,8^ A 0.2-0.3 ppm difference is observed between isomers for the alkylamino carbons. Z-isomer carbon shifts are observed at slightly down field position. Proton NMR also indicates significant differences for these aliphatic protons. ^-isomer signals for -CH2CH2- protons are well resolved and slightly downfield of E.- isomer protons. It is, thus, apparent that the alkyl amino chain interacts with the ring. The downfield chemical shifts relative to ^-isomer values observed for the ^-isomer alkylamino carbons and protons are indica tive of interaction with the electronegative oxygen of the oxepin moiety with positioning of this chain above the aromatic ring of closest proximity as in the diben- zo[a,d]eyeloheptane derivatives. Postulated orientations are shown in Figure 42. 102 Nonprotonated Aromatic and Olefinic Carbon Assignments Quaternary carbon assignments are given by inver- sion-recovery (Tj) experiments and by comparison with model compound data. A spectrum of the downfield car bon signals and chemical shift data are presented in Figure 56 and Table 13, respectively. C11 can be assigned on the basis of the model compound data. Ani- sole and benzyl phenyl ether both have signals of 158- 160 ppm assigned to aromatic carbons bound to oxygen. Considerations of steric rigidity and proximity of pro tons leads to the assignment of C13 to a signal of long T2 at a downfield location determined by comparison with 10,1l-dihydro-5H-dibenzo[a,d]eyeloheptane models as well as 1,1-dipheny1ethy1ene. These models yield values of 146.9-151.9 and 141.6, respectively. As a result of proximity to methylene protons and possibly somewhat decreased rigidity, Tj values for CIO should be shortest of the non-protonated carbons. Signal position should be slightly upfield of C 11, C13, and C 9 as predicted by model compound data. Similar in version-recovery values should be ob tained for the C12/C9 pair. As a result of substituent effects, C12 should correspond to a significantly up field signal. An off-resonance decoupled singlet, indi- 103 cative of nonprotonated carbons, is observed upfield of all other nonprotonated carbons. Inversion recovery values for this signal are essentially the same as that observed for the signal assigned to C9, 6.8/6.1, and 8.9/8.7 for C12/C9 pairs for E- and isomers, res pectively. Differing absolute T^ values may reflect conformational differences. Selective INEPT experiments also confirm assignment of the C9,12 pair for each isomer. Upfield shifts of C 9 and C12 when c is to the alkylamino group are also predicted by theoretical mod- els39.40. Monoprotonated Aromatic and Olefinic Carbons Monoprotonated carbon shifts were defined by homo- and heteronuc1 ear shift-correlated 2D NMR experiments and proton NMR followed by carbon selective decoupling experiments. Peak assignments are shown in Table 13 and 14. Selective decoupling at the proton frequency corresponding to the vinylic proton triplet at 5.9 and 5.6 ppm (E_- and Z^- doxepin, respectively) as well as heteronuc1 ear 2D experiments yield absolute assignment of C 1 6 . Proton NMR and homonuclear shift-correlated 2D spectra identify coupling of two protons (doublets) 104 adjacent to nonprotonated carbons and two protons (trip lets) each adjacent to two protons in addition to a group of unresolved proton signals. The unresolved signals can be attributed to ring A protons which are in a similar environment whereas ring B protons should show additional resolution due to the proximity of oxygen. Figure 1. Heteronuc1 ear 2D experiments allow assessment of the ring A proton signals as well as ring A and ring B carbon-proton chemical shifts correlations. Table 13 and 14. Selective decoupling of ring B signals produced correlations identical to heteronuc lear 2D values. Ring B carbons have been assigned based on model compound data. Table 13, in conjunction with the above heteronuclear 2D correlations. Carbon signals at 120.2- 119.4 and 130.5-130.0 ppm are ring B proton doublets (C4,C1). These correspond to theoretical values of 114.7 and 129.1 ppm for C4 and Cl, respectively. Simi larly, carbon signals at 121.3-121.2 and 130.0-129.6 ppm are ring B proton triplets (C2,C3) corresponding to theoretical values of 120.8 and 128.7 ppm for C2 and C3, respect ively. Ring A proton triplets C 6 and C 7 produce carbon shifts at 12 9.1-128.9 and 128.0-128.5 ppm. Theoretical calculations for these two carbons differ by only 0.1 105 ppm (127.7-127.8 ppm) making comparison to model com pound data impossible. Therefore, chemical shift differences between isomers for ring B signals have been used for estimation and comparison to those of ring A. Essentially no ppm difference between isomers is ob served for C2. A 0.2 ppm difference was observed for the carbon signal at 129.1-128.9 ppm. This has been assigned to the corresponding ring A C7. Slightly greater ppm differences are observed for ring B C3 (0.4 ppm). The signal at 128.0-128.5 ppm has been assigned to the corresponding ring A carbon, C6. Proton doublets (C5,C8) correspond to carbon chemical shifts of 126.3- 127.3 and 127.4-128.6 ppm. Theoretical calculations for these carbons differ by 1 ppm (127.2 and 128.2 for C5 and C8, respectively). Comparison of ring B Cl and C4 indicates only slightly greater shift differences be tween isomers occurs for the C4 position (corresponding to ring A C5) than for Cl (corresponding to C8). Since the model compound chemical shift difference between C5 and C8 is approximately 1 ppm and isomer comparisons are inconclusive, C8 has been assigned to the higher signal at 128.6-127.4 ppm while C5 has been assigned to the lower ppm range of 126.3-127.3 (theoretical value 127.2 ppm) . 106 Carbon— NMR of E- and Z-Dothienin Hydrochloride 1 O Carbon NMR data is presented for and com mercially available E.- dothiepin hydrochloride. Figure 1. Dothiepin has been reported as mainly E^-isomer and as 5% and 95% ^-isomer. A small nonquantitated amount of the ^-isomer was present in the commercial product analyzed. This tricyclic differs from doxepin by the presence of sulfur rather than oxygen in the eyeloheptane or oxepin ring. It has not been studied extensively. X-ray crystallography of similar diben- zo[a,d]eyeloheptane derivatives yield a crystalline structure in which the olefinic substituent is fully extended away from the ring^?, in solution, the alkyl amino olefinic group is oriented above the most adjacent aromatic ring^^. Previous proton NMR of j|-doxepin indi cates that the dibenzoxepin ring can exist in two ther mally dependent conformâtions^^. Figure 41. Current NMR studies indicate differing dibenz[b,e]thiepin ring con- 13 formations. Figure 60, for each isomer based on carbon NMR. Differences of 0.1 ppm or less were observed for olefinic alkylamino carbon signals between isomers. However, significant differences in proton spectra were observed. This allows assessment of substituent orientation above the most adjacent aromatic ring. 107 eo c u c a o O 0 N C /I 0) U-4 O c c CD "M *H C a Ou o 0» •H *H *■> j: ^ Y tt u u E o 0 k "O %) o i l «w U | N | O • • U 10 U3 O vO O k 3 60 108 Figure 61. Carbon^^ NMR shift assignments (Tables 15, 16, and 17) for these compounds were made by comparison of model compound chemical shifts, off-resonance data (Figures 62, 63, 6 4, and 65), inversion-recovery (Tj) deter minations, homo- and heteronuc1 ear shift-correlated 2D NMR spectroscopy (Figures 66, 67, 68, 69, 70, 71, and 72), and selective decoupling and INEPT experiments. Bruker AM-400, WM-500, Nicolet NT-270, and Varian FT-80A 1 3 spectrometers were used for the analysis. Carbon NMR spectra are given in Figures 73, 74, and 75. Proton NMR spectra are given in Figures 76, 77, and 78. All spec tra were obtained using deuterochloroform solutions and tetrametby 1si1ane (TMS) as internal standard. Alkyl Carbon Assignments 1 3 The carbon chemical shift assignments can be predicted by using known substituent chemical shift tables 39,40^ off-resonance data, and by comparison to 6H-dibenzo(b , e)thiepin-11-one NMR data. The intense upfield signal (42.5 ppm), an off-resonance decoupled quartet, can readily be attributed to the N,N-dimethyl carbons. The less intense off-resonance decoupled trip lets at about 24.4 and 56.5 ppm can be attributed to 109 0) E O 00 a 01 o •o o c c f4 «H C a a o O • • O « Æ vO 3 60 110 Table 15. Dothiepin Hydrochloride Alkyl Carbon Assignments. (CH312N- -CH2N- -CH2- -CH2S- Z-dothiepin MCI 42.5 56.6 24.5 34.1 E-dothiepin MCI 42.5 56.5 24.4 33.20 Spectra were obtained using a Varian FT BO-A spectrometer, 100 mg/ml CDC13 solutions and tetramethylsilane as internal standard. Ill 4* Z C C M M 3 o r o ca r o 1 4* C J CO O' o !r? 4) • C M 1 r o CM CM r o 4, CM $ 3 = o : 2 * o •«a 4* C J o f". ■trî 4» 4» M J 4« C M C M CM:S 4i 4» 4» 3 CM r-*.O in 4 M 55 CO «X oo 1 o 4« O ' CO CO 01 4» fc in M 3 *D .g 3 CM CM CM 2 3 “O 3 i r a r o a a 3 r o r o oo in 4 M CO CO 4* CJ O r o CM OI " e- O' in cvi i" CD 0 0 r-' ja r o CMCM CM o t 3 4» M 3 in CM U-3 44 0 3 4* -O 4 M r*'. ca o *¥ CJ r-. O CM OI 4* 4* 0 3 CD cx CM CM CM CM 3 G O 0 3 4 M COCJ ■id* O 4, 0 3 O' CM CM S r o 4« 4 M CM 4» 4< ■id"O U3 O' C? 0 3 C O CJ M 3 M 3 GO OJ CM in CM 4* CM r o 4* 4« T3 4» O 4* C J m C M K > ■ 0 3 4i & C O 4* m 3 Ü3 r o o R CM 4» r o r o r o 4* 4" 4* C J 0 3 O o M 3 CO r o i n CM p j M 3 o 4« 0 3 in CM lO 4« r o r o 4* 3 cr- o r o ro U3 M 3 in oo 4> CM 4» r o 4» CM o o IM. O' -c CM CO CM 3 o r o 0 3 o p3 In 4i in CM CM 4» ■a* 4» a. ca a 1— CM m m o o_ CL c o LU — 4» CJ LU k. a. o C M O *1 z OJ xa s U i i n i n i n HI OI m ca OI s c 3 = = c 3C 1 m 4" no o 2 3 LU > - sxa CM 4. OI OJ u _UH— CJCJ CJ 3 = 4» S' a o > a c 4« e 3C CM c n c n OI 4< C CM o o X CM CM 4« o o L_ tj LU OI CM CJ ac 3 = o a > OI HI u o x c in 3C c n CJ Oi CJ OI OJ a ro CJ J= m j r OJ OJ OJ o 3 1 H- }S 4< r— c n cm 3 Z = 112 1 C M i n t M , 4 4 1 ' ' 0 0 m - T 4 - I 0 3 r o O' o 4 M 8 O' c u MO C M - i n 1 C M 0 4 o . r o w . CM M 3 O ' » 4 M * 2 'O M 3 1 t ' ' CM O' 4 M CU CO i n c x m 1 C M CM CM O l L. 4 M U O - U * 3 o o 1 C M I'-. C m O' i n O O < x O O ' t o O ' * d " o 1 O ' 0 0 M 3 O' c u s L T 3 0 3 t o 0 3 m CM CM CM 2 C'H ■ w 0 4 CM 3 T 3 o O O 1 m t o CO i n o r - ' m m r ' ' *-T* o o < x O O r o O ' t o O'O' CUCU 0 3 C M l " M 3 t ' ' m 2 JO r o r o 1 C M CM CM g a • o - C 3 4 M U * 3 r o CO o r - ' i n 0 0 i n O' 4 M f ' ' < x t ' ' * r o m M 3 m 3 r * ' CM o c u CU O' CM»* O ' o o o 1 0 3 0 3 t o r o I C M 0 4 k . T CM 4 M m 1 M 3 o o 1 « f M 3 O'* t ' ' 0 3 m i n O' 1 0 4 r o O l S o t ' N . CM l " ! 0 3 0 3 CM i n r ~ * 1 R 0 4 0 4 0 3 o o k _ 1 1 M 3 M 3 - i n r o o r " r M . i n CN. 4 M 1' ' < r r o r o O ' o 1 r o 0 4 0 3 CU 0 3 OO HI M 3 - 0 4 i " 0 3 O ' CO CM CM 1 0 4 C M e x k - CM 4 M i n 0 4 0 3 0 4 o 0 3 ■ d * O ' 0 3 0 3 • d * r o O' i n O'O' c u CO 0 3 M 3 I 0 3 0 3 - o JO 1 0 4 1 CM 1 0 4 CM 2 a m e r * a o -Q ! 4 4 O ' o ■ » O M 3 i n 4 M 0 3 0 3 ■ d * i d * ' r o o > O ' M 3 1 M 3 i n o O l c u s O' CM 0 3 0 3 o O . a JO 0 4 CM t C M m r o a a o o “O 1 ' O o O i i n M 3 O' • o t o M 3 r M . 0 4 OO 0 3 o CM CM I m r o i r a C N c * f'-. O 0 3 o o O ' M 3 C O R 0 3 MJ I ^ r o [ ^ O' U 3 r - N . OO r o 1 m M 3 o Cyl! i n f M . 0 4 m r o 1 . p M O O 4 * C J 1 1 ' - CM r o f ' ' O' 1 O ' O' r o 0 3 C M 0 4 M 3 M 3 1 V " c r "T UI to O- 1 r ' p m o M 3 p o t M . M r < # 1 . to to ■ 4 0 O ' 1 0 3 o 04 l" i n 0 3 CM ' R 1 « C CL CO i n - 3 r — C M C L c O o _ o - o UJ L .S C 4 j a c u a c t O i m o o f O k . T 3 4 M i n O i c u o a 1 U U CJ w _ 1 O o OI > > a k . a c y ■ C J 0 4 0 3 O J c n i O Q J o a II Z 04 k. CM 3= ^ o o rfl w k . & . 1 1 o o a O I O l o . CU 2 “•^l^SSSSS t 0 1 0 1 -M U J 4 M a r o I tl c u O j JSi o i ^ r S r a c n S " i 113 M-4 O od X % a o u cd o a •H G 04 a M l -o q ; r—1 P4 cs P vO o u 0) 0) k D 60 Q) • H O M a cd c o CO OJ U 114 ei S g m a o A • u co cd f"4 Cd o c 0) 60 • (4 «H CO w o Td *-4 Xi CJ o •t4 o C*4 u C t3 :> >> o 0 • H 8 P« 0 (U M • iH O U CJ O CL Q CO Ml 0) *-4 . CL co 3 s£> O Ü O CJ w %) g 60 CJ •H o M 0 cd C o co CJ u 115 Pà * g CO tH 0 O Xi M (d o 0) ’0 • r i M O •—I Xi u o w •ü •C 0 •H G pu P 0) $4 •rl 4-» O OJ O P P 00 nj Ni 0) r4 « P 0 SP O o OJ Q) M •O P 60 0) •f-l O M 0 0 0 O CO 0) w 116 «M O Pi X g a o X • k « (0 u co d 0) 00 •o "H •H ca M o "O II .2 a s*s .H *J Ni-s r4 m• Po0 so o o 0) 0) *4 0 60 0) •H ü M 0 0 0 O « OJ M 117 Figure 66. ^-Dothiepin hydrochloride homonuclear shift-correlated 2D NMR. 118 P Figure 67. ^-Dothiepin hydrochloride homonuclear shift-correlated 2D NMR: expanded plot. 119 Figure 68. ^-Dothiepin hydrochloride homo nuclear shift-correlated 2D NMR. 120 ■ « «I » f # # m» * # & a ■ a m m a ^ m v « a t l V « ? * r a a I w a a a a a * a a m * a u ii Figure 69 E-Dothiepin hydrochloride homo nuclear shift-correlated 2D NMR: expanded plot. 121 Figure 70. Z-Dothlepin hydrochloride hetero- nuclear shift-corre la ted 2D NMR. 122 Figure 71. Z-Dothlepin hydrochloride hetero- nuclear shift-correlated 2D NMR: expanded plot. 123 c-MTMieriN 150.1 122.5 121.S 12S.S PPM Figure 72. E-Dothiepln hydrochloride hetero- nuclear shift-correlated 2D NMR. 124 PC z z CO c o .o 0> 01 u •o *o (0 w4 v4 o M t-i o o I— I *-H ^ X u o M 0 o o w u <— I -o -o .c >\ >» u •C Æ o w c c *o f4 #H X a a 0 1 01 x: •H «M xi X w u a 0 o 0) -o *0 1 I W|N| o Q (0 X) m OJ 0 bO k CO 0 01 a CO 125 oc Z z c o Xi « V U eO T 3 ”0 U 0) •D x: X •H u u o o O *4 *4 «-4 •o T) X. X ► < u X X o w c e •o •H 44 a o. j: « V X X *J u CL, o o 01 a) T3 "O 4 4 C I I X e o u | N | o n o (d X • 01 44 f" ,w c 01 > w o 3 -O ec • H • • U 4-1 0 01 a to 126 oc X z C 0 .o 01 01 u •0 *o 0 v4 1-4 V w k, 0 0 01 ^4 0—4 •o MX OO w 0 o o L4 •o •o .c >s X u X: x: 0 u c c 44 -H >% a CL JC 01 01 f4 •H c 4C X: *«-i 4J 4J CL • 0 O 0 m •o •o 1-4 m4 1 1 J= 0 W | N | w 0 0 oc o 0 (0 , T3 *A 1—4 0 f4 01 (w w & 0 0 bO 0 k 4 J U 0 CL m 127 0 U _ 4-1 U 0 a (0 oc z z c o 4 J 01 0 o 13 "O M « H a ki M o o 0 *—l I—I ■V X X 4 - t ü y u o o o 1 M r-* "O "O X >< >> u X X o k c e 1 3 4 4 4 4 >1 a o. X V V *f4 - H c X X • H 4 J 4 4 0.0 0 V o o 44 I I X U | N | O o vO 0 U 0 00 128 a) c eo ai k w u 01 a » PO X z c o 4J y O f r «4 O 01 T3 x: x o Ü 0 0 »4 |4 T5 T> X ►. X u X X o u c c •a 44 44 >. a a J= « 0) c X X 44 4J 4J a o 0 01 A o 4 4 I I x : w | N | 44 O • • A ai X) r~. fs. 0 M 0 00 lu 129 0 0 •H 00 0 u •0 0 •O 0 0 0. X 0 •• 0 M kl U 0 O. 0 Oâ Z z 0 0 4J 0 01 0 T5 •o kl -H 44 a k 1 0 0 0 ^ t-4 T) -C X! 1-4 V U M 0 0 0 w w r-4 «Q TJ X X 0 jC X 0 M G c *rt *H 44 >> a p. X: « 01 4-1 44 e X X: 44 44 44 a 0 o 0) A A 44 1 1 X N | M | 44 0 • A a) X 00 0 U 0 00 bu 130 methylene and N-methylene, respectively. The S-meth ylene group at 33.2-34.1 ppm can be identified by compar ison to the same carbon in 6H-dibenzo(b ,e) thiepin-11-one (3 5.8 ppm). A chemical shift difference between isomers of 0.9 ppm is obtained for the S-methylene carbon while the alkylamino carbons exhibit about 0.1 ppm or less differ ence between isomers. The 0.9 ppm difference observed for the S-methylene carbons observed here indicates that a different conformation may be favored for each isomer. Proton NMR of E- and dothiepin. Figure 78; however, indicates only a small difference in orientation of the -SCH2- protons of the thiepin ring. Two doublets are observed for each isomer. Doublet positions are, how ever, nonsuper imposable (4.8/4.7, 3.4/3.6 ppm: E^/^-). Postulated orientations for the dothiepin isomers based 1 3 on C NMR data are given in Figure 59. Orientation of the alkylamino olefinic substituent above the most ad jacent aromatic ring has been shown for dibenzo[a,d]cyc- loheptane derivatives^®. A similar orientation has been observed for doxepin isomers. The less significant ppm differences between isomers observed for the dothiepin alkylamino group relative to doxepin values may be indi cative of the decreased electronegativity of the sulfur 131 relative to oxygen in the cycloheptane ring. ^-isomer carbon shifts are, however, downfield of the correspon ding Prisoner signals for the alkylamino carbons. Pro ton NMR also indicates significant differences for these aliphatic protons. It is, thus, apparent that the alkylamino chain interacts with the ring. The downfield chemical shifts relative to the E^-isomer values observed for the the ^-isomer alkylamino carbons and protons are indicative of interaction with the electronegative sul fur of the thiepin moiety with positioning of this chain above the aromatic ring of closest proximity. Postu lated orientations are presented in Figure 61. Nonprotonated Aromatic and Olefinic Carbon Assignments Locations of quaternary carbon signals are given by off-resonance decoupled spectra. Assignments are given by inversion recovery (Tj) and selective INEPT experiments and comparison with model compound data. A spectrum of the downfield carbon 1 3 signals and chemical shift data are presented in Figure 74 and Table 15. Selective INEPT experiments at frequencies corresponding to CIS and -CH2S- protons allow assignment of C9 at 142.4 and 138.4 ppm for and dothiepin, respec tively. C12 and C13 are assigned by selective INEPT and Tj experiments followed by comparison to amitriptyline 132 and 5-methy1ene-5H-dibenzo[a,d]eyeloheptane data. The positions of C12-C13 having been isolated by selective INEPT experiments, C12 is assigned to the signal yield ing similar Tj value to that observed for C9 at 135.1 ppm (Z-) and 136.1 ppm (E-). The signal assigned to C13 is of predictably longer T^ and in comparable downfield location to the C13 observed for amitriptyline and 5- methylene-5H-dibenzo[a,d] cycloheptane at 145.2 and 145.3 ppm for Z_- and ^-dothiepin, respectively. Little shift in position between isomers for the nonprotonated ole finic carbon is also predicted by olefinic models. The ClO-Cll pair is similarly isolated by selective INEPT experiments. CIO should have a shorter T^ because of proximity to the methylene protons of the cycloheptane ring. The signal at 134.9 and 136.4 ppm has, thus, been assigned to CIO of Z- and E- dothiepin, respectively. Cll, the last remaining nonprotonated carbon is assigned to 134.7 and 134.0 ppm for and ^-dothiepin. Monoprotonated Aromatic and Olefinic Carbons Monoprotonated carbon shifts are defined by homo- and heteronuc1 ear shift correlated 2D NMR experiments. Table 16, and proton NMR followed by carbon selective decoupling experiments. Selective INEPT experiments 133 also allow estimation of C5 at 127.1 ppm (^-) and 126.8 ppm ( E ^ ) . Peak assignments are shown in Table 16. Selective decoupling at the proton frequency corres ponding to the vinylic proton triplet at 5.6 and 5.9 ppm for and E^- dothiepin as well as heteronuc lear 2D experiments yield absolute assignment of C16 at 125.9 and 126.1 ppm for and dothiepin, respectively. Homonuclear 2D experiments allow estimation of ring components. Two doublets, each adjacent to a non protonated carbon as well as a monoprotonated carbon, and two triplets, each adjacent to two monoprotonated carbons are assigned for each ring. Ring designation is given by selective INEPT definition of C5 location. Heteronuc1 ear 2D experiments yield correlation of proton multiplicity with carbon chemical shifts. Table 16 and 17 . After selective INEPT identification of C 5 the remaining doublet of the C5-C8 ring A pair can be assigned to C8 at 127.5 and 127.6 ppm for Z- and E^- dothiepin, respectively. The ring A triplet pair of C6,7 carbons are assigned by theoretical calculations based on monosubstituted benzene models. Theoretical calculations for C6 and C7 yield values of 128.0-128.6 ppm and 126.9-126.8 ppm, respectively. This allows 134 assignment of the more downfield signal for each isomer to the C6 carbon at 128.4 and 128.8 ppm for and E.- isomers. The more upfield C7 carbon is assigned to the signals at 127.8 ( ^ - ) and 127.7 (E^) ppm. Little chemi cal shift difference should be observed for these car bons which are gamma (C7) and delta (C6) to the double bond. The slightly greater ppm difference observed for the C6 carbons may be attributed to overlap of the Z^- isomer C6 signal with the signal attributed to ring B C3 at 128.4 and 128.1 ppm for Zj- and isomers (theoreti cal estimate, 128.0-128.3 ppm). Ring B C2 is assigned based on theoretical estimates of 126.1-126.7 ppm to the signal at 125.4 (^-) and 125.0 (JE-) ppm. The remaining Cl,4 ring B doublet pair is assigned similarly based on theoretical calculations of 128.5-128.8 ppm (Cl) and 129.7-130.7 ppm (C4). C4 is assigned the downfield signals at 130.5 and 130.7 ppm for Z_- and E^- dothiepin, respectively. Cl is given assignment at 129.0 and 127.3 ppm for Z_- and JE- dothiepin. Conformational differences between isomers may explain the greater shift difference observed for Cl than that observed for the C8 carbon. Similar shift differences are also observed for the other CIO,11 carbons which are beta to the olefinic group. 135 Carbon-^ NMR of 6H-Dibenzothiepin-ll-one Carbon^^ NMR data is presented for this precursor of dothiepin. Figure 1. Carbon ^^ NMR shift assign ments, Table 18, were made by comparison of model com pound chemical shifts, off-resonance data (Figures 79 and 80), inversion-recovery (Tj) determinations, homo- and heteronuclear shift-correlated 2D NMR spectroscopy (Figures 81, 82, 83, 8 4, and 85), and selective INEPT experiments. Bruker AM-400, WM-500, Nicolet NT-270, and Varian FT-80A spectrometers were used for the analysis. Carbon NMR spectra are given on Figures 85 and 86. Proton NMR spectra are given in Figures 87 and 88. All spectra were obtained using deuterochloroform solutions and tetramethy1si1ane (TMS) as internal standard. Alkyl Carbon Assignment The one alkyl cycloheptane carbon of 6-H-dibenzo- thiepin-11-one can be found in the upfield region of the spectrum as predicted by chemical shift tables^^’^®, model compound comparisons, and off-resonance decoupled spectra. This intense upfield signal is observed at 35.8 ppm. Proton NMR yields a singlet for the -SCH2~ protons of the thiepin ring at 4.0 ppm. Probable orientation of the dibenz[b,e]thiepin ring in which the 136 o CM o- 2C o~ CJ #« un % ro ro s o $ =C ro CM M3 -o ro CJ o un -O in >o MJ #1 MJ M3 CM \£?. CM o- o- o~ o- #» CM CM K> *•< #1 i>r M# a*< CD =c ■f r-- -O to CJ 09 to •¥ -o CM 1 5 tn in CM CM o- •*» CM :P ro ro CM CM #1 s o un s ac 09 un un ro un O'* or- CM M* CJ f"- «*• CM r- 09 09 C*M Cn ro CM K> *¥ ■U cvj s un s ro un C O C Q -o- o- oo r- M» CJ M9 ro o M* O'* m — 1 CM oo X# o- S CM ro ro * CM >*> CM un un 00 'î o m un CJ CM ro X#* ro CM r- o o ro ro ro ro ro S3 s un *•* 3= un oo CO un 09 G K> CM CD p— CJ CM o o M) CM o oo o m C 3 : ro ro ro M3 r> |3Q h O CM ro CD CM O CJ CM - O CS| CN CM r~- CM r n CM CM "cL C D CM 1*1 x k #* CN X# o CM CM 3= CM -o M3 ro M3 CD C O C Q -3- 03 ro MJ OO CJ MJ CM 09 F a irT ^ K CM ro CM ro CM ro ro ro K t in •vO 03 o s CJ M3 o- un -o X# un CM s m oo CN CM r - ro un a ® CM ro ro ro CM •** s CJ ro F a or- -o CM K > ro un o- C s X# 03 CM CM CM X# ro CM K X*X X# X# xk L_ Kl O CM X# CJ CD un o ro un CO m MO r-- o- cr- s ro CM CM CD 2 CM ro ro ro X# X# X*t j o CJ o- CM CM C^4 g CM o u n CM CM 09 O r^ 1 CM CM ro ro W) u n s CJ o ro ro -tf ro 09 CM hn If s MJ un ho CM O c> X# :g o~ cr- CM ro ro S x*x X# X*X z m XH o 3C CM S X*t u o s UJ u n W X# Ol O i UJ X# T 3 CD zxz ■o S 3 3C - o M 3 CM X # c . u 33 CA c n "O CJ CJ = x k a O on o CJ CJ X# C 3 S rM UJ era OJ X# c c CM e - PM c 2K o 3 C CM CJ 3Z x*x o o k - o as o UJ II CJ 3 : o 3: M 3 o X# o J3 o .a UJ .X3 3 CD CJ c n CJ Ol CJ CJ OJ X# OJ u ou 03 L. ro era X# xO J = U o r— x*x a I 137 I o PC X Z 0 O Xi U 0 u 0 0 O 0 •H cu Q) •r-4 4J 0 43 O 6 N 0 0 0 U rû O • H 0 Q (X 1 (0 Z vO *0 0 r-4 • (X ON 0 o o 0 0 k *0 0 W) 0 •H O 0 0 0 O (0 0 138 I MM O PC z z 0 o 43 0 Ü 0 (A 0 rH O 0 1 0 *H 00 • H 1 0 0 .w TJ CLT—4 0 0 • i4•rH z UH 4J 0 0 o *0 X o G N 0 0 ki 0 4J X O • H 0 Q CL 1 0 Z VOTJ 0 rH CL O 0 00 O U 0 0 kl T» 0 00 0 •r-i O 0 0 0 O 0 0 kl 139 A X IS 8S8 9§ 81 2-2 mm 86 « tit a s 808 888 II BB 8 8 8 : 8 8 8 r Figure 81. 6H-Dibenzo[b, e]thiepin-ll-one nuclear shift-correlated 2D NMR. 140 Æ flL I I A ooS95? GO OQOCQQ) Q'BO (DGOQ Figure 82. 6H-Dlbenzo[b,e]th1epIn-11-one homonuclear shift-correlated 2D NMR: expanded plot 141 Figure 83. 6H-Dlbenzo[b,e]thiepin-11-one heteronuclear shift-correlated 2D NMR. 142 Figure 84. 6H-Dibenzo[b,e]thiepin-11-one heteronuclear shift-correlated 2D NMR: expanded plot. 143 0 O u cd u I 0 •ri 04 0) 4P o N 0 0) 4P • ri 2 ? Cd v£> m 00 M(U 0 00 • • ri G k O u o 0) P4 co 144 oi S g CO C o 4P U Cd o #-4 r H a •rl CL O •rl 43 4J 0) •û O • N (/) 0 r H Q) Cd 4P 0 • H 00 O • H 1 CO « vO r H 0) •H vO UH 00 0 > QJ O M na d 00 •rl e 0 w 4J ü o> CL 145 J Figure 87. 6H-Dibenzo[b,e3thiepin-ll-one proton NMR spectrum. 146 CH X 2 C O *J 0 w a V c 0 1 I c a 0) 0 N • C co t> t-c j3 g) •rt C Q eo 1 -H X BO vO rH•a 0) * *H 00 **H 00 c ) Û) o *H T3 9 00 ** •H g PL 3 k W O o a co 147 ~ C ^ 2~ protons are oriented away from the shielding of the benzene ring is given in Figure 89. Nonprotonated Aromatic Carbon Assignments Quaternary carbon assignments are given by compar ison to model compound data and by inversion-recovery (Tj) and selective INEPT experiments. The signal ob served at 196.2 can be assigned to C13 based on compari son to the equivalent carbon of dibenzosuberone (195.4 ppm) as well as theoretical calculations based on mono substituted benzene models (196.1-196.4 ppm). Since CIO is bound to the alkyl -CH2" o f the cycloheptane ring it predictably would have the shortest Tj of all non- protonated carbons. A 4.4-9.0 second shorter T^ is observed for the signal at 137.8 ppm which has been assigned to CIO. Alkyl -CH2- proton frequencies en hance signals corresponding to C9,10, and 11 during selective INEPT experiments. No such enhancement should be observed for C12. Thus, C12 can be assigned to the signal at 135.3 ppm. This signal also exhibits the long T 2 predicted by its proximity to sulfur and to the ketone function. The remaining signals differ by only 0.3 ppm. Model compound comparisons also yield small chemical shift differences. C11 is assigned to the 148 G 0 1 I c 1-4 a 0» a> ja 0 N e « j•HO Q 1 % vO o C o (d E w o O' 00 « w 9 W) (B4 149 signal at 141.1 ppm on the basis of inversion recovery data which yields a 1.2 second longer Tj value for this signal. This would be anticipated by the proximity of Cll to sulfur and to the ketone group while C9 is ortho to the alkyl function. Monoprotonated Aromatic Carbons Monoprotonated aromatic carbon shifts are given by homo- and heteronuc1 ear shift correlated 2D NMR and selective INEPT experiments. Multiplicities are also indicated by inversion recovery data of approximately 3.5 seconds for doublet -CH- functions bound to a single -CH- and approximately 2.5 seconds for -CH- triplets bound to two -CH- groups. The selective INEPT technique allows clear assessment of C5 at 126.0 ppm. Homo- and heteronuc1 ear shift correlated 2D spectra allow ring assignment and proton carbon correlation. Knowledge of doublet and triplet pairs for each ring as well as prior assignment of ring A C 5 allows assignment of ring A C 8 to the signal at 129.3 ppm. Monosubstituted benzene models predict C7 upfield of C6 by about 5.7 ppm. A 4.2 difference in chemical shift is observed for the signals assigned to the C6-C7 pair. C7 can thus easily be assigned to 127.8 ppm while C6 is 132.0 ppm. A similar shift difference of approxi 150 mately 6.5 ppm is observed for the ring B C2-C3 triplet pair corresponding to an observed difference of 6.8 ppm. Signals at 132.3 and 125.5 are assigned to C3 and C2, respectively. A 3.8 ppm difference in chemical shift is observed for the C1-C4 pair. Monosubstituted benzene model data on concurrently analyzed samples yield esti mation of Cl 0.6 ppm downfield of C4. A slightly shorter Ti is observed for this signal (132.9 ppm) which is assigned to ring B Cl. Ring B C4 is assigned to the signal at 129.1 ppm. Carbon-^ NMR of Amitriptyline Hydrochloride Carbon NMR data is presented for amitriptyline hydrochloride. Figure 1. X-ray crystallography of di- ben zo [ a ,d ] eye lo hep tane derivatives yields a crystalline structure in which the olefinic substituent is fully extended away from the ring^^. In solution, the alkyl- amino olefinic group is oriented above the most adjacent aromatic ring^^. Figure 90. A low barrier to intercon version for the dibenzo[a,d]eyeloheptane ring of approx imately 15.6 kcal/mole has been reported for amitrip tyline-type drugs^®. A proton NMR analysis of the up field amitriptyline signals yields two somewhat broad signals and two multiplets between 3.3 and 2.7 ppm. 151 e X u a •H kl U •ri B C 0 <4 e k 0 0 O' 01 k 9 60 152 These signals are not well resolved. It is possible that the somewhat broad signals may correspond to the dibenzocycloheptane -CH2CH2- protons and that the mole cule might be flexing during analysis; however, better resolution between signals would be necessary for pre cise estimation. Carbon^^ NMR shift assignments (Tables 19 and 20) for this compound was made by comparison of model com pound chemical shifts, off-resonance data (Figures 91 and 92), inversion-recovery (Tj) determinations, homo- and heteronuclear shift-correlated 2D NMR spectroscopy (Figures 93, 94, 95, and 96), and selective INEPT exper iments. Bruker AM-400, WM-500, Nicolet NT-270, and Varian FT-80A spectrometers were used for the analysis. Carbon^^ NMR spectra are given in Figures 97 and 98. Proton NMR spectra are presented in Figures 99 and 100. All spectra were obtained using deuterchloroform and tetramethy1si1ane (TMS) as internal standard. Alkyl Carbon Assignments The carbon chemical shift ass ignment s can be predicted by using known substituent chemical shift tables 39,40^ off-resonance data, and by comparison to 5-methylene-5H-dibenzo[a,d]eyeloheptane NMR data. The intense upfield signal (42.5 ppm), an off-resonance 153 Table 19. Amitriptyline Hydrochloride Alkyl Carbon Assignments. (CH312N- -CH2N- -CH2- -CH2- aiitriptyline HCl 42.5 56.8 24.4 33.6 32.0 Spectra were obtained using a Varian FT 80-A spectrometer, 100 mg/ml CDC13 solutions and tetramethylsilane as internal standard. 154 CM M3 CM r o 'D M3 t o t o o o i n o C CM o l4 I t o t o CM CM I, CO i n t '» t o i n O' •M ■ o o o t o - CM o - CM Hi r - CM ' CM -D m 1 CM CM MM 1 ■| ", o - UT CM r*M, M3 I f < r r - ' 1 o in CM CU 0 0 l O Ch* O t''. CM o 1 r o CM MO M3 c a . 1 «•* CM CM CM r o CM M3 CN i n r o M 3 r o V ■4M CO o o l O t o CM < h = OJ o oo C M o (_J OQ CM o r o h'-. r o 1 CM 3 O 1 t a I ", CM b~a t o M 3 r o i n O' ro 1'' , ", CM b'J o~ CO »«*- o o M-» OO < r OO I 11*3 Ch- 3 = Hi CM CO -mf 0 0 CJO' m 1 C M o r~ 1 CO CM CM c p x a C M 1 C M 1 CM a i n Ch CM r - . m O' S CO i n r-s. o o o CM CD o i n i n CM CM wi 1 C M o o CM C-4 CM CM a "l ", i n m Ch. Ch. CM M 3 M3 0 3 CD 1 0 3 • o r - i n OI O CD o Ch- U*3 CM o c > r~. O XI r-Z CM l O t o a -e f o J i n CM « r r-4 OO ■ ^ o CM o CO o O p o CD < ? CM 1 C M r o ÜO CM % o CM CM OO CM 1 CM o CM o Ch- CO l O O O CO C M o C D 1 CM CO CM 1 C M f O r o i n i n Ch* C M Ch- M 3 1 r o I f i n t o ->o t-~ i n 1 CO o o CM o o t~~ 1 O r o O ' o O' 2 : r o 1 1 C M 1 r o 1 ^ “* i n CM 'D 1 « f- CM CM O ' r o CM 1 i n o o C--4 i n 1 1 o O' o o S Y 5 ’ 1 I f to cr>- CO -«r < * CJ 1 o o u 'a t o t o C" o o t o t o *"4 & * ^ ^ I# Ch o o s 1 0 3 M3 1 i n i n -, U1 1 c a CL CM Q. CU XICO *-t Ü1 CJ CN> >** < r U J L. CM o z O m 1 Oi Oi o o k - 2 = 1 o I I I I _l U i 3 C k_ s C 1 o o LL. 3K c a . > » C # _ l a c g O o «K k» i . s i l i i l i 1 o o LU = 3 g OI OJ o 1 OJ HI J C t — M-» I s m c u C_3 OJ m O u k < c < r c n S 155 s Z: m 1-4 oa w CO o • H u o f-4 o o u T) OJ a •r4 r 4 0 :3 4U H CL *J •H O 0> M 4U p - • H CA e < (A S % G O mû U cO u (A 1-4 CJ to 'O Û •r4 60 • H O (A r4 Xi TO o r4 o CJ M •H na Û mû > O CJ 13 û •r4 r —1 8 >» 3 4J M Û4 4J • H O M CJ 4J CL •i-l (A 8 1 Figure 93. Amitriptyline hydrochloride homo- nuclear shift-correlated 2D NMR. 158 Figure 94. Amitriptyline hydrochloride homo- nuclear shift-correlated 2D NMR: expanded plot. 159 Figure 95. Amitriptyline hydrochloride hetero- nuclear shift-correlated 2D NMR. 160 Figure 96. Amitriptyline hydrochloride hetero- nuclear shift-correlated 2D NMR: expanded plot. 161 0 O W 0 o OJ 'd M O r-l o o u •d -d d 0 >% 4J 04 8 3 < ON d w d ÔÛ • •H B t*4 d w 4J o Q) CU (0 162 0d X X 0 U o <ü *0 4J U d 0 8 u O □ k OJ 0 d M Q) 0 O 0 0 1-4 (0 X c e i O S o Z % M ss *d < >» o I o o rd m 00 0) 1 0 Z H k w M 0 4J1-4 <ü 0 0 Ai •H 0 0 d M 00 Wi 0 "H m > •rH 00 G *d 0 *0 < f-4 0 00 ^44 ON 0 0 o *4 *d d 00 •• 8 0 d w *j u 0 0 0 163 o i Z z c o *J o a 0) ■o •w k O O o k •o 9) C X 4J a 1-1 k E < o\ OS V k 3 60 • #4 4J V 0 a o 164 06 £ Z e o o k a 9! •o «w k O —4 x: u o k •O X x: « e X u • a « •H r-4 k • « O -k O «k rk C > « O k t3 3 00 •• •H E (k 3 u V a (0 165 decoupled quartet, can readily be attributed to the N,N- dimethyl carbons. The less intense off-resonance de coupled triplets at about 24.4 and 56.8 ppm can be attributed to methylene and N-methylene, respectively. The remaining methylene groups of the cycloheptane ring (overlapping off-resonance triplets) at 33.6 and 32.0 ppm can be identified by comparison to the same carbons in 5-methy1ene-5H-dibenzo[a,d]eyeloheptane (33.3 ppm) as well as by comparison to chemical shift tables and previously reported carbon enrichment experiments^®. Orientation of the alkylamino olefinic substituent above the most adjacent aromatic ring has been shown for dibenzota,d]eyeloheptane derivatives^®. Conformation is given in Figure 90. Nonprotonated Aromatic and Olefinic Carbon Assignments Locations of quaternary carbon signals are given by off-resonance decoupled spectra. Assignments are given by inversion recovery (Tj) and selective INEPT experiments and comparison with model compound data. Assignment of C13 by carbon^^ enrichment (146.9 ppm) has previously been reported^®. A spectrum of the downfield carbon signals and chemical shift data are presented in Figure 98 and Table 21. Selective INEPT experiments 166 allow assignment of C9-C12 at 140.2-139.0 ppm for ami triptyline hydrochloride. Inversion recovery experi ments also indicated pairing of T^ values and comparison to 5-methy1ene-5H-dibenzo[a,d]eyeloheptane data (09,12,141.2 ppm) also leads to this assignment. An upfield position is predicted for the carbon c is to the olefinic alkylamino group. Therefore, C9 is assigned to the 140.2 ppm signal while the 012 carbon corresponds to the signal at 139.0 ppm. The remaining pair, OlO-Oll correspond to the signals at 139.2 and 137.0 ppm. Following the proposed conformation^®, 010 is postulated at the more downfield deshielded location at shorter Tj. Monoprotonated Aromatic and Olefinic Oarbons Monoprotonated carbon shifts are defined by homo- and heteronuc1 ear shift correlated 2D NMR experiments (Table 20). Peak assignments are shown in Table 21. Heteronuclear 2D experiments yield assignment of 016 at 123.8 ppm. Similar assignment was also given previously by carbon enrichment^®. Homonuclear 2D experiments allow estimation of ring components. Two doublets, each adjacent to a nonprotonated carbon as well as a monopro tonated carbon, and two triplets, each adjacent to two monoprotonated carbons are assigned for each ring. Heteronuc1 ear 2D experiments yield correlation of proton 167 multiplicity with carbon chemical shifts. Results are given in Table 20. Comparison to 5-methylene-5H-dibenzo[a,d]eyelohep tane ring assignments for Cl,8 and C4,5 yields a pre dicted value of 128.1 and 128.9 ppm, respectively, for these carbons. However, the ring B Cl carbon should be shielded due to its position beta to the olefinic group and should exhibit a chemical shift upfield of the carbon signals corresponding to the other proton doub lets. This carhon has been assigned to the chemical shift at 127.6 ppm. The remaining chemical shift common to that ring which is correlated to a proton doublet can thus be assigned to C 4 at 128.5 ppm. Ring A C5 should exhibit a similar chemical shift to the ring B C 4 carbon. Thus, C 5 has been assigned to 128.4 ppm. The remaining chemical shift correlated to a proton doublet for that ring can be assigned to 130.2 ppm at a predictably deshielded location relative to the chemical shift assigned to Cl. Comparisons of 5-meth yl ene-5H-d iben zo [ a ,d ] c yc lo hep tane data for C2,7 and C3,6 at 126.2 and 127.7 ppm yield assignments for these carbons at 126.15-126.24 and 128.2-127.7 ppm respectively. Heteronuc1 ear 2-D correlations of carbon chemical shifts to proton triplet pairs corresponding to ring A and ring 168 B allow assignment of C2 at 126.15 and C7 at 126.24 ppm while C3 and C6 are assigned to 128.2 and 127.7 ppm, respectively. Carbon— NMR of Nortriptyline Hydrochloride Carbon^® NMR data is presented for nortriptyline hydrochloride. Figure 1. X-ray crystallography of dibenzo[a,d]cycloheptane derivatives yields a crystal structure in which the olefinic substituent is fully extended away from the ring^^. In solution, the alkyl amino olefinic group is oriented above the most adjacent aromatic ring^®. Figure 90. A low barrier to intercon version for the dibenzo[a,d]eyeloheptane ring of approx imately 15.6 kcal/mole has been reported for amitripty line-type drugs^®. Proton NMR analysis of nortriptyline is similar to that of amitriptyline. Carbon^® NMR shift assignments (Tables 21 and 22) for this compound were made by comparison to amitripty line chemical shifts, off-resonance data (Figures 101 and 102) homonuclear shift-correlated 2D NMR spectroscopy (Figure 103), and selective INEPT experiments. Bruker WM-500 and Varian FT-80A spectrometers were used for the analysis. Carbon^® NMR spectra are given in Figures 104 and 105. Proton NMR spectra are presented in Figure 169 Table 21. Nortriptyline Hydrochloride Alkyl Carbon Assignments. CH3N- -CH2N- -CH2- -CH2- nortriptyline HCl 32.4 48.5 25.7 33.7 32.0 Spectra Here obtained using a Varian FT 80-A spectrometer, 100 mg/ml CDC13 solutions and tetramethylsilane as internal standard. 170 1 r-s e s S 3 r— r o r o 1 *4" r ô •«r ! e s e s S 3 r o e s e o e s e s ira e s 1 ira e s s a 1 M e s - es c o r-~ r-i S 3 i < r r-4. o s a e s e s k O s a - 0 e s e s e s 1 1 —4 es >4 3= 0 s a c o ««r - S 3 44* r ~ Y = g e s e s y -* - •<0 S 3 ira S 3 i s a «X r s 1 • • »¥ • 0 r - >1 O r-Z r o O r o •<-« I — « ^ 4* r - r-» e s e s 1 o o 0 e o r o - r o 1 o - e - 7 - 0 3 e s e s es un ro cr* co 1 "4* e s c o e > < s c o 1 ira 1 e s e s oo a#- o o o o rs o o I— I 1 o ô e s c o 0 0 0 3 e s — ^ s : 1 e s e s e s e s \ -- un es cr- — 4 es I— S3 r o 0 3 . • ■ tio r-k » » " 0 0 u a 0 0 0 0 g ? Y ^ ? Y 5 e s •-» -, u o cr~ cr- e s cr- i-k S 3 4* a c e s < C 0 0 1 S3 - I— . — 4 U"] ■ ■ »4*CJ 0 oo ■ # ■oor~«>4* b O 1 es o o I rs * 0 0 —« I I e s ---# # 1 r o r o es es — 4 e s 0 0 o " ’ § : r o r o -, uo es S3 ^ es es «« 4* CJ e s e s e-j oa ■ • o es - ■ ■ *î* 0 a oo o • a o o c o >•( oo es I o»•=o m I I es 4* o ~ Er es —^ I —^ 4* r o r o lOÜ"3 0*-C5'*C’4a**-*-»-0P 4« 1 r o t o 0 S3 a r-~ *-» ü") » a * «# 1 "S" r o a oo , • a o o r~. # r-. es o o r-' i es 4* 0 r o c o 0 Ch- es — 4 I I r-4 — < 4* rr* r o -* - h- m es o —i es -o 4« 1 «f- e s 0 o ~ r o e s 1 ira "1 a o es 4i cr- o > 0 cr- 7 R ' ' ^ ï 1 ^ KT" S 4* 4« 1 o o ira r o S 3 0 - 0 0 ira •«r S 3 1 u a -, Z lA 1 Cl . CO S.— a—I U"3 iCJ es î4» LU LU e s in es ac — % •as. z ac ^ ~o ro 4# 1 Ol eu LU k_ « o C J ni C J a n m 4* a e - j rd CJ es u — s CJ i_i 4* LU g — 1 =c -rk an es 4* CJ CJ -M CJ ac su 4* ex. n üTi 0 1 II C J Qi 4* a c c =a es 3= c. e s es c. 4« 0 0 r— 0 o c S eu a: S3 0 = 3: o 4* 1 o x a a LU J 3 ai 0 m CJ CJ oj CJ CJoi4« 1 Oi O j m m m 3 C OJ 0 ira < c era a = 171 iw o X X 0 o u cd o > «fi OJ fi l ! «•o d • -H CL O fi f-( O o 0) d M 'd fi bû 0) "H u k fi cd fi o (0 0> u 172 I Bi X ts m pH 0 O xt M CO O • CO 0) rH T ) CO •»-* G W 60 O ‘H f-i CO 4: o o ^ w g (V o c -o If =1 0) • «-I CS Cu O 3 O u 0) 0) k *a 3 60 0> •H U o CO G O CO 0> u 173 Figure 103. Nortriptyline hydrochloride homo- nuclear shift-correlated 2D NMR: expanded plot. 174 ei X X pHCO a o pO u (0 u (U 'O •H U o fH 43 O o u >» QJ c ■M a •H M 4J M O Z < - o Q) M 3 60 •H G Ih 3 U o OJ a CO 175 % Z CO X u CO o OJ •H u o rC o o w na 43 W c A CO c 60 •H M CO O z na . o> in *H O *44 m4 a 3 0) o u -o 3 •H60 ••G pE< 3 u 4J U 0) CL CO 176 106. All spectra were obtained using deuterochloroform and tetramethyIsilane (TMS) as internal standard. Alkyl Carbon Assignments The carbon^^ chemical shift assignments can be predicted by using known substituent chemical shift tables 39,40^ off-resonance data, and by comparison to amitriptyline and 5-methy 1ene-5H-dibenzo[a,d]cyc1ohep tane NMR data. Off-resonance decoupled triplets are observed for chemical shifts at 48.5 and 23.7 ppm. The remaining off-resonance signals overlap significantly and chemical shift assignments are made by comparison with the above model compounds. The off-resonance de coupled triplets at about 25.7 and 48.5 ppm can be attributed to methylene and N-methylene, respectively. The remaining methylene groups of the cycloheptane ring (overlapping of f-resonance triplets) at 33.7 and 32.0 ppm can be identified by comparison to the same carbons in 5-methy1ene-5H-dibenzota,d]cycloheptane (33.3 ppm) and amitriptyline (33.6, 32.0 ppm). The N-methyl carbon is assigned to the remaining chemical shift at 32.4 ppm. Orientation of the alkylamino olefinic substituent above the most adjacent aromatic ring has been shown for dibenzo[a,d]cycloheptane derivatives^^. Conformation is given in Figure 107. 177 pà X X c o *J 0 u a 01 •o •H k o #4 .c o o w •o V c 4 J « o. n •H U <0 4 J C kO -*4 Ô O % m • Ci \0 o *w rH C 4) 0 *4 *0 3 60 ** •H H k 3 k H U a m 178 01 c u a k U k O C 'W o C o 0) E k, O <4-1 C o u o 0» w 9 00 179 Nonprotonated Aromatic and Olefinic Carbon Assignments Locations of quaternary carbon signals are given by off-resonance decoupled spectra. Assignments are given by selective INEPT experiments and comparison with amitriptyline data. Little difference in chemical shift is observed between amitriptyline and nortriptyline for these carbons. A spectrum of the downfield carbon signals and chemical shift data are presented in Figure 105 and Table 24. Selective INEPT experiments allow assignment of C9-C12 at 140.4-139.1 ppm. Comparison to amitriptyline yields assignment of C9 to the 140.4 ppm sig nal while the C12 carbon corresponds to the signal at 139.1 ppm. The remaining pair, ClO-Cll correspond to the signals at 139.1 and 137.0 ppm, respectively. Monoprotonated Aromatic and Olefinic Carbons Monoprotonated carbon shifts are defined by homo- nuclear shift-correlated 2D NMR experiments (Table 25) and by comparison to amitriptyline data. Peak assign ments are shown in Table 22. C16 is assigned by comparison to amitriptyline data at 124.4 ppm. Down field proton NMR is essentially the same for both ami triptyline and nortriptyline samples. Carbon NMR chemical shifts of the downfield signals differ only 180 slightly in ppm value. Differences may be due to the orientation of the alkylamino olefinic group above the most adjacent aromatic ring. Amitriptyline is N,N- dimethyl substituted whereas nortriptyline is N-methyl substituted. Assignments are based on amitriptyline correlations and are presented in Table 24. Carbon-^ NMR of 5-Methvlene-5H-dibenzo[a.d]cycloheptane Carbon^^ NMR data is presented for 5-methy1ene-5H- dibenzo[a,d]cycloheptane. Figure 1. This compound dif fers from both amitriptyline and nortriptyline in that the olefinic carbon is not substituted. Carbon NMR shift assignments (Table 23), were made by comparison of model compound chemical shifts, off-resonance data (Figures 108 and 109), heteronuc1 ear shift-correlated 2D NMR spectroscopy (Figure 110), and selective INEPT exper iments. Bruker WM-500, Nicolet NT-270, and Varian FT- 80A spectrometers were used for the analysis. Carbon 1 3 and proton NMR spectra are given in Figures 111, 112, 113 and 114. All spectra were obtained using deutero chloroform solutions and tetramethyIsilane (TMS) as internal standard. Alkyl Carbon Assignments The signal corresponding to the two alkyl cyclo- 181 ^ U~> li*3 »-• -O •4“ »-• CN # • O lO ■ • • CO ho - • o- o CvJ — » - o — H I M ) U"ï hO -O Ki H* ^ CM - r o ■«»• " • " CNOO O • r"? • ■ CS I H* «» H- t o Kt - o t o t o CN CO IN r-4 ? t o 1 - o H- 04 t o Ç> ? ? r~- --0 uzi s o CN <=><=> r-^ OJI o -O •*« CJ V o . H t o r o . '1 : 3 •%} " * e O CN Ü-1 H • C 4 Ü"> CnI t o I N loL r-Z 04 04 in o~ 04 3= o ; -43 CO t o CJ «C t--. t o cn 04 «=> o - O: 04 c - 1 04 04 ~o 3C CO •43 04 -«"4 04 CJ •V t 2 o 03 t o 04 c> 04 O": C-4 •** SP. ni «# O •Xi X t o o - o CJ «V •V na 00 H* 04 o 03 c-4 e g S 04 SP. ■§ Oi CO 04 CJ 04 oy j : lO 04 o> t o N s cr- CJ 04 04 ü~i r-j •4* •» C-4 04 t o O o O' s 04 ? cr- 03 , -, %CJ OO u*a m t o h-3 O- S OD 04 o -o o - 04 o 04 o . « c cu 1 04 «*» ÜO s «*• ü*a Î m Ul 1 rn t o CO •vO =c t— 04 S ", Qi w -43 «# 13. ■“ -, x z un CJ 04 LU OJ X c . t o =c X -JD Ol cu Ol S S 3 'i "S -43 u na CJ ca. TO " o a C_J 04 CJ Cl > - L. nî XX 04 o > 04 c3 o CJ X m H t o OJ II CJ Ol c ■H O 0 4 X 04 04 L- o fO w =c •43 o XX O o O in CJ CJ m CJ CJ 111 § na na JS J= Cl t— 1— It»% CO :£ S 182 en a o WQ U ca o OJ a CO 4J CL 0) o o >i o -o CO 0 N 0 Q) JD •H G •V 0 1 w 4-1 m o I Q) 0) A a (0 0) I-» 'O Q) 00 O o 0 0 0 O CO 0) 60 M •H I (44 133 en 4 0) CO CO M4 as o 60 k •H I - i 184 Figure 110. 5-Methylene-5H-dibenzo[a,d]cyclo- heptane heteronuclear shift-correlated 2D NMR. 185 CO »H 0 O u CO Ü 0) 0 CO CL (U o r4 u % o -o (0 0 N 0 Of •H 1 m# I % rC u 0) S I l A Q) e H 0 0 U bO w •r< O k 0) CL CD 186 en 0 O U 0 O 0) 0 0 4J CL 0 *0 O »—1 o >> u *0 0 O N 0 0 Xi • H *0 M i n 1 co 0 f—4 0 0 0 0 r4 60 PO • H Æ 0 4J 0 -0 r 4 S 1 Q) i n •H 0) e k 0 0 U 60 4J •H O PL 0> a, CO pd % % 187 « C (8 a « JS o 1— 4 U >1 u m TJ 0 0 N C 0 X i •H •O 1 S uo I 0) G 0 ►. jc w « z I iri B S • k ro *J r-H O r-4 U a « m k 3 06 tes -H z tk c 0 kl o k a 188 01 e E 9 W < f 4J rH V fH 0» Ou 01 » k, 9 OC 60 Z •H z k c 0 u 0 H 189 heptane carbons of 5-methylene-5H-dibenzo[a,d]cyclohep tane can be found in the upfield region of the spectrum as predicted by chemical shift tables^^’^®, model com pound comparisons and off-resonance decoupled spectra. This upfield signal is observed at 33.3 ppm. f Nonprotonated Aromatic Carbon Assignments Locations of quaternary carbons are given by off- resonance decoupled spectra. Quaternary carbon assign ments are given by selective INEPT experiments as well as by comparison to model compound data. A spectrum of 1 5 the downfield carbon signals and the chemical shift data are presented in Figure 112 and Table 23. Selec tive INEPT experiments at the frequency corresponding to the olefinic protons allow assignment of C9,12 at 141.2 ppm. This assignment also corresponds to theoretical calculations based on monosubstituted benzene models of 141.5-137.4 ppm. 013 can be assigned by comparison to model compound data. Amitriptyline and 1,1-dipheny1- ethylene have 013 signals at 146.9 and 150.2 ppm, re spectively. A theoretical value based on substituted ethylene models^® of 147.5 ppm is also obtained. Of the remaining two quaternary carbon signals only the signal at 151.9 ppm approximates these comparisons. The re- 190 maining signal at 138.3 can be assigned to CIO,11. Since CIO,11 is bound to the alkyl -CH2CH2- of the cycloheptane ring it predictably would have the shortest Tj of all nonprotonated carbons. Because of instrument limitations inversion-recovery experiments were not realized for this compound. However, this signal is significantly more intense than those observed at either 141.2 or 151.9 ppm. A more intense signal would be predicted for carbons of shorter Tj. Monoprotonated Aromatic Carbons Monoprotonated aromatic carbon shifts are given by heteronuclear shift correlated 2D NMR and selective INEPT experiments. Assignment of C16 at 117.3 ppm is also given by off-resonance decoupled experiments in which this carbon predictably yields a triplet multipli city. The selective INEPT technique in which methylene proton frequencies are used allows clear assessment of C4,5 at 128.9 ppm. Heteronuclear shift-correlated 2D spectra allow proton carbon multiplicity correlation. Table 23. Knowledge of doublet and triplet pairs as well as prior assignment of C4,5 allows assignment of Cl to the signal at 128.1 ppm. This corresponds closely to mono sub St ituted benzene models which predict C 4 at 128.0 and Cl at 128.2-126.1 ppm. The remaining signals at 191 127.7 and 126.2 ppm correspond to C3,6 and C2,7, respec tively. These have been assigned based on comparison to monosubstituted benzene models which yield values of 1 27.6-1 27.5 ppm for C3,6 and 1 2 5.7-1 25.6 ppm for C 2,7. Carbon-^-^ NMR of Dibenzosuberone Dibenzosuberone, Figure 1, is assigned based on Sadtler^^ spectra and on theoretical calculations based on benzophenone and dibenzyl concurrently run and liter ature model compound data as well as selective INEPT experiments. Varian FT-80A and Bruker WM-500 instru- 1 1 ments were used in the analysis. Carbon NMR shift 1 1 assignments are given in Table 24. Carbon NMR spectra are presented in Figures 115 and 116. Proton NMR is presented in Figure 117. All spectra were obtained using deuterochloroform and tetramethy1si1ane (TMS) as internal standard. Alkyl and Nonprotonated Carbon Assignments The -CH2CH2" carbons can be assigned to the up field position at 34.9 ppm by comparison to chemical shift tables^^'^O j to dibenzyl. The carbonyl carbon is assigned the most downfield signal at 195.4 ppm by comparison with ketone data^®. The remaining non protonated carbons are assigned to the less intense 192 •<-» C-4 cc r U"J ITÎ -43 »-i in C M C 4 hô h-5 C M C M un CM -kO fO C--4 ^ *♦« un in CO o~ m —4 - O *♦. C J "-«ro •*»% CM3C u") ~o o- m CM rs. M3 % 3= UTi f*«k - Û f-> K > r-k CM in -o in l C M ICÏ •*« . c T U") C M M 3 C M C4 I* CM in I CM u"3 in ^ m — 4 in • «a* CO O'* « in R in M3 M3 in CM CM M3 M3 «T M3 —4 M3 M3 • CM O O • • - tn CM c*4 rn m r o CMO' CJ CM "cf- CM CO * OJ 0-4 >*• CO C M r n r o H* O r K> O " r*> t o * CTi i in m < C CM O'- u n M 3 CJ M 3 X u n o 04 O-J CM CM ru O' CJ h O CO O o 0 4 r n CO CO OJ CM s % " a in !¥ OJ S u n CM 3= = c IC c« CO k O ■43 CJ X OJ & in "8 C.3 CM ■n CJCM 4« - a *a 3 C tk. k. Qj g c CJCJ o a 0 4 II C M 11 C M c C_J 3 : CJ = c * CM c E. o C_J CJ k. k- un i n o u n u n o o u in 3 = =c OJ = c i-q ra •n - a -a 1— C J s K- CJ X s 193 G 0 M U O 0) O. (0 qd Z Z 0 o u 0 o 0) 0 O U (U 0 o N 0 0) (U M 0 60 •H El 194 G 0 w O 0) 04 00 z z Z CA 0 O ,0 W 0 U VO 0 »H 600 «H 0) CO kl 0 T3 60 * H • H 0) 1*4 ' H M-i g O *0 195 E 3 k kl U 01 a m a z 2 C O kl 0 k a 01 c 0 k 01 45 3 m 0 N C 01 4 5 01 k 3 eo 196 signals at 141.9 and 138.6 ppm. These correspond to CIO,11 and C9,12, respectively, based on theoretical calculations and Sadtler^^ comparisons. Monoprotonated Carbon Assignments Model compound calculations predict C3,6 at 132.1 ppm whereas the remaining carbons are predicted signifi cantly upfield of this location. These carbons have thus been assigned to the signal at 132.3 ppm. The theoretical value obtained for Cl,8, 129.8 ppm can be associated with the signal at 130.54 ppm. The remaining upfield signals at 126.6 and 129.3 ppm are assigned based on model compound comparisons of 125.7 and 128.2 ppm and Sadtler^^ references to C2,7 and C4,5, res pectively. The assignment of C4,5 is confirmed by se lective INEPT experiments in which this signal is en hanced when the proton frequency corresponding to the cycloheptane -CH2CH2- protons is used in the selective INEPT experiment. Spectra are given in Figures 115, 116, 117, 118, and 119 and data is reported in Table 24. Carbon-^ NMR of 10.11-Dihvdro-5H-Dibenzo[a.d]cvclo- heptane The assignment of 10,11-Dihydro-5H-dibenzo[a,d]cy cloheptane, Figure 1, is based on theoretical cal 197 culations using concurrently run dibenzyl and diphenyl- methane models as well as literature model compound data. A Varian FT-80A NMR was used in the analysis. Carbon^^ NMR shift assignments are given in Table 25. Structure is presented in Figure 118. Carbon^^ NMR spectra are presented in Figures 119 and 120. All spectra were obtained using deuterochloroform and tetra- methylsilane (TMS) as internal standard. Alkyl and Nonprotonated Carbon Assignments The -CH2CH2- carbons can be assigned to the up- field signal at 37.9 ppm by comparison to chemical shift tables^^*^® and to dibenzyl. This signal is approximately twice the abundance of the signal assigned to the -CH2~ group. Nonprotonated carbons are assigned to the less intense signals at 139.2 and 138.9 ppm. These correspond to CIO,11 and 09,12, respectively, based on theoretical comparisons. Monoprotonated Carbon Assignments Cl,8-C4,5 and C2,7-C3,6 signal pairs were observed to merge into two broad signals during the course of analysis. Four separate signals were observed when spectra were accumulated for approximately 200-600 scans. Lengthier analysis (approximately 6000-9000 scans) pro- 198 r*^'O un to CM •UO 1 un o o CM •o C4 CM o o Ü3 M3 CM oo CM OO CO CN o to s 1 Ü-3 , -o C". CM oo 1 CM CO o rs o CM Ï2 1 cr- wrt M3 m CM •o *1 un O 00 O CM CM o 1 m CM CO ry CM 1 un œ 3= O' CO o oo CJ rs o GO CM CM r-" CM CM ac ro CJ 1 o- O' CM CM 1"'.-o CM 1 to o oo X C> CM un CJ CM o CM un CM CM S m CO O' to OO oo CM r". g 1 •o CD 5 &• un CM un CM to CM o un CM CM ui CM :S « C O N G 0) JÛ T3 I X m I 0 k, •o % Æ •H A 1 e o <9 kE O «w e o o 00 « k 3 eo 200 c 0 w CO V 0) c 4 4J a 4 X 0 ^4 V X V *t3 4 0 N C 4 X T3 1 Z m 0 CO (0 w c C T3 4 4 >, Ü O X CO QO •H O O O 1 O O fH O rH ON O ## fH 4 X Cf • (0 3 W to •H O U4 0) a (0 z z 201 m G 0 X M 4 Ü 4 C 4 W a 4 X 0 o >, V •o 4 0 N G 4 X •H -O z m 0 » 4 w t c C •o m 4 4 ►% r-l VU X 4 4 4 •H G Q t o o O 1 •H O O fH 4 O X rH cr\ -o O ^4 rH 4 4 X H M4 « c O > CM 0 fH -o 4 14 4 3 U to W •H U u^ 4 a » PU X z 202 duced only two broad signals. Broadening of the -CH2CH2- signal at 37.9 ppm is also observed during the longer analysis. The conformation of this model as determined by X-ray crystallography^^ is shown in Figure 118. It is probable that the molecule is flexing at the cyclo- heptane -CH2CH2" carbons. Determination of the barrier to inversion of this molecule, which is apparently low, awaits temperature studies which are outside the scope of this thesis. Theoretical calculations for Cl,8-C4,5 and C2,7-C3,6 pairs yield values of 128.8-128.1 and 125.6-125.8 ppm, respectively corresponding to 129.5- 128.9 and 126.5-126.0 ppm signals. Cl,8 is assigned to the most downfield signal at 129.5 based on more down- field theoretical values. The remaining C4,5 is assign ed the signal at 128.9. The remaining pair of signals at 126.5 and 126.0 ppm are assigned to C 2,7 and C3,6, respectively. However, ppm differences based on theoretical values obtained on concurrently run models as very slight and assignment of these pairs can only be tentative. Selective INEPT experiments could be used to define assignment of Cl,8 and C4,5 signals. C2,7 and C3,6 could not be precisely located by this technique. NUCLEAR MAGNETIC RESONANCE ANALYSIS OF THIOXANTHENE DERIVATIVES Carbon-^^ NMR of Z- and E- Thiothixene Carbon^^ NMR data is presented for Z_- and E^thio- thixene, Figure 2. X-ray crystallography^^ of thio thixene indicates a structure in which the molecule is bent at the sulfur and olefin carbon so that two benzene rings are oriented at an angle of 142 degrees from each other. Figure 121. The olefinic substituent is above and away from the inverted "V" formed by the thio- xanthene ring. Carbon^^ NMR data also indicates this olefinic substituent orientation since only slight differences in ppm are observed between isomers for each carbon of the alkylamino chain. Similar results are found for proton NMR. Conformational differences between monosubstituted benzene models and the tricyclic thioxanthene skeleton are severe thereby making model compound comparisons difficult. Anisotropic shielding may, for example, account for the significant upfield shift of the signal assigned to the C13 olefinic carbon. Isomeric effects and geometric effects due to ortho substitution are also not addressed by model compound calculations. There- 203 204 « E O m V e 9) X ü ) ^ V « <4-1 e c o tl V X X c -4 .H O X X ■M U u *J O 0 es •H •H e X Xi u u u o I I «w N | U | O • • o « Æ 0) M S 60 205 fore, assignments are predominantly based upon esti mations using other techniques. Carbon^^ NMR shift assignments (Tables 26, 27 and 28) for these compounds were made by comparison to off- resonance data, (Figures 122, 123, 124, and 125), inversion- recovery (T^) determinations, homo- and heteronuc1 ear 2D NMR spectroscopy (Figures 126, 127, 128, 129, 130, and 131), selective INEPT experiments, and, where appli cable, by comparison to model compound chemical shifts. Bruker AM-400, Nicolet NT-270, and Varian FT-80A spec- 1 ^ trometers were used for the analysis. Carbon NMR spectra are given in Figures 132, 133, and 134. Proton NMR spectra are given in Figures 135, 136, and 137. All spectra were obtained using deuterochloroform solutions and tetramethylsilane (TMS) as internal standard. Alkyl Carbon Assignments The carbon^^ shifts (Figure 134) for the alkyl carbons can be predicted using known substituent chemi cal shift tables 39,40 j off-resonance decoupled data. The intense upfield signal (37.9-38.0 ppm), an off- resonance decoupled quartet, can readily be attributed to the N,N-dimethyl carbons. The less intense off-reson ance decoupled quartet at 46.0-46.1 ppm corresponds the 206 Table 26. Thiothixene Alkyl Carbon Assignments. (CH312N- CH3N- -(NCH2)2- -(CH2N12- -NCH2- -CH2- Z-thiothixene 37.9 46.0 53.1 55.1 58.0 27.5 E-thiothixene 38.0 46.1 53.2 55.2 58.2 27.5 Spectra were obtained using a Varian FT BO-A spectrometer, 100 mg/ml C0C13 solutions and tetramethylsilane as internal standard. 207 o a s CM o r o «-9 C D OO CO CJ 0 3 #9 r o r o CM t o C M CM CM f CM s £ #« s c C M r o r s e n 0 3 Cr- o o CO M 3 #1 CJCO M 3 "oi u n 49 5 9*9 M 3 - 2 ITS t o 49 C M CM CM 49 o 9*9 Q CM IM o o s a s t o r o o o o o C D u n u n • o r o r o M 3 49 C J 0 3 M 3 "ttl 49 C M C M l O 9*9 r*'. M 3 49 C M CM •S 49 s o 9*9 r o u n r o cr. O o 1— s49 = r ~ S; r o r~. < c PM r o K > u n O C M h-4 o 9*9 CJCM o 5 t u CO 9*9 S CM u n r~. i n 9*9 0 0 9*9 CM CM 9*9 S O u n O " - o o : a : O O r o 0 0 < s 0 0 1 u n r-n r o u n CM C J r o r o CM u n 0 3 OO • 2 r o t o CM CM S g 9*9 r o r.-. a s •V CO P'' CD : a < r 'O u n t o O' CJ o o u n C o "eu 9*9 S CM CM 9*9 0 3 CO ■tf. 9*9 CM CM CM 9*9 9*9 49 a s r-M u n o 94> r o 0 0 « a h O 0 0 u n 49 C J o o r o u n CM 0 0 o o s -S CM CM r o r o g 9*9 9*9 a s r.'. o u n •M 0 0 r-. M 3 CJ r o •'O In CM M 3 o 99f CM r o r o 9*9 S 49 ! 9*9 1 9*9 1 OO o 49 C J r o CM o CM - o r o y o M 3 CM r o CMCM r o So u n O s CJ o CO r o 0 3 r o M 3 49 u n r o CM 49 s CMCMCM O 9*9 u n u n CM r o 49 r o t o r o 9*9 9*9 9*9 9*9 u n 1— o o 9*9 CJ o ~ r o u n r o r o 49 - o 0 0 9*9 CMCM o ~ r o r o î o 9*9 9*9 , , <=> 9*9£ CJ Œ u n t o r*^ « 0 u n o o u n 9*9 o 9*9 CM r ^ 9*9 CM CM 9*9 t o 9*9 9*9 49 r o O o 9*9 C J r''. o t o r-» M 3 M 3 P5 CM 9*9± CM 9*9 r o CM r o 9*9 49f S o £9*9 1 u n r*-4 o t". CJ r-~ r o cr~ t o r o CM 4#- <=> o o u n £9*9 s S CMOO 9*9 r o C M 9*9 9*9 9*9 o ~ 9*9 u n £ CM m a s 9*9 OS C U o . c % -.o ~ o 49 CO w o 8 o 1 OJ CJ 9*9 SB ro j a 4 3 V 1 9*9 Ol Ol Oi J- 1 3C 3 : C M 49 • a * o Î5 ro 3 L U c a 0 3 9*9 Oi U c m c m 49 4 M a o Z a s z 9*9§ U « a: CM u n C M Ol 49 cs c C M c o II <«o a s 9*9 o o o U S LU C M o P à o 49 J3 a o cü 2 = C a c Ol C J a s Oi 9*9 k- Ol cu k- ■ rn C J C J c m CJ j C rQ Æ J = ra W & o u ÜTÎ & 1 r— r— . h - 208 CM o 4* m e o o OO < S u n OO 4* 4» r o u n u n r o 4 t r o CM u n - o r o CM 4 t CM CM o r > s ! ? r o 5 1 ! CM p~. < 3 o o r o -M 0 3 0 3 < r CO o o CO M3 4* CJ OO -O 4» 4» M3 MO u n ■ 2 p~. r o 4« CM CM CM S 4 i r o o I z r o r o r o MO CO OO 1 r o u n u n o r o r o - o CJ OO M3 œ * s Î S PM u n r o 1 CM ■tf* r o p~. MO - 2 CM CM R o r o s 49 z r~- 1 ^ m e OO 0 3 m e m e r o r o u n o CM o 49 C J CM O "S u n 49 CM u n c C u n 49 0 0 2 49 CM CM g r o m z z OO "O u n r-'. m e i p .- r o r o u n CM r o CJ r o S • z s 'O 1 CM u n u n 49 0 3 OO r o r o 9*9 CM CM CM 9*9 9*9 * r~w z ■«C o o p .- o o o*> t r ! <-.m 93: - o u n r o 9*9 C J OO u n r o 49 CM r o 9*9 0 0 CO CM CM CM 9*9 49 9*9 9*9 9*9 z r~ . u n o m e P-~ OCi r o CO u n 49 CJ o o r o M3 9*9 CM o o 9*9 o o r ^ : CM CM 9*9 l O r o z9*9 CM O 9*9 C J r ' - m e o u n CM o OO r ~ . MO 49 l O MO S n 49 CM MO M3 o CM r o r o 49 9*9 9*9 z r o CM o CM r o C J o - o s CM 0 0 OO CM CM CM 9*9 r o r o 9*9 9*9 9*9 49 CJ M3 O r - o u n 0 0 r o M3 9*9 u n r o 49 CM o CM C > u n u n r o r o z r o r o r o o o 9*9 CJ o r o u n u n r o r o r o r o o M3 CM 9*9 CM 1* o 9*9 r o r o 9*9 r o z m-4 o 9*9 CJ r ^ M3 u n CO u n M3 o 9*9 CM M3 49 5 CM CM CM 49 m e 9*9 9*9 49 49 r o O 9*9 C J o r o CM o o « 0 % MO M3 9*9 CM p 's p n 49 r o r ^ CM r o r o 9*9 o ~ 49 o pM 49 CJ r o o O' r o u n CM u n o 9*9 CO O'* s CM oci CM CM % 9*9 49 c a u n z CM # a c a c 9*9 a z OL. c S £ MO o •Û M td o 0) d 0) X •r< O •ri Xi H Ml e S cs u cs u pH o 0) 0) 04 w CO d 60 *0 •H 0) M 1—4 04 d o u Of *d 2 1 0 0) o d cO d 0 co 0) M 1 M-i en f—I d o • ^ « M f-* co d o d Q) O d cd M d o fÛ u Cd o 0) d Q> X fC H I Ni CS 0) o c Cd a o co (U tH iw O M s % co a o X co u 1—t Cd cd o d 60 (U • H d (0 df X -d •H rH rd Q) U •H o MH •H d 3 H o 1 •d Ni 0 d m u cs u f—4 o OJ THIOTHIXENE COST Figure 126. Z-Thiothixene homonuclear shift- correlated 2D NMR. 214 E-THIOTHUEHE m u 9 m u •• 7.0 6.0 Figure 127. E-Thlothixene homonuclear shift- correlated 2D NMR. 215 il 11 1 Figure 128. Z-Thiothixene heteronuclear ahift-correlated 2D NMR. 216 jlL-JX Figure 129. ^-Thiothixene heteronuclear shift-correlated 2D NMR: expanded plot. 217 Figure 130. ^-Thiothixene heteronuclear shift-correlated 2D NMR. 218 Figure 131. E-Thlothixene heteronuclear shift-correlated 2D NMR: expanded plot. 219 CO U u o 0) eu (0 Pd X % co 0 O 0) o; w c 0 0 0) 0) u X X *i"4 «H lU Æ Æ g 4-1 -W 0)0 0 X *1-1 t 4 •H ^ 43 43 4J 4J 44 I I O Ni Ml • 1-1 H CM CO 0) u 0 60 •H M 2 2 0 J 0 D O Z) 0 u 4J u 0 a (0 M S Z 0 o 0 0 k 0 0 0 0) 0 ü X X • H «H 0) *C ^ 0 •U 4J (U 0 O X •i-( M 43 rC 4J 4J 1 I . W| Ni H Cd 43 en en 0 u 0 • 60H • M (0 r H 0 0 60 221 UUL 1 3 Figure 134. Thiothixene carbon NMR spectra upfield 6 igna Is. a. ^-thiothixene b. Z-thiothixene 222 WiCO 4J u « a m ot X z c o 4J « 01 0 C G k 0) Of a X X •r4 •H « x: e 4-> V O o X •H •H f4 XX M H H 4-1 1 1 O M | N | x-l JC $ • H CO a m m o> k 9 60 to (0 c bO •H m T5 1-4 Of •H M-l c > 0 T3 to w 4J u Of a m X z c 0 4J Of Of 0 c c k Of Of a XX •H •H Of JC c U w Of 0 o K •H •H Æ H H 4J • 1 0 N | W | •H •• H vO m Of M S bO 224 m 0 C bO » •O i-i Of M-4 a 3 cd k U 0 Of a » Qci z z c 0 u Of U 0 e C k OfV CL X X "p4 .H ti x: X c W 4J u o 0 X -w •k ÆX ^ H H 4J • 1 0 M|N| •H X • • H « X m a u 0 60 •H k 225 CHgN- group. The remaining off-resonance alkyl signals are triplets corresponding to -CH2 " carbons. The signal at 27.5 ppm is readily attributed to the -CH2 not asso ciated with nitrogen both by its upfield position as predicted by chemical shift tables and its smaller in tensity relative to the carbons of the piperazine ring. Similarly, the remaining smaller triplet can be assign ed to -NCH2 " at 38.0-58.2 ppm by similar estimations. The carbons of the piperazine ring can be attributed to the intense signals corresponding to two carbons each at 55.1-55.2 and 53. 1 -53.2 ppm. The signal at 53.1-53.2 ppm has been assigned to the N-(CH2 )2 “ ia closer prox imity to the CHgN- (46 ppm) while the remaining N- (0 8 2 )2 “ has been assigned the more downfield location corresponding to the signal at 55.1-55.2 ppm since it is in a predictably similar environment as the -CH2N- at 58 ppm. Both carbon^^ and proton NMR exhibit little dif ference in upfield signals. The greatest difference (0.2 ppm) occurs for the NCH2 carbon. This may be a function of olefinic substituent orientation rather than interaction with the aromatic rings. Nonprotonated Aromatic and Olefinic Carbon assignments Quaternary carbon assignments are given by inver- sion-recovery (Tj) and selective INEPT experiments as 226 well as by comparison of isomer data. CIO can be read ily assigned as a result of selective INEPT experiments which can be done at proton frequencies corresponding to both Cl4 and Cl. There would be no enhancement of the signal observed for the CIO carbon. Thus, CIO can be assigned to the signal at 130.4 and 132.6 ppm for Z_- and ^-thiothixene, respectively. C9, C12, and C13 carbons can be identified by selective INEPT experiments using the monoprotonated C14 proton frequency. C13 should have a long T 2 because of increased rigidity and lack of neighboring protons. Little chemical shift difference should be observed between isomers for olefinic carbons. Similarity in location should be observed when compared to chlorprothixene since this compound differs only in C 2 substitution and alkylamino substituent. C13 has thus been assigned to the signals at 135.0 and 135.3 ppm for and E- thiothixene. Selective INEPT experiments allow assessment of C9-C12 at 137.7-139.3 and 134.2- 133.1 ppm for and thiothixene. C12 is assigned to the signal at 137.7 and 133.1 ppm for and thio thixene, respectively. This represents a shift of 4.6 ppm between isomers for these alpha carbons. 09 has been assigned to signals of 134.2 and 139.3 ppm (a shift of 5.1 ppm) for and E^- thiothixene. This follows 227 upfield shifts of carbons beta to the double bond of 2.2 and 2.9 ppm for CIO and Cl carbons and a shift of 0.7 ppm for C4 which is gamma to the double bond. The remaining nonprotonated carbons C2 and Cl1 can be assigned by comparison to CIO data. The CIO signal shifts downfield 2.2 ppm between Z.- and isomers. This corresponds favorably with a Cl upfield shift of 2.9 ppm discussed subsequently. These carbons are beta to the double bond. The Cl 1 carbon is on ring B as is Cl. It, therefore, should shift upfield between and isomers. Cl1 is in a similar environment to ring A CIO. CIO shifts 2.2 ppm. An anticipated shift of 2.2 ppm upfield should be observed for the C11 carbon. Of the two remaining nonprotonated signals only the com bination 140.0 (Z.-) ppm and 138.2 (E.-) ppm correspond to a similar shift (1.8 ppm upfield). These signals have, therefore, been assigned to Cll. The remaining C2 sig nal has been assigned by default to 133.4 and 134.4 ppm for Z^- and E^- isomers. Since C2 is substituted, the effects of isomer configuration may indeed be minimized. This ppm value for C2 also agrees favorably with theoretical values of 133.9-133.6 ppm for this carbon. Honoprotonated Aromatic and Olefinic Carbons Honoprotonated carbon chemical shifts were de- 228 fined by homo- and heteronuclear shift-correlated 2D NMR and selective INEPT experiments. Peak assignments are shown in Tables 27 and 28. Homonuclear 2D NMR allows ring assignment. Two monoprotonated carbons (2 doub lets) which are adjacent to both nonprotonated and mono protonated carbons and two monoprotonated carbons (2 triplets) which are adjacent to other monoprotonated carbons are identified for ring A. Substitution at C2 allows identification of the Cl proton as a singlet adjacent to nonprotonated carbons and two monoprotonated carbons, observed as proton doublets, which are adjacent to a monoprotonated and nonprotonated carbon (ring B). Ring B proton chemical shifts are downfield of those of ring A due to sulfonamide substitution at the C2 posi tion. Ring B is further identified by the presence of coupling between the predicted singlet and doublet pair observed by homonuclear 2D NMR. Heteronuc1 ear 2D experiments allow assessment of carbon-proton chemical shift correlations. Tables 27 and 28, The ring B singlet is readily assigned to Cl at 127.7 (Z.-) and 124.8 (E.-) ppm. Selective INEPT experi ments at the Cl proton frequency allows estimation of three-bond coupling and identification of C3 at 125.9 229 (Z.-) and 125.7 (E~) ppm. The remaining ring B carbon, C4, can be assigned by elimination at 127.0 (Z^) and 126.3 (E-) ppm. Ring A carbons can be assigned by assessing isomer differences for comparable carbons. ^-Thiothixene C5 and C8 are assigned to the overlapping carbon signal at 125.8 ppm. This overlapping signal corresponds to the remaining two proton doublet signals (ring A doublets) isolated by homo- and heteronuclear 2D NMR. Since these molecules are essentially symmetrical with respect to the double bond, both C 4 and C 5 and Cl and C 8 should exhibit similar but opposite shifts in ppm depending on isomer configuration. For C4, which is gamma to the double bond, ppm values shift upfield by 0.7 ppm for Z^- and E- isomers. A shift upfield of 2.9 ppm is observed for Cl which is beta to the double bond. Homo- and heteronuc 1 ear 2D NMR allow identification of J|-Thio- thixene C5-C8 at 126.8-128.9 ppm. A downfield shift of 1.1 and 3.1 ppm is observed for these signals, respec tively when compared to the 125.8 ppm signal identified as C5 and C8 for ^-thiothixene. By comparison to data for Cl and C4, C5 can be assigned to the signal at 126.8 ppm, while C8 is assigned to the signal at 128.9 ppm. 230 The remaining ring A proton triplets C6 and C7 can also be identified by comparison of shift differences between isomers. ^-Thiothixene C6-7 corresponds to signals at 127.5 and 127.1 ppm. Whereas E_-thiothixene signals correspond to 127.7 and 126.9 ppm. C3 exhibits a 0.2 ppm upfield shift between and E_- isomers. This carbon is delta to the double bond and therefore should show little difference between isomers. Comparison of the two possible signals allowed for C6 and C7 for each isomer produces only one combination of less than 0.5 ppm. Assignment of C6 to 127.5 ppm (^-) and 126.7 ppm (^-) allows a downfield shift of 0.1 ppm between iso mers. This corresponds well with the 0.2 ppm upfield shift observed for C3. The remaining signals are as signed by elimination to C7 at 127.2 and 126.7 ppm for Z_- and E_- isomers. 1 1 Carbon— NMR of Z- and E-Chlorprothixene 1 1 Carbon NMR data is presented for and E-chlor- prothixene, Figure 2. X-ray crystallography^^ of chlor- prothixene indicates a structure in which the molecule is bent at the sulfur and olefin carbon so that the two benzene rings are oriented at a angle of 141.6 degrees from each other, Figure 138. The olefinic substituent 231 to u 4) B 0 to •H 4) to C 4) X JS 4J 0 a u 0 « 4> f4 B e £ V 4) u X X •H •H 00 m « k 3 00 232 is oriented above and away from the inverted "V" formed by the thioxanthene ring. Carbon 1 NMR data also indi cates this olefinic substituent orientation, since essentially no difference in ppm values were observed between isomers for each carbon of the alkylamino chain. Similar results were observed for proton NMR. Conformational differences between monosubstituted benzene models and the tricyclic thioxanthene skeleton are severe thereby making model compound comparisons difficult. Anisotropic shielding may, for example, account for the significant upfield shift of the signal assigned to the C13 olefinic carbon. Isomeric effects and geometric effects due to ortho substitution are also not addressed by model compound calculations. Therefore, assignments are predominately based upon estimations using other techniques. Carbon^^ NMR shift assignments (Tables 29, 30, and 31) for these compounds were made by comparison to off- resonance data (Figures 139, 140, 141, and 142), inver- sion-recovery (Tj) determinations, homo- and heteronu- clear 2D NMR spectroscopy (Figures 143, 144, 145, 146, 147, and 148), selective INEPT experiments, and, where applicable, by comparsion to model compound chemical shifts . Bruker AM-400 and WM-500, Nicolet NT-270, and 233 Table 29. Chlorprothixene Alkyl Carbon Assignments. (CH312N- -CH2N- -CH2- 2-chlorprothixene 45.4 59.5 28.0 |-chlorprothixene 45.4 59.5 28.1 Spectra were obtained using a Varian FT 80-A spectrometer, 100 mg/ml solutions, and tetramethylsilane as internal standard. 234 o - o o «•4 03 1 CO -o "oJ ^ 1 hn 04 un :3: I 04 04 tn 1 1 1 04 •O r-H. pH. «X pH. - PH •O un 1 03 r-H -43 1 hCÎ -Ô kO ex. r-H —« 1 ^ 04 04 1 _ -43 «h 04 ro ] ■ CO a a ro m r-s 04 CO o o o -O ro m 04 M) o o 1 hn ro un oô CO -Ô -S r-H CN 04 m ! CO 04 04 s 1 04 o2 ro . O o 1 ^ hn ro « r o - "W —• CO m ^ C » O - i ^ CO CO -o XJ -40 CD <33 «*• 1 «tf. m r o IT3 r o •tr i 03 CO -o OJ 04 CO un i" I CO -43 j=> r-H R R I 04 04 2 ro 1 1 1 A -o -M ^ r-H j ^ - un CO 04 04 04 .4-4 un ■ep "| -<»- •O ro hO ro oo 04 oo CO 1 04 ro o . un 04 04 1 m ro ro in o . r— o O 1 CO r-H. 04 OH 04 to CO r-H. ro oo 04 04 o 04 ro 04 ro I ro ro ro -J 1 “ - un 04 r-H. o- o o o* O CD ro 04 04 un 04 <=•«•o o 1 un 04 O ' oa r 04 04 04 04 un hn ro I ro ro t 2 1 1 un Oh r-H -O o o ! r-H. Oh o ro un O c 1 m o> un 04 “1R S I CO o r-H un s ,■ ■ I ^ 1 CD _* 04 m tn in 1 e C3 c - LU L- O. O Ol O 1 Z JO OJ Ol cr L_ U■“ L_ \ 1 I Oi «—• o m ro Ul W .+J u OJ I o Ol > 3 O un un un 3 e L_ u m CJ s re HI un 3 = 4-4 O CD. a II •JD 3 = hO o o l j t - 2 & OI 0 4 W o 1 o a J 3 Ol OJ S ut =c 1 I tu c3 V 1 Ol OJ # a* C_J t n — 4 JZ U 3 -J m x z rS 01 OJ g o < c oo 04 itT 04 r-H O i -o œ -M 04 r-. un ro o- oa 03 O o» roCO ro U-* Ol 04• oo- l3Q <«* _T oô ro ro o «Vro <3 • pH un ro 04 ' Y R PH Y R o- hO r— ro ro un 04 R R Ph <=> un O ro 04 04 ?S o r-H r o 0 3 - o r-H g 1* g g u n 04 o o " e t- -43 r-H œ 04 u a 0 4 i * 03 O >♦* CJ Ol o r-H -43 ro -O ro ! 04 co ro 04 ro $ SOl s Ol un <=> O s CJ un •a* r-H in s Q) O 0 (0 0 0 00 0) M 1 M-l<4-1 O j CO 0 O *jO U 0 Ü 0) 0 Q) X o >4 04 u o xs u Wl , 8 . 0 G\ O CO 4J m-l Ü 0) u 0 0 0 0 0 0 M 1 R co 0 O M 0 Ü • 0 O "B k •-< 0< B k "H O ‘k 8 O• u0 0 o a 0 a 0 (0 0 U 1 M-t U4 O X X 0 o M 0 O 0 0 0 X o u CL U O 1-4 X3 O Ni B • 0 -4 W U ^ U 0 0 CL U 0 0 60 '0 •H 0 Du 1-4 CL 0 O U 0 *0 239 0 o 0 0 0 O 0 0 U IW LW O 04 X Z co 0 O X# o 0 o 0 0 r4 0 0 0 0 X 60 •H • H X: 0 4J O u r4 CL 0 M •H O M-l f-4 0 X: 0 o O 1 *0 N i 8 0 CM k •0* 4J m4 O 0 0 CL k 0 0 60 *0 •i4 0 Pu 1-4 CL 0 O o 0 •0 240 CNLOKMflrHIIENC ïa IJl 0 mm Figure 143. ^-chlorprothixene homonuclear shift correlated 2D NMR. 241 0 O JU Figure 144. Z-chlorprothixene homonuclear shift- correlated 2D NMR: expanded plot. 242 7 .3 6 .9 PPM Figure 145. E-chlorprothixene homonuclear shift- correlated 2d NMR. 243 E-CHLmraeiniiiiir C® 0 ^ 0? . ~ï\« O 0) Figure 146. iE-chlorprothixene homonuclear shift- correlated 2D NMR: expanded plot. 244 aS^^eOIHlXENE 3 N*il, <■ iiWif w 130.5 129.5 127.5 1)6.5 1)5.5 PPM Figure 147. ^-chlorprothixene heteronuclear shift-correlated 2D NMR. 245 l-CHLOItfllOTHl»Nr PROTON CAROON CORRELRTCO s 150.0 1 2 0 .0 12C.0 Figure 148. ^-chlorprothixene heteronuclear shift-correlated 2D NMR. 246 Varian FT-80A spectrometers were used for the analysis. Carbon^^ NMR spectra are given in Figures 149, 150, and 151. Proton NMR spectra are given in Figures 152, 153, and 154. All spectra were obtained using deuterochloro- form solutions and tetramethylsilane (IMS) as internal s tandard. Alkyl Carbon Assignments The carbon chemical shift assignments can be predicted by using known substituent chemical shift tables 39,40 j off-resonance data. The intense up field signal (45.4 ppm), an off-resonance decoupled quartet, can readily be attributed to the N,N-dimethyl carbons. The less intense off-resonance decoupled trip lets at about 28.0 and 59.5 ppm can be attributed to 1 3 methylene and N-methylene, respectively. Both carbon and proton NMR exhibit essentially no difference in upfield signals between isomers. The alkyl carbons do not, therefore, appear to significantly interact with ring carbons. Nonprotonated Aromatic and Olefinic Carbon Assignments Locations of quaternary carbon signals are given by off-resonance decoupled spectra. Assignments are given by inversion recovery (Tj) and selective INEPT 247 CO u u o 0) ÇL, CO X Z a o OJ o> w o •H5 0 248 CO U . u o w CL co s % a o 0) 0) U e fi <0 0) Q) O • i-lX *H X 0) Æ 43 a 4J 44 Q) O o X H ^ •r-( MÛ4 CLW 4J 0 O O I— I r 4 u 43 43 CL Ü O W 1 I . O n| Ml 1-4 43 U (0 «fi • co O «-4 m co ÙOfi 0) ‘H Li CO fi 60 T3 •i4 1-4 Pt4 O O %) 249 CO U u o Q) eu CO Pd s fi O Xi 0) OJ U f i f i CO 0) OJ ü X X • i4 «»4 OJ 43 43 fi 44 44 OJ O O X U U CL CL M U 0 O o 1-4 1-4 u 4 3 4 3 CL Ü O Li 1 I, O M l N i ^4 43 U 1-4 m CO 1-4 CO OJ fi M 60 fi• H 60 CO • H Pu -O 1-4 OJ • H L4 CL fi 250 cd u u V OJ a 0) z z c 0 44 01 OJ 0 B c u 9) OJ a XX •H •H 0) j : j b e w 44 OJ 0 0 X k w a a SI «4 w 0 0 o r-4 k si 43 a u a k 1 1 o W l N l j= •• u (d43 CSJ Ul OJ U 60 251 m CO TJ 01 •i-i e » 0 •a 0) w 4J u V a m OO z z e 0 u 01 V 0 b B k 01 V a X X •H 1-1 01 X X c *J k « o 0 X k k •f4 a a X k k w o 0 0 t-4 k X X a u V k 1 1 0 N|U| r-l X •• o CD rn ir> 01 M a 00 252 00 CO C 60 •H (0 %) f—4 OJ •H M-l CL 9 (d M 4J u 0) CL 00 Cd Z z c 0 4J 0) OJ 0 c C u « OJ CL X X •H 0) X z c 4J 4J OJ o 0 X k u «H a & 43 k k U o 0 0 rH r-4 w 43 Z a u ü u 1 1 0 N|M| mW X •# u 0 <)' tn V k 9 60 •H I k 253 experiments. A spectrum of the downfield carbon signals and chemical shift data are presented in Figure 150 and Tables 30 and 31. Little shift in position between isomers for the nonprotonated olefinic carbon (C13) is predicted by olefinic models. C13 can be assigned by comparison with thiothixene C13 ppm values as well as by selective INEPT experiments at 135.6 and 135.6 ppm for 7^- and ^-ch lorproth ixene. Selective INEPT experiments also allow identification of C9-C12 at 138.1-140.3 and 135.4-133.3 ppm for and E^chlor- prothixene. Similar T^ values are also observed for these signal pairs. C12 is assigned to the signal at 138.1 and 133.3 ppm for and ^-isomers, respectively. This represents a upfield shift of 4.8 ppm between isomers for these carbons which are alpha to the double bond. C 9 has been assigned to the signals at 135.4 and 140.3 ppm for and ^-isomers, respectively (a 4.9 ppm downfield shift). This follows the upfield shift of carbons which are beta to the double bond such as the 2.7 ppm upfield shift for ring B Cl. These C 9 and 012 carbon shifts also correspond to shifts observed for the thiothixene isomers. CIO can be assigned as a result of selective INEPT experiments at proton frequencies corresponding to C14 254 and Cl protons. There would be no enhancement of signal observed for the CIO carbon. Thus, CIO can be assigned to the signal at 133.4 ppm for ^-chlorprothixene. Pre vious data for thiothixene isomers predicts an upfield shift in ppm for the ^-isomer of about 2 ppm. The signal assigned to CIO for the ^-isomer corresponds to this shift at 131.4 ppm. Similarly, the relative posi tion of the C11 signal should, as compared to thio thixene, be located about 2 ppm downfield for the Zj- isomer relative to the ^-isomer position. C11 has therefore been assigned to the signal at 132.4 ppm for ^-chlorprothixene and 130.4 ppm for ^-chlorprothixene. The remaining carbon C 2 can be assigned to the signal at 131.7 (Z-) and 132.4 (E.-) ppm. A theoretical value of 132.7-133,1 ppm is anticipated for this carbon. Monoprotonated Aromatic and Olefinic Carbons Monoprotonated carbon chemical shifts were defined by homo- and hetero- nuclear shift correlated 2D NMR and selective INEPT experiments. Peak assignments are pre sented in Tables 30 and 31. Homonuclear 2D allows ring assignment. Two monoprotonated carbons (two doublets) which are adjacent to both nonprotonated and monoproton ated carbons and two monoprotonated carbons (two trip 255 lets) which are adjacent to other monoprotonated carbons are identified for ring A. Substitution at C2 allows identification of the Cl proton as a singlet adjacent to nonprotonated carbons and two monoprotonated carbons, observed as proton doublets, which is adjacent to a monoprotonated and nonprotonated carbon (ring B). Ring B is further identified by the presence of coupling between the predicted singlet and doublet pair observed by homonuclear 2D NMR. Heteronuc1 ear 2D experiments allow assessment of carbon-proton chemical shift correlations. Tables 30 and 31. The ring B singlet is readily assigned to Cl at 128.3 (Z_~) and 125.7 (E-) ppm. Selective INEPT experi ments at the Cl proton frequency allows estimation of three-bond coupling and identification of C3 at 127.0 (Z_-) and 126.6 (E^) ppm. The remaining ring B carbon, C4, can be assigned by elimination at 127.7 (Z.-) and 126.8 (E.-) ppm. The upfield shifts of these signals between Z^- and ^-isomers (2.7, 0.4, and 0.9 ppm for Cl, C3, and C4) compares favorably with those obtained for thiothixene isomers (2.9, 0.2, 0.7 ppm) for the equi valent carbon signals. Ring A carbons can be assigned by assessing isomer differences for comparable carbons. ^-Chlorprothixene 256 C5 and C8 are assigned to the overlapping carbon signal at 125.8 ppm. This overlapping carbon signal, as in thiothixene, corresponds to the remaining two proton doublet signals (ring A doublets) isolated by homo- and heteronuclear 2D NMR. Since these molecules are es sentially symmetrical with respect to the double bond, both C4, C5 and Cl, C8 should exhibit similar but opposite shifts in ppm depending on isomer configura tion. For C4, which is gamma to the double bond, ppm values shift upfield by 0.9 ppm for Z_- and isomers. A shift upfield of 2.7 ppm is observed for Cl which is beta to the double bond. Homo- and heteronuclear 2D NMR allow identification of jE-chlorprothixene C5-C8 at 126.7 and 128.7 ppm. A downfield shift of 1.0 and 2.9 ppm is observed for these signals, respectively when compared to the overlapping 125.8 ppm signal identified as C5 and C8 for Z^chlorprothixene. By comparison to data for Cl and C4, C 5 can be assigned to the signal at 126.7 ppm, while C8 is assigned to the signal at 128.7 ppm for E_-ch lorprothixene. These results compare favor ably with thiothixene data. The remaining ring A proton triplets C 6 and C 7 can also be identified by comparison of shift differences between isomers. ^-Chlorprothixene C6-C7 corresponds to 257 signals at 127.1 and 126.9 ppm. ^-Chlorprothixene sig nals correspond to 127.2 and 126.1 ppm. C3 exhibits a 0.4 ppm upfield shift between Z_- and E_- isomers. This carbon is delta to the double bond and should show minimal difference relative to C7 shifts between iso mers. Comparison of the two possible signals allowed for C 6 and C 7 for each isomer produces two possible downfield shifts between isomers for the C6 carbon of 0.4 and 0.2 ppm. C6 is assigned to the pair of signals corresponding to the 0.2 ppm shift by comparison to model compound data in which C6 ppm values are predicted downfield of C7 carbons. C6 is assigned to the signals at 127.1 (^-) and 127.2 (E^-) ppm. C 7 is assigned by elimination to the signals at 126.9 and 126.1 ppm for Z^- and E^chlorprothixene. EXPERIMENTAL 13 Carbon NMR and o££-resonance data were obtained on a Varian FT-80A spectrometer located at the United States Pharmacopeia, Rockville, Maryland using a sweep width of 4000 Hz (200 ppm) and pulse width of 45 d e grees. Solutions of 100 mg/ml in deuterochloroform were analyzed using TMS as internal standard in 5mm o.d. tubes. Samples were prepared immediately prior to use. An acquisition time of 2 seconds and 16K data points were used in the analysis. Selective decoupling, inversion-recovery (T^), homo- and heteronuclear 2D experiments and proton and carbon-13 spectra were obtained on a Bruker AM-400 spec trometer at Bruker Instruments, Inc., Billerica, Massachusetts or a Bruker WM-500 spectrometer located at Yale University, New Haven, Connecticut using a sweep width of 16000 Hz (160 ppm) or 25150 Hz (200 ppm) and varying pulse widths. Solutions of 25 or 50 mg/ml in d eu teroch1oroform were analyzed using TMS as internal standard in 5mm o.d. tubes. Samples were prepared immediately prior to use. An acquisition time of approximately 1 second and 32K data points were used in the analysis. Proton NMR was accomplished using the 258 259 same solutions, a sweep width of 5000 Hz (12 ppm) or 5600 Hz (11 ppm) and varying acquisition time of 3 seconds. Selective INEPT data were obtained using a Bruker WM-500 spectrometer located at Yale University, New Haven, Connecticut or a Nicolet NT-270 spectrometer located at the National Institutes of Health, Bethesda, Maryland. Conditions were varied according to the sample analyzed. Samples were prepared in deutero- chloroform using TMS as internal standard. Drug and isomeric samples were provided by Dr. L.T. Grady of the United States Pharmacopeia, Rockville, Maryland. Dothiepin isomeric samples were provided by Dr. Spooner, Boots Chemical Co, Ltd., Nottingham, Eng land. Dothiepin reference standard and 6H-dibenzo- [b ,e]thiepin-ll-one samples were provided by Mr. J. Johnson, British Pharmacopoeia, London, England. Dr. Y . Segall of the Israeli Institute for Biological Research, Ness-Ziona provided 5-methy1ene-5H-dibenzo[a,d]cyc1o- heptane. Model compounds were obtained commercially. REFERENCES 1. Martinda 1e , The Extra Pharmacopeia, Twenty-Sixth Edition. London: The Pharmaceutical Press, 1969. 2. Remington's Pharmaceutical Sciences. Easton, Penn.: Mark Publishing Co., 1975. 3. The United States Pharmacopeia, Twentieth Revis ion. Easton, Penn.: Mack Publishing Co., 1980. 4. USAN and the USP Dictionary of Drug Names. Easton, Penn.: Mack Publishing Co., 1984. 5. L. W. Po and W. J. Irwin, Pharm. Pharmaco 1., 3 2, 25(1980). 6. W . J. Irwin and L. W . Po, Proc. Ana 1 yt. Div. Chem. Soc., 329(1979). 7. M. T. Rosseel, M. G. Bogaert, £jt a_l. , Fres. Z . Anal. Chem., 290, 158(1978). 8. M. T. Rosseel, M. G . Bogaert, e_t a^. , J_^ Pharm. Sc i. , 67(6), 802(1978). 9. G . deGroot and J. G . Leferink, JU. Ana 1. Toxicol., 2, 13(1978). 10. D. C. Hobbs, Biochem. Pharmacol., 18, 1941(1969). 11. The Pharmaceutical Codex, Eleventh Edition.. London: The Pharmaceutical Press, 1979. 12. Drugs, 1, 194(1971). 260 261 13. A. J. Lewis, Mod er n Drug Encycloped ia. New York: Yorke Medical Books, 1981. 14. R. M. Finder, R. N . Brodgen, a^., Drugs, 13, 161(1977). 15. K. Shein, Br. J . Pharmacol., 6 2, 567(1978). 16. K. P. Maguire and G. P. Burrows, Br. J . Clin. Pharmacol., 12, 405(1981). 17. E. Richelson and S. Divinetz-Romero, Bio. Psych., 12(6), 771(1977). 18. B. H. C. Westerlink, R. Le jeune, £_t a_l. , Eur. J . Pharmaco1., 42, 179(1977). 19. C. Sterlin, T. A. Ban, and L. Jarrold, Cur r. Ther. Res., 14(4) , 205(1972). 20. J. D. Barchas, P. A. Berger, al^. , Psychopharma cology. New York: Oxford University Press, 1977 21. F . Muren and B.M. Bloom, Med Chem. , 13, 17(1970), 22. L. W. Po and W. J. Irwin, ^ Pharm. Pharmacol., 21 » 512(1979). 23. P. A. Bombardt and R. 0. Friedel, Commun. Psycho- pharm. , ]., 49(1977). 24. J. P. Schaeffer, Chem. Commun., 743(1967). 25. Wenner-Gren Center Int. S ymp. Ser . , 2 5, 147(1976). 26. M. Schorderet, J. McDermed, and P. Magistretti, J. Physiol.(Paris).. 74, 509(1978). 262 27. J. Overall, £jt £_!• , Clin. Pharm. Ther. , 10(1), 36(1968). 28. S. J. Enna, J. P. Bennett, e_t aj^. , Nature, 263 , 338(1976). 29. A. A. Kurland, P. Alcides, e_t al^. , Cur r. Ther. Res., 9(6). 298(1967). 30. A. Weissman, Psychopharmacol., 12, 142(1968). 31. A. A. Sugarman and H. Stolberg, Curr. Ther. Res., 7(5) , 310(1975). 32. T. A. Ban and H. E. Lehman, Pis. Nerv. Syst., 3 6(9), 473(1975). 33. L. L. Iversen, Science, 188, 1084(1975). 34. B. S. Bunney, J. R. Walters, e_t a^» , Pharmaco 1. Expt. Ther., 185(3), 560(1973). 35. F. A. Weisel, L . B J erkens ted t, a_l • * Acta Pharmacol. Toxicol., 43, 129(1978). 36. R. J. Wyatt, Psychopharmacol. Bull. , 12(3), 5(1973). 37. L. Bjerkenstedt and L.B. Gulberg, Arch. Psychiat. Neurol. Sci., 224, 107(1977). 38. G . Sedvall and L. Bjerkenstedt, Life Science, 23, 425(1978). 39. F . W. Wehrli and T. Wirthlin, Interpretation of Carbon-13 NMR Spectra. London: Heyden, 1978. 263 13 40. E. Breltmaler and W. Voelter, — C NMR Spec troscopy. New York: Verlag Chemle, 1978. 41. Carbon-13 NMR. Philadelphia: Sadtler Research Laboratories, Inc., 1984. 42. E. Breitmaier, G. Haas, and W. Voelter, Atlas of Carbon-13 NMR Data. London: Heyden, 1979. 43. -“ Ç Data Bank, Vol. Karlsruhe: Bruker Physik, 1976. 44. D. F. Ewing, Or g. Mag. Res., 12, 499(1979). 45. J. Poirot-Lagubeau and P. Mesnard, Ann. Pharm. Franc.. 33(5), 279(1975). 46. Y. Asscher, D. Avnir, ^ aj.. , Pharm. Sci., 71(1), 122(1982). 47. T. DePaulis, D . Kelder, and S. B. Ross, Mo 1. Pharma col. , lu, 596(1978). 48. D. H. Hawkins and I. Midgley, Pharm. Pharmaco 1. , 30, 547(1978). 49. J. P. Reboul, B. Cristau, and G. Pepe, Ac ta Cryst., B3 7, 398(1981). 50. NIH/EPA Chemical Information Systems Database, Com puter Sciences Corporation, Falls Church, Vir ginia. Searched January, 1984. 51. J. P. Schaeffer, Chem. Commun., 743(1967). 52. M. L. Post and 0. Kennard, Ac ta Cryst., B30, 1044(1974).