Beitriige zur Tabakforschung International · Volume 12 · No. 2 · June 1983 Structural Study of Nicotine Salts* by Thomas A. Perfettt. Research and Development, R. ]. Reynolds Tobacco Company, Winston-Salem, North Carolina, V. S. A. SUMMARY ren. Mit aliphatischen Monocarbonsiiuren, beginnend mit Essigsaure, bildet Nicotio Salze, die ein Saure/Base­ The structures of three types of nicotine salts have been Verhiiltnis von 3: 1 haben. Bei diesen Salzen entspricht determined. These salts have acid to base ratios of either die Bindung der ersten Siiure der der 1 : 1-Salze, wah­ 1: 1, 2: 1, or 3: 1. Salt formation between organic acids rend die anderen beiden Siiuren dimersieren und sich an and nicotine is dependent upon the structure of the den Stickstoff der Pyridingruppe binden. acids (aliphatic or aromatic) and their functionality. The Zur Strukturaufk.liirung wurden folgende Verfahren ein­ 1 : 1 salts of nicotine have amino acids or benzoic-type gesetzt: Infrarotspektroskopie (IR), Ultraviolettspektro­ acids bound to the N-methylpyrrolidine nitrogen of skopie (UV), magnetische Protonenresonanzspektro­ nicotine. The 2 : 1 salts are found to bind to one acid skopie (PMR), magnetische Kohlenstoffresonanzspek­ group as in the 1 : 1 salts and a second to the nitrogen of troskopie (CMR) und Desorptionsfeldmassenspektro­ the pyridine ring. The 2 : 1 salts of nicotine are formed skopie (FD-MS). with formic acid, aliphatic dicarboxylic acids, and/or nitroaromatic acids. Nicotine forms 3: 1 salts with aliphatic monocarboxylic acids starting with acetic acid. RESUME Here one acid is bound as in the 1 : 1 salts while the other two acids dimerize and bind to the nitrogen of the La structure de trois types de sels de nicotine a ete deter­ pyridine group. minee, ceux-ci pri!sentant un rapport acide/base de re­ Infrared (IR), ultraviolet (UV), proton nuclear mag­ spectivement 1 : 1, 2 : 1 et 3 : 1. La constitution de sel netic resonance (PMR), and carbon nuclear magnetic entre les acides organiques et la nicotine depend de la resonance (CMR) spectroscopy as well as field desorp­ structure des acides (aliphatique ou aromatique) et des tion- mass spectroscopy (FD-MS) were used in this groupes fonctionnels de ceux-ci. Les sels 1 : 1 pri!sentent investigation of the structure of nicotine salts. des acides amines ou des acides de type benzolque lies a I' azote N~methylpyrrolidine de la nicotine. Pour les sels de rapport 2 : 1, l'un des acides est lies comme dans le ZUSAMMENFASSUNG cas des sels 1 : 1 et le deuxieme acide se combine a l'azote du cycle de pyridine. Les sels de nicotine du Die Struktur von drei Nicotinsalztypen mit dem 5aure/ rapport 2: 1 soot constitues d'acide formique, d'acides Base-Verhiihnis von 1 : 1, 2 : 1 und 3 : 1 wurde bestimmt. aliphatiques dicarboxyliques et/ou d'acides nitroaroma­ Die Salzbildung zwischen organischen Sauren und Ni­ tiques. La nicotine constitue des sels d'un rapport cotin hiingt von der Struktur (aliphatisch oder aroma­ acide/base de 3 : 1, a partir d'acides monocarboJQrliques tisch) der 5auren und deren funktionellen Gruppen ab. aliphatiques, a commencer par l'acicfe acetique. Dans ce Bei den 1 : 1-Salztypen sind Aminosiiuren oder benzoe­ cas, la liaison du premier acide correspond a cdle des siiureah.nliche Sauren an den N-Methylpyrrolid.in-Stick­ sels du rappon 1 : 1, tandis que les deux autres acides se stoff des Nicotin gebunden. Bei den 2: 1-Salztypen ist dimerisent et se combinent a l'azote du groupe pyridine. ~ die eine Siiure wie bei den 1 : 1-Salzen und die zweite Pour l'etude de la structure des sels de nicotine, on a· Siiure an den Stickstoff des Pyridinringes gebunden. Die utilise les precedes suivants: spectroscopie infrarouge 2: 1-Nicotinsalze bilden sich mit Ameisensiiure, alipha­ (IR), spectroscopie l'ultraviolet (UV), spectroscopie tischen Dicarbonsiiuren und/oder nitroaromatischen Sau- a magnetique a resonance protonique (PMR), spectrosco­ pie magnetique a resonance carbonique (CMR) et spec­ * Received: 22nd July 1981 - a«.q>ted: 8th Nov~mber 1982. troscopie de masse du champ de desorption (FD-MS). 43 Table 1. Infrared absorption bands (cm-1) of nicotine salts. 9 Dimerization, OH-bonding Acid H-bonding -coo and/or C-0 stretching Others References Formic 37-2300 1725 1590 B 1200B 2120-1970++ 3, 4, 21 Acetic 32-2200 1725 B 1570 B 1430B 1265 B 1050 1009 3, 4, 21 1715 B 1360 B 2100-1900 _ Propionic 35-2300 1725 1595 1462 1380 B 1275 1071 3, 4, 21 1578 1465 1212 2100-1850 Butyric 32-2400 1727 D* 1582 1460 1400 1270 1092 1041 4, 8, 21 1717 D 1442 1200 2010-1900 2-Methylbutyric 32-2400 1722 15980 1460 1382 1261 1152 4, 8, 21 1569 D 1429 1203 2010-1900 3-Methylbutyric 32-2400 1725 D 1565 B 1468 1370 1292 1120 1098 4, 8, 21 1717 D 1431 1385 1200 2110-1850 Valeric 32-2300 1721 1570 1449 1190 1101 1090 4, 8, 20, 21 1430-1380 B 2100-1850 Lauric 32-2200 1717 1575 1457 1403 1260-1180 1110 12, 14 2120-1820 Tartaric 37-2300 1730 1652 B 1565 1265 1130 1075 872 10, 17, 18 1211 1108 1060 Citric 37-2200 1728 1585 1400 1215 810 2060-1880 Malic 3400 B 1702 1605 B 1450 B 1300 1233 1098 31-2200 1578 B 1170 Oxalic 37-2200 1715 1604 1200 2090-1980 15, 7 3350 Benzoic 2960 B 1710 B 1600 1449 1380 1272 1119 1070 3, 8, 9 2780 B 1582 Gentisic 32-2400 1575 148~ 1340 1275 1192 1022 3, 5, 8, 9 2700-2250 1430 1235 1121-1011 Gallic 34-2200 1693 1540 B 1350 B 1194 B 1035 3, 5, 8, 9 Phenylacetic 31-2200 1720 1580 1495 2100-1850 3, 6, 8, 9 1455 Salicylic 1628 1590 1430 1290 1135 3, 8, 9 Phthalic 2600-1900 B 1692 1550 1450 B 1360 1200 B 1120 1020 3, 8, 9 1105 1095 1010 Picric** 1630 1550 1340 1270 1152 1980 6, 22 1610 1529 1310 1178 1088 2100 Sulfosalicylic 31-2500 1695 1612 1290 1162 1071 9 1590 1260 1120 1021 Tannic 37-2200 1712 1601 1595 1325 B 1200B 2, 11 1090 1030 Pectic 37-2200 1730 1601 1140 1090 1, 16, 23 3370 Alginic 37-2300 1740 1609 B 1409 1080 1015 13, 16 1031 Hydrochloric** 34-2200 2050 B 1640 1560 B 1470 1335 1265 1000 24 2000 1617 1210 1015 Chloroplatinic** 3540 3200-3160 2720B 1600 1310 1210 1003 668 19 3480 3110-3080 1630 1255 1185 Silicotungstic** 3530 3070 2720 B 1620 B 1270 1190 912 780 12 3370 1567 1200 1010 870 675 Pyruvic 37-2300 T* 1715 B 1622 B 1430 1160 B 5 1350 Glutamic 32-2200 1670 1642 1610 B+ 1452 1315-1258 1128 25 1235 Aspartic 3140 1690 1620 ~560 B+ 1500 1350-1213 1119 1900 25 32-2200 B 1310-1140 1072 2070 • D • doublet, B • broad, T ~ triplet. ** Frequencies do not conform to headings. + Indicative of zwltterlon formation. ++ Frequencies In the ranQ;. of 2100-1820 are those Indicative of ammonium and lmmlnlum salts. 44 INTRODUCTION Dezelic et al. on the structure of the 2 : 1 salts of nic­ otine and dicarboxylic acids were confusing, and addi­ The molecular composition and structure of nicotine tional structural analyses were needed (3). Because of salts have been topics of investigation and discussion for this ambiguity, a structural study of several classes of many years. Controversy over the composition of nic­ 1 : 1, 2 : 1, and 3 : 1 nicotine salts was undertaken. otine salts arises from the fact that these salts exist with varying ratios of acid to base. While this is not unusual in itself, the presence of two basic sites in the nicotine molecule and the existence of 1 : 1, 2 : 1, and 3 : 1 salts MATERIALS AND METHODS makes it somewhat difficult to state a priori what the structure of a particular salt is. Chemicals Infrared (IR) and ultraviolet (UV) spectroscopic studies have been made of the aromatic acid and dicarboxylic Nicotine (Eastman) was purified by treatment with acid salts of nicotine in an attempt to elucidate their solid sodium hydroxide, filtration, and distillation under structure (3, 5). The data support the structures assigned­ vacuum. The nicotine obtained was a colorless liquid by. Dezelic et al. (4, 7) for the 1: 1 and 2: 1 salts of (boiling-point: 246-7 °C). All acids used in this report nicotine and aromatic acids. The conclusions reached by were commercially available and were reagent grade or better. Further purification was not needed. References for Table 1: Preparation of Salts 1. Baier, W. E.: U. S. Patent 2,207,694 (July 9, 1940). 2. Batchelder, C. H.: U. S. Patent 2,152,236 (March 28, 1939). The preparations for all nicotine, pyridine, and pyrrol­ 3. Dezelic, M.: Rad. Jug. Akad. Znan. i Umjet knj. 263 (82) idine salts can be found in the literature. Appropriate (1939) 157-168. references are noted as each compound is discussed 4. Dezelic, M., J. Grujic-Vasic and S. Ramic: Glasnik Dru§tva (Table 1). Hemi~ara Technol. N. R. Bosne i Hercegovine 12 (1963) 53-58. 5. Dezelic, M., and B. Nikolin: Glasnik Dru§tva Hemi~ara Instrumentation Technol. N. R. Bosne i Hercegovine 10 (1961) 55-62. Infrared spectra were obtained with a Perkin-Elmer 283 6. Dezelic, M., and B. Nikolin: Spectrochimica Acta (Part A) 23 infrared spectrophotometer. Samples were prepared as (1967) 1149-1153. Nujol* mulls on AgCl plates. A large variety of nic­ 7. Dezelic, M., B. Nikolin and R. Popovic: Glasnik Dru§tva otine salts were analyzed to establish a data base Hemi~ara Technol.