Carbon-centered radicals in cigarette smoke: acyl and alkylaminocarbonyl radicals.

The widely accepted mechanism of formation for carbon-centered radicals in the gas-phase cigarette smoke involves reactions of NO(2) and alkadienes. However, specific examples of such radicals have never been isolated from fresh cigarette smoke or their structure determined. We have identified two previously unrecognized classes of carbon-centered radicals, alkylaminocarbonyl and acyl radicals, that are unrelated to radicals that form by NO(x) chemistry. The combined abundance of these mainstream smoke radicals is significantly higher than the alkyl radicals previously quantified by electron paramagnetic resonance (EPR) solution spin-trapping methods. The new radicals were trapped directly from smoke with either 3-amino-proxyl (3AP) or 3-cyano-proxyl radical on a solid support and identified by combination of chemical synthesis, deuterium labeling, high-resolution mass spectrometry, nuclear magnetic resonance (NMR) spectroscopy, and ab initio quantum mechanical calculations. 3AP-R adducts were quantified both by high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and by high-performance liquid chromatography with fluorescence detection (HPLC/FLD). Seven acyl and 11 alkylaminocarbonyl radicals were identified in the whole smoke of cigarettes made from single tobacco varieties and blended tobacco research cigarettes. The overall yield of these radicals was measured to be 168-245 nmol/cigarette from machine-smoked cigarettes under Federal Trade Commission (FTC) conditions. The yield was significantly reduced when the gas-phase smoke was separated from whole smoke by filtration through a 0.1 microm Cambridge filter pad or upon aging whole smoke in an inert tube.

Esters of pyromellitic acid. Part II. Esters of chiral alcohols: para pyromellitate diesters as a novel class of resolving agents and use of pyromellitates as duplicands for chiral purification.

Methods are presented for the preparation of pyromellitate esters of chiral terpene alcohols, including d- (3) or l-menthol (4), d-isomenthol (7), l-borneol (8), or d- (5) or l-isopinocampheol (6). Alcoholysis of PMDA in CH2Cl2/Et3N led to the formation of monoesters (e.g., 18) or diesters (11, 12), as needed, relying on the differential reactivity of the two anhydride groups. The easily isolated para diester (11) crystallized before the meta diester (12) from HOAc. Nicotine (1, 14) was efficiently resolved as 1:1 salts with the menthyl (11a, 11b) or bornyl (11f) para diesters, prototypes of what promises to be a large class of novel resolving agents. Recrystallization of para-di-d-menthyl pyromellitate (11a) greatly improved the chiral purity of the contained d-menthol (3), an example of purification by "duplication". An alternative synthesis of specific diesters took advantage of the easily separated benzyl diesters and their derived acid chlorides (19, 21), with the benzyl esters serving as temporary blocking groups removable by catalytic hydrogenolysis. Pyromellitate tetraesters (26) were prepared by base-catalyzed transesterification of the tetraethyl ester (25). Tri- l-menthyl pyromellitate (27b) was obtained by catalytic hydrogenolysis of benzyl tri-l-menthyl pyromellitate (31b), itself prepared from the alcoholysis of benzyl pyromellitate triacid chloride (30) with l-menthol (4).

Esters of pyromellitic acid. Part I. Esters of achiral alcohols: regioselective synthesis of partial and mixed pyromellitate esters, mechanism of transesterification in the quantitative esterification of the pyromellitate system using orthoformate esters, and a facile synthesis of the ortho pyromellitate diester substitution pattern.

Mild conditions and reversible anhydride formation allow a relative differentiation to be made of the four equivalent carbonyl groups of pyromellitic dianhydride (PMDA, benzene-1,2,4,5-tetracarboxylic dianhydride) in esterification, leading to regioselective methods to generate a wide range of partially or totally esterified products or products bearing differing esterifying groups at the different positions. Pyromellitate monoester anhydrides form efficiently in dichloromethane/triethylamine from 1 equiv of the alcohol. Under the same conditions, two different alcohols can be made to react sequentially. With 2 equiv of an alcohol, the usual mixture of meta and para diesters is obtained, separated by crystallization from HOAc. Meta and para dibenzyl pyromellitates served as regiospecific sources of other diesters, by further esterification followed by hydrogenolysis. Refluxing orthoformate triesters were found to effect quantitative esterification of the pyromellitate system under autocatalytic conditions; minor ester exchange with pre-existing esters (0-5% of total product) was ascribed to reversible anhydride formation. For general esterification with alcohols, partial ester acid chlorides were obtained using oxalyl chloride. Pyromellitate triesters afforded the ortho diester anhydrides upon distillation, thereby providing facile entry into the mostly novel ortho substitution pattern in this system. The requisite triesters were prepared by selective saponification or by the prior incorporation of one benzyl ester substituent, which could be removed by catalytic hydrogenolysis. The various benzyl esters of pyromellitates hydrogenolyzed smoothly to release the carboxylic acid groups without disturbance of pyromellitate aromaticity.