- Mechanisms of Acid-Catalyzed Proton Exchange in N-Methyl Amides
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Kinetics of acid-catalyzed proton exchange in an extensive series of N-methyl amides, RCONHCH3, were followed by NMR line-shape analysis in aqueous solution.Electron-withdrawing substituents retard the reaction, but the only good correlation is between log kH+ for substituted N-methyl acetamides and the pKa of the corresponding RCOOH.The correlation shows a change in slope, from 0.43 for amides with electron-withdrawing substituents to ca. 1.84 for other amides.This change is taken as evidence for a changeover from the imidic acid mechanism to the N-protonation mechanism.In particular, it is concluded that peptides and proteins represent amides with electron-withdrawing substituents, so that the NH protons of their backbone exchange predominantly via the imidic acid.The difference in slopes and the changeover in mechanism, as well as the comparison between primary and secondary amides, are rationalized in terms of substituent effects and transition-state structures.
- Perrin, Charles L.,Arrhenius, Gloria M. L.
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- PROCESS FOR PRODUCING N-METHYL SUCCINIMIDE
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The invention includes methods of processing an initial di-carbonyl compound by conversion to a cyclic compound. The cyclic compound is reacted with an alkyating agent to form a derivative having an alkylated ring nitrogen. The invention encompasses a method of producing an N-alkyl product. Amonia content of a solution is adjusted to produce a ratio of ammonia to di-carboxylate compound of from about 1:1 to about 1.5:1. An alkylating agent is added and the initial compound is alkylated and cyclized. The invention includes methods of making N-methyl pyrrolidinone (NMP). Aqueous ammonia and succinate is introduced into a vessel and ammonia is adjusted to provide a ratio of ammonia to succinate of less than 2:1. A methylating agent is reacted with succinate at a temperature of from greater than 100 °C to about 400 °C to produce N-methyl succinimide which is purified and hydrogenated to form NMP.
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- Specificity of DNA alkylation by 1-(2-chloroethyl)-3-alkyl-3- acyltriazenes depends on the structure of the acyl group: Kinetic and product studies
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The reactions of calf thymus DNA with ten 1-(2-chloroethyl)-3-alkyl-3- acyltriazenes of varying acyl side chain structure were studied alone, or in the presence of porcine liver esterase in pH 7.0 phosphate buffer. In several of the key triazenes, the acyl substituent contained a free carboxylic acid group. With esterase present in the reaction mixture, the resultant levels of DNA alkylation could be correlated with the kinetic rates of decomposition of the triazenes. Under these conditions, the predominant pathway of decomposition involved deacylation of the parent triazene and eventual production of an alkanediazonium ion. This intermediate subsequently alkylated DNA-guanine to give 7-alkylguanine as the principal reaction product. In the absence of esterase, the order of DNA alkylation for all of the acyltriazenes did not correlate with their respective rates of decomposition, leading to the conclusion that the triazenes did not decompose by the expected mode of uncatalyzed N(2)-N(3) heterolyic cleavage. The major DNA alkylation product from the N(3)-methyltriazenes was 7-methylguanine, instead of the expected 7-(chloroethyl)- and 7-(hydroxyethyl)guanine products, which suggested that the acyl group was being hydrolyzed. However, acyltriazenes with an N(3)-benzyl group rather than a methyl in this position produced very little 7-benzylguanine product, contrary to prediction. An alternative mechanism involving internally assisted hydrolysis of the side chain ester is proposed to explain these results. NMR product analysis and computational studies were carried out to lend support to the postulated mechanism.
- Smith,Schmidt,Czerwinski,Taneyhill,Snyder,Kline,Michejda,Smith Jr.
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p. 466 - 475
(2007/10/03)
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- Conformation-directing effects of a single intramolecular amide-amide hydrogen bond: Variable-temperature NMR and IR studies on a homologous diamide series
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We have studied intramolecular hydrogen bonding in a homologous series of diamides (compounds 1-6) in methylene chloride, 9:1 carbon tetrachloride/benzene, and acetonitrile. By correlating variable-temperature 1H NMR and IR measurements, we have shown that the temperature dependence of the amide proton NMR chemical shift (Δδ/ΔT) can provide qualitative (and in some cases quantitative) information on the thermodynamic relationship between the intramolecularly hydrogen bonded and non-hydrogen-bonded states of flexible molecules. Among the hydrogen-bonded ring sizes represented in the diamide series, the intramolecular interaction is particularly enthalpically favorable in the nine-membered hydrogen-bonded ring (compound 4). Variable-temperature IR and NMR data indicate that the internally hydrogen bonded state of diamide 4 is 1.4-1.6 kcal/mol more favorable enthalpically than the non-hydrogen-bonded state, in methylene chloride solution; the non-hydrogen-bonded state is 6.8-8.3 eu more favorable entropically in this solvent. In contrast, there appear to be much smaller enthalpy differences between the internally hydrogen bonded and non-hydrogen-bonded states of diamides 2 and 3. Our findings are important methodologically because the temperature dependences of amide proton chemical shifts are commonly used to elucidate peptide conformation in solution. Our results show that previous "rules" for the interpretation of such data are incomplete. In non-hydrogen-bonding solvents, small amide proton Δδ/ΔT values have been taken to mean that the proton is either entirely free of hydrogen bonding or completely locked in an intramolecular hydrogen bond over the temperature range studied. We demonstrate that an amide proton can be equilibrating between intramolecularly hydrogen bonded and non-hydrogen-bonded states and still manifest a small chemical shift temperature dependence (implying that the hydrogen-bonded and non-hydrogen-bonded states are of similar enthalpy).
- Gellman, Samuel H.,Dado, Gregory P.,Liang, Gui-Bai,Adams, Bruce R.
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p. 1164 - 1173
(2007/10/02)
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