Quantum chemical studies of alkyldinitrogen species implicated in nitrosamine carcinogenesis

Abstract

. Can. J. Chem. 67, 625 (1989). Ab initio calculations (Hartree-Fock) at the level of 3-21G and 6-31G* as well as MP2/6-31G* have been performed on the carcinogen dimethylnitrosamine and its products of oxidative metabolism E-(and Z-) hydroxymethylmethylnitrosamines and certain ester conjugates. The E-and Z-hydroxymethylmethylnitrosamines are found to be close in energy and to be configurationally stable as is found experimentally. Alternative pathways are examined for the spontaneous decomposition of the primary metabolite in aqueous solution. Direct cleavage of E-hydroxymethylmethylnitrosamine to Z-methanediazohydroxide and formaldehyde is highly endothermic. Protonation of the NO group of the hydroxylated metabolite strongly stabilizes this species in contrast to nitrosoureas but in accord with experiment. Incorporation of water together with consideration of entropy effects satisfactorily accounts for the spontaneous exothermic decomposition of E-hydroxymethylmethylnitrosamine in aqueous media, as well as its relative stability in aprotic media. Ab initio calculations were also performed on selected nitrosoiminium ions which participate in the enzymatic activation and metabolism of certain dialkylnitrosamine carcinogens.Key words: carcinogenesis, dimethylnitrosamine, ab initio calculations, nitrosoiminium ions.

Ab InitioQuantum-Mechanical Study of the Stability of Cyclic α-Acetoxy-N-nitrosamines: Amine N→NO Dative Bonding in α-Hydroxy-N-nitrosaminesversusN→Carbocation Dative Bonding inN-Nitrosiminium Ions

“…The NN bond lengths in 3 and 4 are 1.441 and 1.457 Å, respectively. In an earlier report it was stressed that the NN bonds in nitrosiminium ions are very long (>1.58 Å) and the conclusion was put forth that nitrosiminium ions should be considered as ion−molecule complexes between NO + and an imine . Our results show that the long NN bonds found earlier are artifacts of the RHF/3-21G level used in that work.…”

“…Calculations on dimethylnitrosamine and its metabolite hydroxydimethylnitrosamine were reported,21a and methylnitrosamine and the decomposition of hydroxymethylnitrosamine were studied in detail 21b. Sapse et al studied dimethylnitrosamine, their isomeric hydroxydimethylnitrosamines and their ester conjugates using RHF/6-31G* structures and with MP2/6-31G*// RHF/6-31G* energy calculations. In particular, several nitrosiminium ions were considered in this study, albeit at the much lower level RHF/3-21G, and the energy difference between E - and Z -isomers was found to be very small.…”

“…Calculations and measurements of the rotational barriers of some symmetrical nitrosamines gave barriers of 19−23 kcal/mol which equals about one-third of the energy of a NN π-bond . The only previous report of rotational barriers in nitrosiminium ions (6−8 kcal/mol) is based on RHF/3-21G energy data computed for nonoptimized structures …”

“…29 The only previous report of rotational barriers in nitrosiminium ions (6-8 kcal/mol) is based on RHF/3-21G energy data computed for nonoptimized structures. 22 The rotation about the N-N bond in the nitrosamines may follow two pathways. The rotation may be such that the nitroso O-atom either approaches or avoids a close approach of the hydroxyl substituent.…”

Computational Prediction of Metabolic alpha-Carbon Hydroxylation Potential of N-Nitrosamines: Overcoming Data Limitations for Carcinogenicity Assessment

“…Specifically, SARs have shown potential as regulatory agencies have utilized surrogate-based SARs to establish acceptable intake levels for some nitrosamine impurities 20 , and several SAR-based studies have been recently published [21][22][23] . Quantum chemical approaches have also been applied to calculate the reactivity of Nnitrosamines, as demonstrated by Wenzel et al 24 and others 25,26 .…”