An MNDO molecular orbital study of the reactions of protonated oxirane with guanine

Ford, George P.; Smith, Christopher T.

doi:10.1002/qua.560320810

Cited by 4 publications

(3 citation statements)

References 16 publications

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“…5 The electrostatic potential "above" the amino groups in adenine and cytosine is only marginally attractive and in guanine is entirely repulsive (66). Even under the polarizing influence of the approaching electrophile, the electrostatic attraction at the guanine N2 site is a small fraction of that in the 06/7 region (62). Thus, despite the larger covalent interaction for N2-alkylation, the overall stabilization at this position (covalent and electrostatic) is considerably less than for either O6 or 7 attack.…”

Section: Resultsmentioning

confidence: 99%

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Prediction of nucleoside-carcinogen reactivity. Alkylation of adenine, cytosine, guanine, and thymine and their deoxynucleosides by alkanediazonium ions

Ford¹,

Scribner²

1990

Chem. Res. Toxicol.

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MNDO semiempirical molecular orbital calculations for the SN2 alkylation of nucleic acid bases and deoxynucleosides by the methane-, ethane-, and propanediazonium ions are presented. An approximate correlation is demonstrated between the calculated relative activation enthalpies for attack at alternative base sites and the related experimental quantities for DNA modification by alkylnitrosoureas. The empirically observed shift from N- to O-alkylation with increasing complexity of the alkylating agent is reproduced by the calculations and rationalized by using an extension of a model worked out previously for the analogous reactions of simple nucleophiles. According to this model, the energetics of the related SN1 reactions, while not directly involved, have a profound influence on the SN2 transition-state geometries. For reactions in which the SN1 dissociation is unfavorable the forming bond to the incoming nucleophiles in the related SN2 transition state tends to be short and covalent interactions, which favor N-alkylation, play a significant role. When the SN1 reaction is more facile, the SN2 transition states are "looser" and the covalent interactions correspondingly smaller, leading to an overall shift away from N-alkylation. Consideration of the form of the electrostatic potential around the base, in conjunction with these ideas, provides a detailed explanation of the behavior of electrophiles toward the guanine N2-, 7-, and O6-positions. This model unifies much of the language already used in discussions of nucleic acid regiochemistry. At the same time it is consistent with the geometries and charge distributions in the transition states calculated for the gas-phase reaction processes.

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Section: Resultsmentioning

confidence: 99%

“…Interestingly, the types of electrophiles that do modify these sites are all extensively delocalized (8, 9, 79). Here the electrostatic differences between alternative base sites should be of less consequence since the positive charge will be effectively more distant from the reaction site (26,62).…”

Section: Resultsmentioning

confidence: 99%

Prediction of nucleoside-carcinogen reactivity. Alkylation of adenine, cytosine, guanine, and thymine and their deoxynucleosides by alkanediazonium ions

Ford¹,

Scribner²

1990

Chem. Res. Toxicol.

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“…Moreover, oxirane reactions with NuH reagents model the alkylation of DNA molecules with water-soluble diol epoxides formed during the enzyme-catalysed body's metabolism of polynuclear aromatic hydrocarbons [7]. www.prkm.co.uk…”

Section: Introductionmentioning

confidence: 99%

Behaviour Modelling of Organic Bases in the Oxyalkylation Reaction of Proton-Containing Nucleophiles

Bakhtin

Швед

Bespalko

et al. 2018

Progress in Reaction Kinetics and Mechanism

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The mechanism of action of nucleophilic and non-nucleophilic bases in the system “acetic acid (HOAc) – epichlorohydrin (ECH) – R3X (R = alkyl, X = N, P)” has been studied. The observed orders of the reaction with respect to the components were found. It has been proved that the catalytic activity of the starting bases is determined by their nucleophilicity, rather than basicity. It is shown that the crucial stage of the reaction is the quaternisation of the starting base with the formation of a reactive intermediate, the acetate anion. Monitoring of possible paths of oxirane ring-opening by the initial base and the acetate anion was carried out. The behaviour of the model base, triphenylphosphine, in the quaternisation reaction was studied by UV spectroscopy. The rate constants of quaternisation in the reaction of tribenzylamine and triphenylphosphine with ECH have been estimated. The activation parameters of the stages of oxirane ring-opening by trimethylamine and the acetate anion were calculated using a quantum chemical method. It has been shown that the starting base attacks only the activated oxirane, while the acetate anion is capable of nucleophilic opening of both activated and non-activated ECH rings. A scheme for the catalytic opening of the oxirane ring by the bases in the system “ECH – HOAc – R3X” is proposed, which includes a series of both consecutive and parallel stages leading to the formation of the reaction product.

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An MNDO molecular orbital study of the reactions of protonated oxirane derivatives (XCHCH₂OH⁺, X = CN, Cl, CH₃, Ph) with simple nucleophiles. Implications for regioselectivity in the reactions of electrophiles with nucleic acid bases

Ford¹,

Smith²

1989

J Comput Chem

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The gas-phase analogs of the classical SN1 and SN2 reactions of nucleophiles with a series of protonated oxiranes bearing the substituents CN, C1, Me, and Ph were studied using MNDO semiempirical molecular orbital theory. The transition states for nucleophilic attack on the intact rings are calculated to become progressively more "SN1-like," as the ability of the substituent group to stabilize the corresponding ring opened carbenium ion increases. At the same time the activation barriers become progressively smaller and their relative values for different nucleophiles approach the order expected on the basis of a purely electrostatic attraction between the reacting moieties. Exactly the opposite trends are calculated for the transition states for nucleophilic attack on the intermediate carbenium ions. As the stabilities of the latter increase the extent of bond formation, and transfer of charge to the incoming nucleophile also increase. Here, the relative barriers for attack by different nucleophiles approach the order expected on the basis of a superposition of both covalent and electrostatic interactions in which the former dominate. These results support a previously suggested rationalization for the enhanced reactivities of certain alkylating agents towards the exocyclic oxygen atoms, rather than the ring nitrogens, of the nucleic acid bases. They also suggest a new explanation for the tendencies of aralkylating electrophiles to modify the exocyclic amino groups of the nucleic acid bases: sites which are unreactive towards simple alkylating agents.

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An MNDO molecular orbital study of the reactions of protonated oxirane with guanine

Cited by 4 publications

References 16 publications

Prediction of nucleoside-carcinogen reactivity. Alkylation of adenine, cytosine, guanine, and thymine and their deoxynucleosides by alkanediazonium ions

Prediction of nucleoside-carcinogen reactivity. Alkylation of adenine, cytosine, guanine, and thymine and their deoxynucleosides by alkanediazonium ions

Behaviour Modelling of Organic Bases in the Oxyalkylation Reaction of Proton-Containing Nucleophiles

An MNDO molecular orbital study of the reactions of protonated oxirane derivatives (XCHCH₂OH⁺, X = CN, Cl, CH₃, Ph) with simple nucleophiles. Implications for regioselectivity in the reactions of electrophiles with nucleic acid bases

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An MNDO molecular orbital study of the reactions of protonated oxirane with guanine

Cited by 4 publications

References 16 publications

Prediction of nucleoside-carcinogen reactivity. Alkylation of adenine, cytosine, guanine, and thymine and their deoxynucleosides by alkanediazonium ions

Prediction of nucleoside-carcinogen reactivity. Alkylation of adenine, cytosine, guanine, and thymine and their deoxynucleosides by alkanediazonium ions

Behaviour Modelling of Organic Bases in the Oxyalkylation Reaction of Proton-Containing Nucleophiles

An MNDO molecular orbital study of the reactions of protonated oxirane derivatives (XCHCH2OH+, X = CN, Cl, CH3, Ph) with simple nucleophiles. Implications for regioselectivity in the reactions of electrophiles with nucleic acid bases

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An MNDO molecular orbital study of the reactions of protonated oxirane derivatives (XCHCH₂OH⁺, X = CN, Cl, CH₃, Ph) with simple nucleophiles. Implications for regioselectivity in the reactions of electrophiles with nucleic acid bases