The mechanism for nucleophilic substitution of α-carbonyl derivatives. Application of the valence-bond configuration mixing model

McLennan, Duncan J.; Pross, Addy

doi:10.1039/p29840000981

Cited by 30 publications

(20 citation statements)

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“…PhCOCH 2Br) compared to regular alkyl derivatives (e.g. 1 [25]. Whereas PhCOCH 2Br is more reactive than RBr toward strong nucleophiles [23], a Hammett p study also shows it to be more selective [24].…”

Section: Nucleophilic Aliphatic Substitutionmentioning

confidence: 93%

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Limitations of the Reactivity—Selectivity Principle. Application to Free Radical Addition to Alkenes and Nucleophilic Aliphatic Substitution

Pross

1985

Israel Journal of Chemistry

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The limitations of the reactivity—selectivity principle (RSP) are discussed in terms of the qualitative configuration mixing (CM) model. It is concluded that the RSP is expected to break down for cases in which the reaction transition state takes on character largely absent in reactants or products, though not all breakdowns of the RSP are attributed to this cause. This conclusion is illustrated with two model reactions that do not follow the RSP: (a) radical addition to alkenes, and (b) nucleophilic aliphatic substitution. Analysis leads us to agree with previous statements by Jencks and Arnett that the RSP should be abandoned as a predictive tool.

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Section: Nucleophilic Aliphatic Substitutionmentioning

confidence: 93%

“…3) is now apparent. while the TS for RCOCH 2 Br substitution will be described by three resonance forms: configuration, 7, in order to build up the reaction profile [25]. It is through this analogy that the limitations of the RSP become evident.…”

Section: Breakdown Of the Rspmentioning

confidence: 99%

Limitations of the Reactivity—Selectivity Principle. Application to Free Radical Addition to Alkenes and Nucleophilic Aliphatic Substitution

Pross

1985

Israel Journal of Chemistry

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“…This effect is believed to result from an enolate-type transition state [166] or from a reaction mechanism in which the nucleophiles initially add to the carbonyl group and then undergo intramolecular 1,2-migration with simultaneous displacement of the leaving group [167] (Scheme 4.43). The latter proposal would also explain the strong decrease of reactivity of phenacyl derivatives on introduction of ortho substituents on the arene.…”

Section: 35mentioning

confidence: 99%

Aliphatic Nucleophilic Substitutions: Problematic Electrophiles

Dörwald

2004

Side Reactions in Organic Synthesis

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Nucleophilic substitutions at sp 3 -hybridized carbon are among the most useful synthetic transformations, and have been thoroughly investigated [1][2][3]. The success of these reactions depends mainly on the structures of the nucleophile and electrophile, their concentration, and on the solvent and reaction temperature chosen. The structure of the electrophile in nucleophilic substitutions is of critical importance, because many unwanted side reactions result from unexpected reactivity of the electrophile.In Scheme 4.1 the mechanisms of typical monomolecular (Sn1) and bimolecular (Sn2) nucleophilic substitutions at a neutral electrophile with an anionic nucleophile are sketched. Sn1 reactions usually occur when the electrophile is sterically

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“…9) but by its conjugation with the p electron pair of the attacked carbon atom of AH. [10][11][12][13][14] It was also sug gested that this effect could lead to the transformation of the reagent in TS into the enolate form. 15 In addition, stabilization of TS was sometimes accounted for by such factors as the promotion of the indirect interaction be tween the frontier orbitals of the substrate and the reagent by the carbonyl group, 16 high electron affinity of the re agent (see Ref.…”

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Mechanism of the reaction of neutral and anionic N-nucleophiles with α-halocarbonyl compounds

2007

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N Acylalkylation of neutral and anionic N nucleophiles with α halocarbonyl compounds was investigated by quantum chemical methods in terms of the density functional theory and by experimental methods for 2,3 dihydroimidazo[2,1 b]quinazolin 1(10)H 5 one, its N anion, and simpler model structures. High reactivity of these reagents is determined primarily by stabilization of transition states (TS) by bridge bonds involving halogen or nitrogen atoms rather than by conjugation, as has been commonly accepted. Bridged TS are formed by both the substitution mechanism S N 2 and the addition-elimination mechanism. α Haloalkyl sub stituted zwitterions, which are potential intermediates of stepwise N acylalkylation of neutral N nucleophiles, do not exist in the isolated state, but they are rather efficiently stabilized upon solvation. These zwitterions, as well as analogous O anions generated from anionic N nucleo philes, can serve as intermediates of N acylalkylation, as was demonstrated by localization of the corresponding TS.Key words: acylalkylation, transition states, bridge bonds, α halocarbonyl com pounds, 2,3 dihydroimidazo[2,1 b]quinazolin 1(10)H 5 one, N anion of 2,3 dihydroimid azo[2,1 b]quinazolin 1(10)H 5 one, tetrahedral intermediates, addition-elimination mechanism.When studying N acylalkylation of 2,3 dihydroimid azo[2,1 b]quinazolin 1(10)H 5 one (1) with bielectro philic α haloketones (α acylalkyl halides (AH)) 2, we noticed that there is uncertainty in the interpretation of the mechanism of these synthetically important trans formations. 1a,b For example, the character and the num ber of reaction steps, the role of the second electrophilic center of AH (the CO group) in N acylalkylation, and the factors responsible for higher reactivity of AH compared to that of usual alkyl halides remain unclear.Taking into account the second reaction order, 2-4 the N acylalkylation, like the acylalkylation as a whole, is most commonly considered as the nucleophilic substitu tion by the S N 2 mechanism (see, for example, Refs 5-8). In this case, high activity of AH is generally explained by stabilization of the transition state (TS) of the reaction by the CO group, stabilization being provided not directly by the electron withdrawing character of this group (cf. Ref. 9) but by its conjugation with the p electron pair of the attacked carbon atom of AH. 10-14 It was also sug gested that this effect could lead to the transformation of the reagent in TS into the enolate form. 15 In addition, stabilization of TS was sometimes accounted for by such factors as the promotion of the indirect interaction be tween the frontier orbitals of the substrate and the reagent by the carbonyl group, 16 high electron affinity of the re agent (see Ref. 17),* and, finally, the formation of addi tional nonclassical bonds between the nucleophile or (and) * In the present study, the terms "reagent" and "substrate" are used in the sense opposite to that used in S N 2 reactions based on the classification of the reaction under consideration as acyl a...

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The mechanism for nucleophilic substitution of α-carbonyl derivatives. Application of the valence-bond configuration mixing model

Cited by 30 publications

References 5 publications

Limitations of the Reactivity—Selectivity Principle. Application to Free Radical Addition to Alkenes and Nucleophilic Aliphatic Substitution

Limitations of the Reactivity—Selectivity Principle. Application to Free Radical Addition to Alkenes and Nucleophilic Aliphatic Substitution

Aliphatic Nucleophilic Substitutions: Problematic Electrophiles

Mechanism of the reaction of neutral and anionic N-nucleophiles with α-halocarbonyl compounds

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