Mechanism of the Reaction of α-Haloketones with Weakley Basic Nucleophilic Reagents

Pearson, Ralph G.; Langer, Stanley H.; Williams, Forrest V.; McGuire, William J.

doi:10.1021/ja01140a040

Cited by 54 publications

(29 citation statements)

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Section: Resultsmentioning

confidence: 99%

“…The specific reaction studied, shown in Figure 1, is that of phenacyl bromide 1 with pyridine 2 to form the phenacyl pyridinium bromide salt 3. Its kinetics, which are second-order, have been investigated by a number of authors, e.g., [29][30][31][32][33] .Before describing the methodology and its application, we verify experimentally the validity of the computational approach used in Step 2 to obtain liquid-phase reaction rate constants, based on 4 conventional transition state theory (CTST) 34,35 and a continuum solvation model, as accurate calculations remain challenging. 36 The SMD continuum solvation model 37 is known to predict energies of solvation well, although larger deviations can be noted for alcohols.…”

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confidence: 99%

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Computer-aided molecular design of solvents for accelerated reaction kinetics

et al. 2013

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ABSTRACT:Solvents crucially alter the rates and selectivity of liquid-phase organic reactions, often hindering the development of new synthetic routes or, if chosen wisely, facilitating routes by improving rates and selectivities. To address this challenge, a systematic methodology is proposed that quickly identifies improved reaction solvents by combining quantum mechanical computations of the reaction rate constant in a few solvents with a computer-aided molecular design (CAMD) procedure. The approach allows the identification of a high-performance solvent within a very large set of possible molecules. The validity of our CAMD approach is demonstrated through application to a classical nucleophilic-substitution reaction for the study of solvent effects, the Menschutkin reaction. The results are successfully validated via in-situ kinetic experiments. A space of 1341 solvents is explored in silico, but requiring quantum mechanical calculations of the rate constant in only 9 solvents, and uncovering a solvent that increases the rate constant by 40%.What is the best solvent for a given chemical reaction? Given that the rate and selectivity of chemical reactions can vary by several orders of magnitude in different solvents, 1,2 this question has important ramifications for the exploration of novel reaction routes and the development of industrial processes. 3,4 When investigating new liquid-phase reactions, it is essential to find a solvent that promotes the desired reaction without excessive catalyst deactivation, side-product formation, or solubility limitations. Indeed, a poor solvent choice can result in a missed opportunity to investigate novel chemistry or catalysts. At the process-development level, the problem of solvent choice is 2 compounded by the numerous safety, environmental and process constraints that must be satisfied.Yet, few tools exist to support this decision, especially when it affects reaction kinetics, and researchers are often left to choose on the basis of qualitative chemical knowledge and/or extensive and costly experimental investigations.Advances in the understanding of liquid-phase reactions remain a topic of intense academic interest 5 and practical relevance, as illustrated by identification of the development of solvent selection techniques as a key priority area by the ACS Green Chemistry roundtable. 6 A very promising avenue of research in this direction is the development of Computer-Aided Molecular Design (CAMD) techniques. CAMD offers systematic methodologies, typically in the form of algorithms, to identify chemical species/molecular structures that perform a chosen function best (e.g., maximize the rate of a given reaction). The resulting molecular designs can be used to guide experiments in an otherwise huge space of possibilities. CAMD techniques have been widely applied in the context of solvent design for separations, and have had a significant impact on academic and industrial practice. 7 In a batch extractive distillation for fine chemicals processing, for example, ...

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Computer-aided molecular design of solvents for accelerated reaction kinetics

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“…Interpretation of the enhanced reactivity of ahalocarbonyl compounds suggested in this paper corresponds to an intermediate region of the reaction coordinate in between the very early stage of the process (usually discussed in terms of electrostatics [10]) and the transition state [9]. On the other hand, our interpretation is valid within an extended interval of intermolecular resonance parameters.…”

Section: Discussionmentioning

confidence: 49%

“…[9] about a greater ability of the carbonyl group to delocalize the acquired negative charge owing to the supposed increased polarizability of the CyO bond vs. that of the CyC bond. An alternative explanation of the same phenomenon in terms of electrostatics also deserves mentioning here, namely by an additional electrostatic attraction of the carbonyl dipole for the approaching nucleophile [10] which is also called dual attraction [11]. This way of interpretation evidently refers to the very early stage of the reaction.…”

Section: Introductionmentioning

confidence: 96%

On the origin of the enhanced reactivity of α-halocarbonyl compounds in SN2 processes

Gineitytė

2003

Journal of Molecular Structure: THEOCHEM

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Bimolecular nucleophilic substitution (S N 2) reactions of allyl halogenides (Z-C a H 2-HC b yC g H 2 ; Z ¼ Halogen) and of respective substituted ketones (Z-C a H 2-RC b yO RyCH 3 , C 2 H 5 , etc.) are comparatively studied using the semilocalized quantum-chemical approach suggested previously [J. Mol. Struct. (Theochem) 541 (2001) 1] and based on the power series for the one-electron density matrix [J. Mol. Struct. (Theochem) 343 (1995) 183]. Contributions of the direct (through-space) interaction between the electron-donating orbital of nucleophile and the electron-accepting orbital of the nucleofuge-containing (Z-C a) bond and of various indirect (through-bond) interactions between the same orbitals to the population acquired by the nucleofuge Z during the reaction process may be considered separately and explicitly in this approach. Moreover, orbitals of the nearest-neighborhood of the Z-C a bond play the role of the principal mediators in the indirect interactions. On this basis, the C b yC g and C b yO bonds are compared in respect of mediating abilities of their p-orbitals in the above-mentioned indirect interactions and thereby of their contributions to relative rates of S N 2 processes. It is demonstrated that the indirect participation of the bonding p-orbital of the C b yC g bond contributes to lowering of the total population acquired by the nucleofuge Z owing to the nucleophilic attack and thereby of the relative reaction rate, whereas the increment of the antibonding orbital gives rise to an opposite effect. For highly electron-donating (soft) nucleophiles, the second contribution predominates over the first one, and this fact serves to account for the known higher reactivity of allyl halogenides as compared to respective alkyl halogenides. Furthermore, passing from the C b yC g to the C b yO bond is shown to be accompanied by such changes in shapes and one-electron energies of bond orbitals that ensure a significant reduction of the absolute value of the negative increment of the bonding orbital and a simultaneous increase of the positive contribution of the antibonding orbital to the total population acquired by the nucleofuge. This principal result of the paper forms the basis for a new interpretation of the largely increased reactivity of a-halocarbonyl compounds vs. their hydrocarbon analogues in terms of direct and indirect interactions of bond orbitals. q

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“…Nucleophilic attack at the tetrahedral carbon atom of the hydrate is sterically hindered (substituents at the @-carbon decrease sN2 reactivity; cf. OSTERMAN- GOLKAR et al 1970), whereas the steric requirements of the carbonyl group are low ( PEARSON et al 1952). Chloroacetaldehyde and chloroacetone are characterized by a high reactivity towards thiosulphate compared with the reactivity towards water.…”

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confidence: 99%