Computational studies nucleophilic substitution

Fox, J. M., Dmitrenko, O., Liao, L.-A., Bach, R. D. Computational Studies of Nucleophilic Substitution at Carbonyl Carbon the Sn2 Mechanism versus the Tetrahedral Intermediate in Organic Synthesis. J. Org. Chem. 2004, 69, 7317-7328. 

This chapter deals with silyl-substituted carbocations. In Section II results of quantum chemical ab initio calculations of energies and structures of silyl-substituted carbocations are summarized1. Throughout the whole chapter results of ab initio calculations which relate directly to the experimental observation of silyl-substituted carbocations and their reactions are reviewed. Section m reports on gas phase studies and Section IV on solvolytic investigations of reactions which involve silyl-substituted carbocation intermediates and transition states. Section V summarizes the structure elucidation studies on stable silyl-substituted carbocations. It includes ultra-fast optical spectroscopic methods for the detection of transient intermediates in solution, NMR spectroscopic investigations of silyl-substituted carbocations in superacids and non-nucleophilic solvents, concomitant computational studies of model cation and X-ray crystallography of some silyl-substituted carbocations which can be prepared as crystals of salts. 

This chapter presents computational studies of organic reactions that involve anions. These reactions are usually not grouped together in textbooks. However, these reactions are fundamentally variations on a theme. Anions, acting as nucleophiles, can attack sp carbon atoms we call these as nucleophilic substitution reactions that follow either the S l or 8 2 mechanism. Reactions where the nucleophile attacks sp or sp carbon atoms are addition reactions. The 1,2- and... 

Stereocontrol in nucleophilic acyl substitution might at first appear to be not an issue, since the carbonyl carbon is achiral. However, if the incoming nucleophile or the leaving group are chiral, then the TS and intermediates could be diasterotopic, and selectivity can occur (see Scheme 6.5). Houk and Birman address this in a computational study of kinetic resolution of carboxylic acids. They found that the Felkin-Anh model applies, extending its applicability to the nucleophilic acyl substitution. 

Another important example of hypervalent bonding is the transition state in the Sn2 nucleophilic substitution reaction, which has the same orbital configuration and electron count as a 10-electron hypervalent system. For nucleophilic substitution, the hypervalent species is a transition state rather than a stable species, as shown schematically in Figure 5. Experimental and computational studies on transition states are generally difficult. Stable hypervalent systems can serve as more tractable benchmarks to test the accuracy of computational techniques used on 10-electron systems. 

Widdowson, Rzepa and coworkers reported ab initio and MNDO-d SCF-MO computational studies of the extrusion reactions of diaryliodonium fluorides [202-204]. The results of these studies, in particular, predicted that the intermediates and transition states in these reactions might involve dimeric, trimeric and tetrameric structures. The regioselectivity of nucleophilic substitution in these reactions was investigated theoretically and supported by some experimental observations. 

One of the most spectacular application of solvent effects evaluation by computer simulation techniques is the study of nucleophilic addition and the bimolecular nucleophilic substitution Sj 2 reactions. 

Although the nucleophilic aromatic substitution of electron-deficient arenas with nucleophiles has been known for more than 100 years, to the best of our knowledge, there is no review on the asymmetric version of this reaction [1,2], Within the context of this chapter, we have classified the main approaches involving asymmetric nucleophihc aromatic substitution reactions (Sj Ar ). We detail the current mechanistic understanding based on experimental and computational studies, and we summarize a selection of representative synthetic apphcations. 

Scheme 5 shows also configuration 25 which describes an electron transfer from the nucelophile to the cation radical. The VB mixing between 25 and the reactant state 23 is proportional to the overlap of the nucleophile with the substitution process. Consequently, the electron transfer configuration will mix into the TS for the nucleophilic cleavage reaction, and vice versa. This has been shown in recent computational studies. ... 

Computational studies of chemical reactions dynamics at liquid/vapor and liquid/liquid interfaces to date include the following types of reactions isomerization, photodissociation, acid dissociation, electron transfer, proton transfer, ion transfer, and nucleophilic substitution. These studies have been motivated by experimental observations and fundamental scientific interest in understanding how the unique surface properties affect chemical reactivity. Some of these studies have been reviewed.Here we present two examples selected to demonstrate the computational steps described above and their relation to the concepts developed in earlier sections. The focus is on contrasting the surface reactivity with that in the bulk and on examining surface effects in light of the knowledge about the structure and dynamics of neat interface and interfacial solvation, discussed earlier in the chapter. 

With a-substituted pyrrolidine catalysts, there are a few mechanistic issues that deserve to be mentioned. Firstly, the formation of pyrrolidine enamine with the nucleophilic partner could encounter increased steric encumbrance near the amino nitrogen that can result in reduced efficiency. Secondly, alternative mechanisms without the involvement of enamines could also be operating [40]. However, among the limited set of available computational studies on a-substituted pyrrolidines, the enamine pathway has been effective towards rationalizing the stereochemical outcome of the reaction. In most of these, a steric control driven transition state model has been invoked wherein the incoming electrophile is guided towards the enamine double bond from the face opposite to that of the bulky a-substituent. 

A review has been published regarding computational studies of arenes, linear polycyclic aromatics, and their reactivities in electrophilic and nucleophilic processes. There have also been reviews of theoretical studies of electron delocalization and its relevance to electrophilic substitution, and of mechanisms of activation of carbon-hydrogen bonds to reactions with electrophiles. ... 

Additional experimental, theoretical, and computational work is needed to acquire a complete understanding of the microscopic dynamics of gas-phase SN2 nucleophilic substitution reactions. Experimental measurements of the SN2 reaction rate versus excitation of specific vibrational modes of RY (equation 1) are needed, as are experimental studies of the dissociation and isomerization rates of the X--RY complex versus specific excitations of the complex s intermolecular and intramolecular modes. Experimental studies that probe the molecular dynamics of the [X-. r - Y]- central barrier region would also be extremely useful. 

The data in Table 9 also allows one to reach conclusions regarding the elec-trophilicity vs nucleophilicity of the partially-fluorinated radicals since the three styrene substrates have a considerable range in IP values. /1-Fluorine, and to a lesser extent y-fluorine, substitution would appear to have a small impact on electrophilicity, whereas a single a-fluorine substituent seems to impart slightly nucleophilic properties. In a recent study, Takeuchi et al. have examined both computationally and experimentally radicals which bear both an a-fluorine substituent and an electron withdrawing ester function. They found that the a-fluorine substituent makes such radicals more electrophilic, but that they still add more readily to styrene than they do to acrylonitrile [127],... 

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