Addition reactions philicity

Carbene protonation has been amply demonstrated by product studies, time-resolved spectroscopy, and kinetic measurements. The ability of singlet carbenes to accept a proton is not adequately described by the traditional scale of carbene philicities, which is based on addition reactions with alkenes. In particular, aryl- and diarylcarbenes excel as proton acceptors but would traditionally be classified as electrophiles. 

Philicity. A principal feature of the carbene-alkene addition reaction (Scheme 7.1) is the carbene s phihcity, that is the electronic character of its selectivity or response to the alkene s substituents. Early work of SkeU and Garner and Doering and Henderson showed that CBr2 and CCI2 preferentially... 

A deeper understanding of carbenic philicity requires a more detailed representation of the addition reaction transition state than that afforded by structure 4. Early MO calculations furnished structure 6 as representative of the transition state for addition of a singlet carbene to an alkene (Fig. 7.6). " ... 

Extreme cases were reactions of the least stabilized, most reactive carbene (Y = CF3, X = Br) with the more reactive alkene (CH3)2C=C(CH3)2, and the most stabilized, least reactive carbene (Y = CH3O, X = F) with the less reactive alkene (1-hexene). The rate constants, as measured by LFP, were 1.7 x 10 and 5.0 X lO M s, respectively, spanning an interval of 34,000. In agreement with Houk s ideas,the reactions were entropy dominated (A5 —22 to —29e.u.). The AG barriers were 5.0 kcal/mol for the faster reaction and 11 kcal/ mol for the slower reaction, mainly because of entropic contributions the AH components were only —1.6 and +2.5 kcal/mol, respectively. Despite the dominance of entropy in these reactive carbene addition reactions, a kind of de facto enthalpic control operates. The entropies of activation are all very similar, so that in any comparison of the reactivities of alkene pairs (i.e., ferei)> the rate constant ratios reflect differences in AA//t, which ultimately appear in AAG. Thus, car-benic philicity, which is the pattern created by carbenic reactivity, behaves in accord with our qualitative ideas about structure-reactivity relations, as modulated by substiment effects in both the carbene and alkene partners of the addition reactions. " Finally, volumes of activation were measured for the additions of CgHsCCl to (CH3)2C=C(CH3)2 and frani-pentene in both methylcyclohexane and acetonitrile. The measured absolute rate constants increased with increasing pressure Ayf ranged from —10 to —18 cm /mol and were independent of solvent. These results were consistent with an early, and not very polar transition state for the addition reaction. 

In general, inert SSE s tend to favor coupling reactions between two or more substrate molecules whereas those with nucleophilic or electrophilic properties favor substitution or addition reactions. As an example the anodic oxidation of durene 78 on platinum can be controlled to give substitution product only in a strongly nucleophilic SSE (Eq. (17) ) and coupling product only in a non-nucleo-philic SSE (Eq. (20)). In SSE s of intermediate nucleophilicity, both types of products are formed (Eqs. (18) and (19)). 

The elementary reactions of carbocationic polymerizations can be separated into three types. Deactivation of carbenium ions with anions and transfer to counteranion are ion-ion reactions, propagation and transfer to monomer are ion-dipole reactions, and ionization is a dipole-dipole reaction [274]. Ion-ion and dipole-dipole reactions with polar transition states experience the strongest solvent effects. Carbocationic propagation is an ion-dipole reaction in which a growing carbenium ion adds electro-philically to an alkene it should be weakly accelerated in less polar solvents because the charge is more dispersed in the transition state than in the ground state [276]. However, a model addition reaction of bis(p-methoxyphenyl)carbenium ions to 2-methyl- 1-pentene is two times faster in nitroethane (e = 28) than in methylene chloride (e = 9) at - 30° C [193]. However, this is a minor effect which corresponds to only ddG = 2 kJ morit may also be influenced by specific solvation, polarizability, etc. [276,277]. 

Another micle<)philic addition reaction—this time in reirerae is involved in the chemical defense mechanism by which the millipede Aphe-loria corrugata protects itself from predators. When attacked by ants, it secretes the cyanohydrin maridcl-oniti ile and an enzyme that catalyze the decomposition of mandelonitriie into benzaldehyde and HCN.The millipede actually protects itself by discharging poiBonoua HCN at its attackers. 

The electrophilicity index also accounts for the electrophilic activation/deactivation effects promoted by EW and electron-releasing substituents even beyond the case of cycloaddition processes. These effects are assessed as responses at the active site of the molecules. The empirical Hammett-like relationships found between the global and local electrophilicity indexes and the reaction rate coefficients correctly account for the substrate selectivity in Friedel-Crafts reactions, the reactivity of carbenium ions, the hydrolysis of esters, the reactivity at the carbon-carbon double bonds in conjugated Michael additions, the philicity pattern of carbenes and the superelectrophilicity of nitronium, oxonium and carboxonium ions. This last application is a very promising area of application. The enhanced electrophilicity pattern in these series results from... 

Eq. 4 enabled an empirical analysis of carbenic selectivity (or philicity). (1) It correlated the selectivities of many of the carbenes that had been studied up to 1976. [8,17] (2) It quantitated the qualitative concepts of carbene-aUcene addition reactions that were prevalent. (3) Most importantly, it could be used to estimate the selectivity of new carbenes. (4) It led to the identification of ambi-philic carbenes. (5) It would later be found to parallel conclusions drawn from ah intio electronic structure calculations of carbene-alkene addition reactions. Eet s examine features (1) - (4) ah initio calculational results will be considered below, in Section 2.1. 

Nevertheless, the use of relative reactivities to characterize carbenic philicity is restrictive the apparent philicity is related to the alkenes selected for the relative reactivity measurements. What if the set of alkenes were expanded by the addition of an even more electron-deficient alkene Such a test was applied in 1987 [65], using a-chloroacrylonitrile, 26, which is more 7t-electron deficient than acrylonitrile, 27. We found that PhCF or PhCCl added 15 or 13 times, respectively, more rapidly to 26 than to 27. In preferring the more electron-deficient olefin, the carbenes exhibited nucleophilic character. However, because they also behave as electrophiles toward other alkenes (Table 4), they must in reality be ambiphiles. In fact, we now realize that all carbenes have the potential for nucleophilic reactions with olefins the crucial factor is whether the carbene s filled a orbital (HOMO)/alkene vacant Ji orbital (LUMO) interaction is stronger than the carbene s vacant p orbital (LUMO)/aIkene filled k orbital (HOMO) interaction in the transition state of the addition reaction. [63]... 

It was clear that we needed a better theoretical Iramework to parallel and permit interpretation of carbenic philicity. Two crucial developments occurred around 1980 the application of ab initio computational methods and frontier molecular orbital (FMO) theory to carbene/alkene addition reactions, and the measurement of absolute rate constants for these reactions by laser flash photolysis (LFP). Together, these approaches greatly clarified our understanding of carbenic selectivity and philicity, and defined the current state of the art. ... 

Despite the dominance of entropy in these reactive carbene addition reactions a kind of defacto enthalpic control operates the entropies of activation are all very similar, so that in any comparison of the reactivities of alkene pairs (i.e., rgi), the rate constant ratios reflect differences in AAHi, which ultimately appear in AAGf Thus carbenic philicity, which is the pattern created by carbenic reactivity, behaves in accord with our qualitative ideas about structure/reactivity relations, as modulated by substituent effects in both the carbene and alkene partners of the addition reactions. [66,99]... 

Although we have restricted our discussions of carbenic philicity to carbene/ alkene addition reactions, the use of other substrates can also be informative. For example, both MeCOMe and (MeO)2C react with (oligomeric) methanol in pentane to give the formal 0-FI insertion products, 36 and 37, respectively. [72,73] As we would expect, the reaction of MeCOMe (7x10 M" s" ) is more rapid than that of (MeO)2C (2.5 x 10 M" s" ). Further study of the reactions of (MeO)2C with a wide range of hydroxylic substrates shows that log inversely proportional to the of ROFI, affording a Bronsted relation with a = -0.66. [107] Furthermore, from the absolute rate constants for (MeO)2C reactions with MeOH and MeOD, the primary kinetic isotope effect for the... 

The philicity of a carbene directly depends on the structure of the transition state of an addition reaction. The rules of orbital symmetry conservation forbid the least-motion C2v-symmetry reaction path [41]. For electrophilic carbenes, characterized by predominance of the n — p interaction, preferable is the so-called 7r-approach (Fig. 8.3). In the case of nucleophilic carbenes, optimum conditions for the overlap between the (Tcxy 7r -orbitals are provided by the asymmetrical cr-approach (Fig. 8.3b). By making use of certain assumptions, Rondan, Houk, and Moss [44, 45] calculated the overlap integrals Sjj between the corresponding frontier orbitals of carbene and alkene for the n- and the (7-approaches. Then, having computed the energies of those orbitals, they obtained the energies of stabilization of the composite system arising in two... 

A characteristic of transition states of the carbene-to-alkene addition reactions, particularly sensitive to the philicity of a carbene, is the angle of slope of the carbene plane relative to the double-bond plane. According to calculations [44, 45] one may hold that the carbenes for which in the transition states of addition to alkenes the angle a < 45° are electrophilic. The angle a > 50° is typical of nucleophilic carbenes, while the 45° < a < 50° region relates to the ambiphilic carbenes. Ab initio [44, 52, 53] and semiempirical (MNDO) [54] calculations of pathways of addition reactions of various carbenes have verified this dependence. 

The overall reaction catalyzed by epoxide hydrolases is the addition of a H20 molecule to an epoxide. Alkene oxides, thus, yield diols (Fig. 10.5), whereas arene oxides yield dihydrodiols (cf. Fig. 10.8). In earlier studies, it had been postulated that epoxide hydrolases act by enhancing the nucleo-philicity of a H20 molecule and directing it to attack an epoxide, as pictured in Fig. 10.5, a [59] [60], Further evidence such as the lack of incorporation of 180 from H2180 into the substrate, the isolation of an ester intermediate, and the effects of group-selective reagents and carefully designed inhibitors led to a more-elaborate model [59][61 - 67]. As pictured in Fig. 10.5,b, nucleophilic attack of the substrate is mediated by a carboxylate group in the catalytic site to form an ester intermediate. In a second step, an activated H20... 

In spite of the known tendency of norbornene and related systems to undergo rearrangements of the Wagner-Meerwein type during eleetro-philic addition, no such rearrangement was observed when norbornene underwent cycloaddition with the acridizinium or the. A/ -methylenium benzamide cation. As Schmidt correctly pointed out, this lack of rearrangement is an argument for a concerted reaction. Alternatively, if the cycloaddition is nonsynchronous, the time interval between step 1 and step 2 must be very short. 

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