Stability nucleophilic addition

The mechanism for formation of benzaldehyde diethyl acetal which proceeds m two stages is presented m Figure 17 9 The first stage (steps 1-3) involves formation of a hemiacetal m the second stage (steps 4-7) the hemiacetal is converted to the acetal Nucleophilic addition to the carbonyl group characterizes the first stage carbocation chemistry the second The key carbocation intermediate is stabilized by electron release from oxygen... 

One of the most important and general trends in organic chemistry is the increase in carbocation stability with additional alkyl substitution. This stability relationship is fundamental to imderstanding many aspects of reactivity, especially of nucleophilic... 

Q Nucleophilic addition of hydroxide ion to the electron-poor aromatic ring takes place, yielding a stabilized carbanion intermediate. 

The hydration reaction just described is typical of what happens when an aldehyde ot ketone is treated with a nucleophile of the type H-Y, where the Y atom is electronegative and can stabilize a negative charge (oxygen, halogen, or sulfur, for instance). In such reactions, the nucleophilic addition is reversible, with the equilibrium generally favoring the carbonyl reactant rather than the tetrahedral addition product. In other words, treatment of an aldehyde or... 

Reduction Conversion of Nitriles into Amines Reduction of a nitrile with LiAIH4 gives a primary amine, RNH . The reaction occurs by nucleophilic addition of hydride ion to the polar C=N bond, yielding an imine anion, which still contains a C=N bond and therefore undergoes a second nucleophilic addition of hydride to give a dianion. Both monoanion and dianion intermediates are undoubtedly stabilized by Lewis acid-base complexafion to an aluminum species, facilitating the second addition that would otherwise be difficult Protonation of the dianion by addition of water in a subsequent step gives the amine. 

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

I-Oialkoxy carbonyl compounds are a special class of chiral alkoxy carbonyl compounds because they combine the structural features, and, therefore, also the stereochemical behavior, of 7-alkoxy and /i-alkoxy carbonyl compounds. Prediction of the stereochemical outcome of nucleophilic additions to these substrates is very difficult and often impossible. As exemplified with isopropylidene glyceraldehyde (Table 15), one of the most widely investigated a,/J-di-alkoxy carbonyl compoundsI0S, the predominant formation of the syn-diastereomer 2 may be attributed to the formation of the a-chelate 1 A. The opposite stereochemistry can be rationalized by assuming the Felkin-Anh-type transition state IB. Formation of the /(-chelate 1C, which stabilizes the Felkin-Anh transition state, also leads to the predominant formation of the atm -diastereomeric reaction product. 

Thus, polymerization will always occur when kp > k<, -E k ([solv] + pC ]). In the case of highly electron-donating substituents the stability of the radical cations may be so great that k > kp + k ([solv] -E PC ]) and most of the ions diffuse into the solution. By contrast, if — given electron-withdrawing subsituents and high oxidation potential — k ([solv] + PC ]) becomes greater than kp -E k, then the nucleophilic addition will dominate and the polymerization will be suppressed. 

Such an intermediate ean also stabilize itself by combining with a positive species. When it does, the reaction is nucleophilic addition to a C=C double bond (see Chapter 15). It is not surprising that with vinylie substrates addition and substitution often compete. For chloroquinones, where the charge is spread by resonance, tetrahedral intermediates have been isolated ... 

Protonation of the enolate ion is chiefly at the oxygen, which is more negative than the carbon, but this produces the enol, which tautomerizes. So, although the net result of the reaction is addition to a carbon-carbon double bond, the mechanism is 1,4 nucleophilic addition to the C=C—C=0 (or similar) system and is thus very similar to the mechanism of addition to carbon-oxygen double and similar bonds (see Chapter 16). When Z is CN or a C=0 group, it is also possible for Y to attack at this carbon, and this reaction sometimes competes. When it happens, it is called 1,2 addition. 1,4 Addition to these substrates is also known as conjugate addition. The Y ion almost never attacks at the 3 position, since the resulting carbanion would have no resonance stabilization " ... 

The Knoevenagel reaction has many similarities to the Michael addition, in which a base is required to form a carbanion Ifom an activated methylene precursor which subsequently undergoes nucleophilic addition to an alkene containing a group such as an ester capable of stabilizing the resulting anion by delocalization. These reactions are widely used for... 

This section deals with reactions that correspond to Pathway C, defined earlier (p. 64), that lead to formation of alkenes. The reactions discussed include those of phosphorus-stabilized nucleophiles (Wittig and related reactions), a a-silyl (Peterson reaction) and a-sulfonyl (Julia olefination) with aldehydes and ketones. These important rections can be used to convert a carbonyl group to an alkene by reaction with a carbon nucleophile. In each case, the addition step is followed by an elimination. 

The pyridine family of heteroaromatic nitrogen compounds is reactive toward nucleophilic substitution at the C(2) and C(4) positions. The nitrogen atom serves to activate the ring toward nucleophilic attack by stabilizing the addition intermediate. This kind of substitution reaction is especially important in the chemistry of pyrimidines. 

In Entry 5, the carbanion-stabilizing ability of the sulfonyl group enables lithiation and is then reductively removed after alkylation. The reagent in Entry 6 is prepared by dilithiation of allyl hydrosulfide using n-bulyl lithium. After nucleophilic addition and S-alkylation, a masked aldehyde is present in the form of a vinyl thioether. Entry 7 uses the epoxidation of a vinyl silane to form a 7-hydroxy aldehyde masked as a cyclic acetal. Entries 8 and 9 use nucleophilic cuprate reagents to introduce alkyl groups containing aldehydes masked as acetals. 

Such nucleophilic displacements are likely to be addition-elimination reactions, whether or not radical anions are also interposed as intermediates. The addition of methoxide ion to 2-nitrofuran in methanol or dimethyl sulfoxide affords a deep red salt of the anion 69 PMR shows the 5-proton has the greatest upfield shift, the 3- and 4-protons remaining vinylic in type.18 7 The similar additions in the thiophene series are less complete, presumably because oxygen is relatively electronegative and the furan aromaticity relatively low. Additional electronegative substituents increase the rate of addition and a second nitro group makes it necessary to use stopped flow techniques of rate measurement.141 In contrast, one acyl group (benzoyl or carboxy) does not stabilize an addition product and seldom promotes nucleophilic substitution by weaker nucleophiles such as ammonia. Whereas... 

In summary, there now exists a body of data for the reactions of carbocations where the values of kjkp span a range of > 106-fold (Table 1). This requires that variations in the substituents at a cationic center result in a >8 kcal mol-1 differential stabilization of the transition states for nucleophile addition and proton transfer which have not yet been fully rationalized. We discuss in this review the explanations for the large changes in the rate constant ratio for partitioning of carbocations between reaction with Bronsted and Lewis bases that sometimes result from apparently small changes in carbocation structure. 

The more favorable partitioning of [1+ ] to form [l]-OH than to form [2] must be due, at least in part, to the 4.0 kcal mol-1 larger thermodynamic driving force for the former reaction (Kadd = 900 for conversion of [2] to [l]-OH, Table 1). However, thermodynamics alone cannot account for the relative values of ks and kp for reactions of [1+] that are limited by the rate of chemical bond formation, which may be as large as 600. A ratio of kjkp = 600 would correspond to a 3.8 kcal mol-1 difference in the activation barriers for ks and kp, which is almost as large as the 4.0 kcal mol 1 difference in the stability of [1]-OH and [2]. However, only a small fraction of this difference should be expressed at the relatively early transition states for the reactions of [1+], because these reactions are strongly favored thermodynamically. These results are consistent with the conclusion that nucleophile addition to [1+] is an inherently easier reaction than deprotonation of this carbocation, and therefore that nucleophile addition has a smaller Marcus intrinsic barrier. However, they do not allow for a rigorous estimate of the relative intrinsic barriers As — Ap for these reactions. 

Fig. 6 Hypothetical free energy reaction coordinate profiles for the interconversion of X-[8]-OH and X-[9] (R = H) and X-[10]-OH and X-[ll] (R = CH3) through the corresponding carbocations. The arrows indicate the proposed eifects of the addition of a pair of ortAo-methyl groups to X-[8]-OH, X-[8+] and X-[9] to give X-[10]-OH, X-[10+] and X-[ll]. A Effect of a pair of or/Ao-methyl groups on the stability of cumyl alcohols. B Effect of a pair of or/Ao-methyl groups on the stability of cumyl carbocations. C Effect of a pair of ortho-methyl groups on the stability of the transition state for nucleophilic addition of water to cumyl carbocations. D Effect of a pair of orf/io-methyl groups on the stability of the transition state for deprotonation of cumyl carbocations.

The results of ab initio calculations provide evidence that Me2NC(S)-[14+] is stabilized by resonance electron donation from the a-thioamide group (A, Scheme 12) and by covalent bridging of sulfur to the benzylic carbon (B, Scheme 12).96 Direct resonance stabilization of the carbocation will increase the barrier to the nucleophile addition reaction, because of the requirement for the relatively large fractional loss of the stabilizing resonance interaction (A, Scheme 12) at the transition state for nucleophile addition to a-substituted benzyl carbocations.8,13,28 91-93 If the solvent adds exclusively to an open carbocation that is the minor species in a mixture of open and closed ions, then... 

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