Substitution at Carbonyl

The two-step mechanism for substitution at carbonyl C is much more reasonable than a one-step, Sn2 mechanism for several reasons. The C=0 rrbond is higher in energy than the C(sp )—X bond, so it s easier to break. Moreover, addition of Nu to the C=0 tt bond can occur along a trajectory that is out of the plane of the carbonyl group, whereas an Sn2 trajectory must be in the crowded plane of the carbonyl group. In addition to these theoretical considerations, plenty of experimental evidence suggests that the two-step mechanism is always operative. (See any physical organic chemistry textbook for details.) 

Primary amines react with many esters just upon mixing to give amides. The amines are sufficiently nucleophilic to add to the ester carbonyl. After deprotonation of N, the alkoxy group is a much better leaving group, so collapse of the tetrahedral intermediate occurs with expulsion of OR to give the amide as the product. 

Transesterification of esters occurs by a mechanism very much like amide synthesis, but the reaction requires a catalytic amount of base (usually the Na salt 

The reaction of alcohols with enolizable acyl chlorides or anhydrides can proceed by two different mechanisms. One is the addition-elimination mechanism that has already been discussed  

The other is a two-step, elimination-addition mechanism. In the elimination step, S-elimination occurs by an E2 mechanism to give a ketene, a very reactive compound that is not usually isolable. In the addition step, the alkoxide adds to the electrophilic carbonyl C of the ketene to give the enolate of an ester. Acyl chlorides lacking a-hydrogens (t-BuCOCl, ArCOCl), of course, can react only by the addition-elimination mechanism. 

Transesterification of esters occurs by a mechanism very much like amide synthesis, but the reaction requires a catalytic amount of base (usually the Na salt of the alcohol). The nucleophile is the alkoxide. The reaction is driven in the forward direction by the use of a large excess of the starting alcohol. 

R Xl fast R Cl fast R DMAP fast R DMAP fast R Nu 

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Chapters 1 and 2 dealt with formation of new carbon-carbon bonds by reactions in which one carbon acts as the nucleophile and another as the electrophile. In this chapter we turn our attention to noncarbon nucleophiles. Nucleophilic substitution is used in a variety of interconversions of functional groups. We discuss substitution at both sp3 carbon and carbonyl groups. Substitution at saturated carbon usually involves the Sjv2 mechanism, whereas substitution at carbonyl groups usually occurs by addition-elimination. 

Contrary to conventional reactivity arguments, which imply that substitution at carbonyls by electronegative atoms reduces electron density at the carbonyl carbon and hence promotes addition to carbonyls, a systematic study of 13C NMR shift data for ester carbonyls shows that electron density is actually greater at such carbons (reactivity enhancement is actually due to destabilisation of the ground states of the esters by the electron-withdrawing substituents).132,133 Our observations are in line with those of Neovonen et al. Electron-withdrawing nitrogen in... 

It is useful to classify the more polar solvents (e > 15) into two categories depending on whether they are protic or aprotic. It is found that reactions involving bases, as for example SN2 substitutions (Chapter 4), E2 eliminations (Chapter 7), and substitutions at carbonyl groups (Chapter 8), proceed much faster in dipolar aprotic than in protic solvents, typically by factors of three to four powers of ten and sometimes by as much as six powers of ten.31... 

Predicting the Products of Nucleophilic Substitutions at Carbonyl Groups... 

Sulfur chemistry in action can you make sensible suggestions based on what you know Revision o Chapters 10 (conjugate addition), 12 (substitution at carbonyl groups), and 23 (electrophilic alkenes. ... 

Nucleophilic substitution at carbonyl molecules cyclic compounds ch33... 

Substitution at carbonyl groups chl2 Substitution of the oxygen atom of carbonyl groups chl4 Stereochemistry chl6... 

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. 

Existing textbooks usually fail to show how common mechanistic steps link seemingly disparate reactions, or how seemingly similar transformations often have wildly disparate mechanisms. For example, substitutions at carbonyls and nucleophilic aromatic substitutions are usually dealt with in separate chapters in other textbooks, despite the fact that the mechanisms are essentially identical. This textbook, by contrast, is organized according to mechanistic types, not ac-... 

Nucleophilic substitution at carbonyl Stable and unstable Imlnes Synthesis of alkenes ch27 ... 

Substitutions at carbonyl groups chll ch12 Effects of temperature on reactions Why the solvent matters Rate equations and their link to mechanism ... 

Substitution at carbonyl groups chIO reactions compounds as nucleophiles ch21... 

The photoelectron spectra of the compounds RCS2 CF3 (R = F, Cl, or CFs-S) have been analysed with reference to the spectra of the thioketones R2CS (R = F, Cl, or alkylthio) and through CNDO calculations the CFs-S group has a substituent effect comparable to that of chlorine. i A study of the reactions of the acid derivatives XCO SCl (X = F or Cl) has shown that nucleophilic substitution at carbonyl carbon is more rapid with the dichloro-compound (X = Cl), although the S—Q bonds in both compounds are of comparable reactivity some chemical conversions of the fluoro-compound are shown in Sicheme 32. 

Anomeric and double anomeric effects in phosphates The unusual stereoelectronic properties of negatively charged oxygen as a source of donor orbitals play a role in the formation of tetrahedral intermediates in nucleophilic addition/substitution at carbonyl. It also has important consequences for phosphate transfer reactions - one of the key types of chemical events in biology. 

Nucleophilic Substitution at Carbonyl Carbon 51 Table 3.3 Illustration of the 2x2 array performed in a parallel, phase transfer microreactor. 

NucleophiUc substitution at carbonyl carbon, takes place in bimolecu-lar carboxylic ester hydrolysis with acyl-oxygen fission (21) by the... 

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