Carbonyl carbon, nucleophilicity order

The cyclization involves a nucleophilic attack of the malonic ester car-banion on the carbonyl carbon atom of the aldehyde, and the substituted malonic ester carbanion attacks the electron-deficient carbon atom bearing the iodine atom, or in the reverse order, to give 119. The hydroxyl group generated in the first step of the reaction attacks the carbon atom, giving the pyranose product. 

Four-carbon annulation onto the caprolactam ring is accomplished by intramolecular nucleophilic addition of an a-sulfinyl carbanion to the carbonyl group in order to obtain sulfinoenamine 110 (03OBC3495). Moreover, thiocaprolactam (111a) and its Michael adduct 111b, via... 

Similar qualitative relationships between reaction mechanism and the stability of the putative reactive intermediates have been observed for a variety of organic reactions, including alkene-forming elimination reactions, and nucleophilic substitution at vinylic" and at carbonyl carbon. The nomenclature for reaction mechanisms has evolved through the years and we will adopt the International Union of Pure and Applied Chemistry (lUPAC) nomenclature and refer to stepwise substitution (SnI) as Dn + An (Scheme 2.1 A) and concerted bimolecular substitution (Sn2) as AnDn (Scheme 2.IB), except when we want to emphasize that the distinction in reaction mechanism is based solely upon the experimentally determined kinetic order of the reaction with respect to the nucleophile. 

For substitution at a carbonyl carbon, the nucleophilicity order is not the same as it is at a saturated carbon, but follows the basicity order more closely. The reason is presumably that the carbonyl carbon, with its partial positive charge, resembles a proton more than does the carbon at a saturated center. That is, a carbonyl carbon is a much harder acid than a saturated carbon. The following nucleophilicity order for these substrates has been de-termmined 321 Me2C=NO- > EtO" > MeO > OH" > OAr- > N-f > F" > H20 > Br" I". Soft bases are ineffective at a carbonyl carbon.322 In a reaction carried out in the gas phase with alkoxide nucleophiles OR solvated by only one molecule of an alcohol R OH, it was found that both RO and R O" attacked the formate substrate (HCOOR") about equally, though in the unsolvated case, the more basic alkoxide is the better nucleophile.323 In this study, the product ion R"0 was also solvated by one molecule of ROH or R OH. 

The order of nucleophilicity toward a sulfonyl sulfur has been reported as OH > RNH2 > N3 > F > AcO" > Cl > H20 > I. 1732 This order is similar to that at a carbonyl carbon (p. 351). Both of these substrates can be regarded as relatively hard acids, compared to a saturated carbon which is considerably softer and which has a different order of nucleophilicity (p. 350). 

By knowing (or estimating) the pKa of a proton to be removed, it is possible to choose a base with a higher p Ka in order to have essentially complete conversion to the anionic carbon nucleophile. When these conditions are met, proton exchange occurs readily and a carbon nucleophile is produced. It must be remembered, however, that many bases can serve as nucleophiles. If the structural feature which acidified the C-H proton is an electrophile, then a nucleophilic base cannot be used. For example, butyl lithium (pKa > 45) converts phenylacetylene (pKa 25) smoothly to its conjugate base by proton removal, whereas it reacts as a nucleophile with the carbonyl group of acetophenone in spite of the fact that die a protons of acetophenone have pKa = 21 and are thus more acidic than the terminal proton in phenylacetylene. 

Decomposition of Caro s acid is catalysed by acetone.324 A kinetic study in aqueous alkaline medium indicates simple second-order kinetics. Nucleophilic addition of S052- to the carbonyl carbon leads to oxirane by reaction with another SOs2- to give... 

Carboxylic acid derivatives differ gready in their reactivity towards nucleophiles. The order in which they react parallels the leaving group ability of the group Z bonded to the carbonyl carbon. 

As a result, aldehydes and ketones react with nucleophiles. The relative reactivity of the carbonyl group is determined by the number of R groups bonded to it. As the number of R groups around the carbonyl carbon increases, the reactivity of the carbonyl compound decreases, resulting in the following order of reactivity ... 

It seems likely as a consequence that a carbanion may be formed under these experimental conditions at the carbon vicinal to the sulfone group. This anion then would be conveniently placed at a six-carbon-atom distance from the electrophilic carbonyl, thus providing an expedient base to form the C-C bond clearly required for the construction of the six-membered ring of II. However, ketones become tertiary alcohols upon attack by carbon nucleophiles. Consequently, one of the alpha C-C bonds next to this ketone must be broken in order to preserve the ketone of the final product. The electron reorganization that would follow is consistent with a concomitant extrusion of tosylate anion. This is illustrated by three-dimensional structures IV and V (see Scheme 11.1)... 

In general, the alkaline hydrolysis is a second order reaction between ester and hydroxyl ion and involves the rupture of the C—OR link. Remick gives the following mechanism for the alkaline hydrolysis of esters a nucleophilic attack on the carbonyl carbon atom by the hydroxyl ion (first step) simultaneously with, or followed by, an electrophilic attack of the water molecule (second step), which, by a displacement mechanism, breaks the C—OR linkage which has already been weakened by the repulsive effect of the free negative pole. 

The thiolates, though less sensitive to basicity, are more reactive than oxygen anions over the total accessible range of basicity, but intersect the amine line at ca. pA 12. Other reactive nucleophiles which do not fall in the amine, thiolate, or oxygen anion categories are fluoride, thiosulfate, nitrite, azide, and sulfite. Halides other than fluoride, and also thiocyanate, nitrate, sulfate, and thiourea have no reactivity towards p-nitrophenyl acetate (Jencks and Carriuolo, 1960a). The total lack of reactivity of thiocyanate, iodide, bromide, and thiourea, all very polarizable nucleophiles which are reactive to sp carbon, rules out any possibility that polarizability is at all important in nucleophilic reactions at the carbonyl carbon. In general, the order of nucleophilic reactivity to p-nitrophenyl acetate correlates well with nucleophilic reactivity to other carboxylic acid derivatives (see later). Nitrite, however, shows... 

On the other hand, with aryl sulfonates (58) (R = aryl), nucleophilic substitution occurs with preferential sulfur-oxygen bond cleavage since aryl substituents show little tendency to undergo nucleophilic attack (Scheme 44). The relative order of nucleophilicity towards the sulfur atom is similar to that obtaining at a carbonyl carbon atom4b and is reported to be as shown in Figure 3. 

It is widely accepted that the carbonyl reactivity toward nucleophiles increases in the order aldehyde>ketone>ester>amide [6]. This reactivity order is simply based on the extent to which each carbonyl carbon is sterically and electronically activated. However, reactivities might change when these carbonyl substrates are subjected to a Lewis acid. It is generally assumed that the coordination capability of the carbonyl oxygen to Lewis acids is the means by which Lewis acids activate carbonyl substrates. Thus, in some re.spects, the reaction rate parallels the Lewis basicity of the carbonyls. Furthermore, the reactivity of a carbonyl substrate depends on the reaction type as well as the Lewis acid employed. Special care must be taken in assessing the relationship between the relative reaction rate, the relative Lewis basicity, and the inherent carbonyl reactivity of each substrate. It is instructive to take a look at the following example (Schemes 2-2 and 2-3 Fig. 2-1). 

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