Acid nucleophilic addition reactions

A very elegant expansion of the synthetic utility of this intramolecular amination was the insertion reactions into ethereal G-H bonds. Du Bois and co-workers have exploited this reactivity to prepare cyclic sulfamates that are then used as iminium ion equivalents. Upon treatment with a suitable Lewis acid, nucleophilic addition reactions... 

Because of thetr electron deficient nature, fluoroolefms are often nucleophihcally attacked by alcohols and alkoxides Ethers are commonly produced by these addition and addition-elimination reactions The wide availability of alcohols and fliioroolefins has established the generality of the nucleophilic addition reactions The mechanism of the addition reaction is generally believed to proceed by attack at a vinylic carbon to produce an intermediate fluorocarbanion as the rate-determining slow step The intermediate carbanion may react with a proton source to yield the saturated addition product Alternatively, the intermediate carbanion may, by elimination of P-halogen, lead to an unsaturated ether, often an enol or vinylic ether These addition and addition-elimination reactions have been previously reviewed [1, 2] The intermediate carbanions resulting from nucleophilic attack on fluoroolefins have also been trapped in situ with carbon dioxide, carbonates, and esters of fluorinated acids [3, 4, 5] (equations 1 and 2)... 

The nucleophilic addition reaction of urea to formaldehyde produces mainly monomethylol urea and some dimethylol urea. When the mixture is heated in presence of an acid, condensation occurs, and water is released. This is accompanied by the formation of a cross inked polymer ... 

The second fundamental reaction of carbonyl compounds, nucleophilic acyl substitution, is related to the nucleophilic addition reaction just discussed but occurs only with carboxylic acid derivatives rather than with aldehydes and ketones. When the carbonyl group of a carboxylic acid derivative reacts with a nucleophile, addition occurs in the usual way, but the initially formed tetra-... 

Evidently, a pH of 4.5 represents a compromise between the need for some acid to catalyze the rate-limiting dehydration step but not too much acid so as to avoid complete protonation of the amine. Each individual nucleophilic addition reaction has its own requirements, and reaction conditions must be optimized to obtain maximum reaction rates. 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

Step 4 of Figure 29.12 Oxidative Decarboxylation The transformation of cr-ketoglutarate to succinyl CoA in step 4 is a multistep process just like the transformation of pyruvate to acetyl CoA that we saw in Figure 29.11. In both cases, an -keto acid loses C02 and is oxidized to a thioester in a series of steps catalyzed by a multienzynie dehydrogenase complex. As in the conversion of pyruvate to acetyl CoA, the reaction involves an initial nucleophilic addition reaction to a-ketoglutarate by thiamin diphosphate vlide, followed by decarboxylation, reaction with lipoamide, elimination of TPP vlide, and finally a transesterification of the dihydrolipoamide thioester with coenzyme A. 

Step 1 of Figure 29.14 Transimination The first step in transamination is trans-imination—the reaction of the PLP—enzyme imine with an a-amino acid to give a PLP—amino acid imine plus expelled enzyme as the leaving group. The reaction occurs by nucleophilic addition of the amino acid -NH2 group to the C=N bond of the PLP imine, much as an amine adds to the C=0 bond of a ketone or aldehyde in a nucleophilic addition reaction (Section 19.8). The pro-tonated diamine intermediate undergoes a proton transfer and expels the lysine amino group in the enzyme to complete the step. 

Walden, Paul, 360 Walden inversion. 359-360 Wang resin, solid-phase peptide synthesis and. 1037 Water, acid-base behavior of, 50 dipole moment of, 39 electrostatic potential map of. 53 nucleophilic addition reactions of, 705-706 pKaof, 51-52... 

Results of nucleophilic addition reactions to various a-oxo 4,5-dihydrooxazoles are summarized in Table 24. In general, the diastereoselectivity of these reactions is low to moderate, although an increased selectivity is found in the presence of triethylamine or N,N,N, N -te-tramethylethylenediamine, which slow down the rate of reaction. Nevertheless, enantiomerical-ly pure 2-hydroxy carboxylic acids can be prepared by this method, since the diastereomeric addition products are separable either by recrystallization or HPLC21. 

Besides high effectiveness in the diastereoselective control of nucleophilic addition reactions, another major goal in the design of chiral auxiliaries is the use of readily available, chiral starting materials. The hexahydro-l//-pyrrolo[l,2-c]imidazole derivatives 9a-e are examples which use the inexpensive amino acid L-proline (7) as starting material. 

The electron-donor N -oxide oxygen atom of a nitrone makes it suitable for com-plexation and protonation. Such properties of nitrones have been widely used to influence their reactivity, using Lewis acids and protonation in nucleophilic addition reactions (see Section 2.6.6). In this chapter, the chemistry of nitrones with various metal ions [Zn (II), Cu(II), Mn (II), Ni (II), Fe (II), Fe (III), Ru (II), Os (II), Rh (I), UO2 2 ] (375, 382, 442-445), and diarylboron chelates is described (234—237, 446). Accurate descriptions of the structures of all complexes have been established by X-ray analysis. 

This is a further example of a carbonyl-electrophile complex, and equivalent to the conjugate acid, so that the subsequent nucleophilic addition reaction parallels that in hemiacetal formation. Loss of the leaving group occurs first in an SNl-like process with the cation stabilized by the neighbouring oxygen an SN2-like process would be inhibited sterically. It is also possible to rationalize why base catalysis does not work. Base would simply remove a proton from the hydroxyl to initiate hemiacetal decomposition back to the aldehyde - what is needed is to transform the hydroxyl into a leaving group (see Section 6.1.4), hence the requirement for protonation. 

Murahashi and co-workers (49) extensively studied the synthesis of nitrones such as 29 by a decarboxylative oxidation of proline derivatives (Scheme 12.12). However, these nitrones were primarily used in nucleophilic addition reactions rather than 1,3-dipolar cycloadditions. Others have synthesized cyclic nitrones 30 and 31 having a chiral center adjacent to the nitrogen atom (50,51). Saito and co-workers (51) applied nitrone 31 in reactions with fumaric and maleic acid... 

The hydrogen (known as an a-hydrogen) bonded to a carbon adjacent to a carbonyl carbon (called an a-carbon) is acidic enough to be removed by a strong base, usually NaOH, to form an enolate anion. The enolate anion adds to the carbonyl carbon of a second molecule of aldehyde or ketone via nucleophilic addition reaction. 

If the nucleophile is a neutral molecule with a lone pair of electrons (H2O, ROH), it requires an acid catalyst for nucleophilic addition reaction to occur. Under acidic conditions, the carhonyl group becomes protonated, and thus is activated towards nucleophilic acyl substitution. Attack by a weak nucleophile generates the tetrahedral intermediate. A simultaneous deprotonation and loss of the leaving group reforms the carbonyl C=0 double bond. 

Methacrylonitrile (1) differs from 2 only in that it has a methyl (CH3) group on the a-carbon atom. It too is widely used in the preparation of homopolymers and copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. In a study conducted by the NTP in which 1 was administered orally to mice for 2 years, there was no evidence that it caused cancer, although other less serious toxic effects were noted [27]. Because 1 does not cause cancer, but undergoes many of the same nucleophilic addition reactions as 2 at the (3-carbon, it is sometimes used as a safer commercial replacement for 2, such as in the manufacture of an acrylonitrile-butadiene-styrene-like polymer that provides improved barrier properties to gases such as carbon dioxide in carbonated beverage containers. 

When a stepwise ionic addition reaction involves nucleophilic attack at carbon as a first step, it is described as a nucleophilic addition. Reactions of this type often are catalyzed by bases, which generate the required nucleophile. For example, consider the addition of some weakly acidic reagent HX to an alkene. In the presence of a strong base ( OH), HX could give up its proton to form the conjugate base Xe, which is expected to be a much better nucleophile than HX ... 

Many nucleophilic addition reactions have considerable synthetic value, particularly those involving addition of carbon acids, such as HCN, because they provide ways of forming carbon-carbon bonds. More of their utility will be discussed in Chapters 14, 17, and 18. 

Carboxylic acids, acid chlorides, acid anhydrides and esters get reduced to primary alcohols when treated with lithium aluminium hydride (LiAlH) (Fig.M). The reaction involves nucleophilic substitution by a hydride ion to give an intermediate aldehyde. This cannot be isolated since the aldehyde immediately undergoes a nucleophilic addition reaction with another hydride ion (Fig.N). The detailed mechanism is as shown in fig.O. 

Coordination of the Lewis acid zinc(II) chloride to glycosyl imines has strong influence on the stereodifferentiation in nucleophilic addition reactions to these imines (see Scheme 3). 

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