Nucleophilic additions groups

Example Solvation can have a profound effect on the potential energy profile for a reaction. Jorgensen s research group provided important insights into the role of solvation. Consider the nucleophilic addition of the hydroxide anion to formaldehyde ... 

With the dicyclohexylcarbodiimide (DCQ reagent racemization is more pronounced in polar solvents such as DMF than in CHjCl2, for example. An efficient method for reduction of racemization in coupling with DCC is to use additives such as N-hydroxysuccinimide or l-hydroxybenzotriazole. A possible explanation for this effect of nucleophilic additives is that they compete with the amino component for the acyl group to form active esters, which in turn reaa without racemization. There are some other condensation agents (e.g. 2-ethyl-7-hydroxybenz[d]isoxazolium and l-ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline) that have been found not to lead to significant racemization. They have, however, not been widely tested in peptide synthesis. 

The rearrangement discovered by Kolosova et al. probably involves such reactivit (159). This reaction provides a good preparative method for various 5-amino-methylthiazoles (Scheme 43). No mechanism is proposed in the report, and it is not easy to understand how the C-5 enamine-like position competes with the very nucleophilic thiocarbonyl group of the formed A-4-thiazoline-2-thione. An alternative mechanism could start with ethanol addition at C-2. leading to the A-4-thiazoline (90) (Scheme 44). In this intermediate, C-5 nucleophilic reactivity would be favored bv the true enaminic structure. After alkylation on C-5,... 

The reaction of amines with the 4-phenylazo derivative (228) results in their rearrangement into triazolines. Depending on the basicity of the amines and the size of the alkoxy group, three different triazolines (229. 230, and 231) are obtained (Scheme 117) (454. 459, 472). In all cases, the first step involves nucleophilic addition of the amine to the carbonyl group followed by ring opening and further ring closure. 

Aldehydes and Ketones Nucleophilic Addition to the Carbonyl Group... 

ALDEHYDES AND KETONES NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP... 

Although the present chapter includes the usual collection of topics designed to acquaint us with a particular class of compounds its central theme is a fundamental reaction type nucleophilic addition to carbonyl groups The principles of nucleophilic addition to aide hydes and ketones developed here will be seen to have broad applicability m later chap ters when transformations of various derivatives of carboxylic acids are discussed... 

The most important chemical property of the carbonyl group is its tendency to undergo nucleophilic addition reactions of the type represented m the general equation... 

The next section explores the mechanism of nucleophilic addition to aldehydes and ketones There we 11 discuss their hydration a reaction m which water adds to the C=0 group After we use this reaction to develop some general principles we 11 then survey a number of related reactions of synthetic mechanistic or biological interest... 

Step 1 Nucleophilic addition of hydroxide ion to the carbonyl group ... 

Steric and electronic effects influence the rate of nucleophilic addition to a proton ated carbonyl group m much the same way as they do for the case of a neutral one and protonated aldehydes react faster than protonated ketones... 

Cyanohydrin formation is reversible and the position of equilibrium depends on the steric and electronic factors governing nucleophilic addition to carbonyl groups described m the preceding section Aldehydes and unhindered ketones give good yields of cyanohydrins... 

Many of the most interesting and useful reactions of aldehydes and ketones involve trans formation of the initial product of nucleophilic addition to some other substance under the reaction conditions An example is the reaction of aldehydes with alcohols under con ditions of acid catalysis The expected product of nucleophilic addition of the alcohol to the carbonyl group is called a hemiacetal The product actually isolated however cor responds to reaction of one mole of the aldehyde with two moles of alcohol to give gem mal diethers known as acetals... 

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... 

Steps 1-3 Acid catalyzed nucleophilic addition of 1 mole of ethanol to the carbonyl group The details of these steps are analogous to the three steps of acid catalyzed hydration in Figure 17 7 The product of these three steps is a hemiacetal... 

The carbinolamine is formed by nucleophilic addition of the amine to the carbonyl group Its dehydration gives the imine product... 

A number of compounds of the general type H2NZ react with aldehydes and ketones m a manner analogous to that of primary amines The carbonyl group (C=0) IS converted to C=NZ and a molecule of water is formed Table 17 4 presents exam pies of some of these reactions The mechanism by which each proceeds is similar to the nucleophilic addition-elimination mechanism described for the reaction of primary amines with aldehydes and ketones... 

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