Grignard reagent reaction with formaldehyde

It should be noted that, on reaction with Grignard reagents, aldehydes will produce secondary alcohols, whereas ketones will form tertiary alcohols. Often forgotten is the possibility of synthesizing primary alcohols by using formaldehyde as the substrate. 

Formaldehyde reacts with Grignard reagents to form primary alcohols. Sample reaction 22-8... 

Reaction with Grignard Reagents (Section 16.5A) Treating formaldehyde with a... 

The type of alcohol produced depends on the carbonyl compound. Substituents present on the carbonyl group of an aldehyde or ketone stay there—they become substituents on the carbon that bears the hydroxyl group in the product. Thus as shown in Table 14.1, formaldehyde reacts with Grignard reagents to yield primary alcohols, aldehydes yield secondary alcohols, and ketones yield tertiary alcohols. Analogous reactions take place with organolithium reagents. 

Alcohol synthesis via the reaction of Grignard reagents with carbonyl com pounds (Section 14 6) This is one of the most useful reactions in synthetic organ ic chemistry Grignard reagents react with formaldehyde to yield primary alco hols with aldehydes to give secondary alcohols and with ketones to form terti ary alcohols... 

M-Substitution of primary aliphatic amines R1NH2 (R1 = t-Bu, CsHn, cyclopentyl, cyclohexyl, PhMeCH etc.) to yield R2CH2NHR1 (R2 = Et, Ph or PhCH2) is accomplished by condensation of the amine with benzotriazole and formaldehyde, followed by reaction of the products with Grignard reagents (equation 45)126. 

The reaction of aldehydes and ketones with Grignard reagents is a useful method of synthesising primary, secondary, and tertiary alcohols (Following fig.). Primary alcohols can be obtained from formaldehydes, secondary alcohols can be obtained from aldehydes, and tertiary alcohols can be obtained from ketones. The reaction involves the formation of a carbon-carbon bond and so this is an important way of building up complex organic structures from simple starting materials. 

The reactions of Grignard reagents with different types of carbonyl groups yield a number of important functional groups. For example, reaction with formaldehyde yields 1° alcohols with higher aldehydes, 2° alcohols with ketones, 3° alcohols with esters, 3° alcohols with acyl halides, ketones with N,N-dialkylformamides, aldehydes and with carbon dioxide, carboxylic acids. 

The Grignard reagent from 2-thenyl chloride can be obtained by the use of the "cyclic reactor.However, rearrangement occurs in its reaction with carbon dioxide, ethyl chlorocarbonate, acetyl chloride, formaldehyde, and ethylene oxide to 3-substituted 2-methylthio-phenes, Only in the case of carbon dioxide has the normal product also been isolated. 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

One way to create a carbon-carbon bond is to react a Grignard reagent with a carbonyl compound. The result of this reaction is an alcohol derived from an aldehyde. Formaldehyde gives a primary alcohol, but any other aldehyde gives a secondary alcohol. Ketones and esters both react to form tertiary alcohols. 

Only formaldehyde yields a primary alcohol by reaction with a Grignard reagent. Figure 14-3 illustrates the reaction of ethylmagnesium bromide with formaldehyde to form 1-propanol. More-complicated alcohols, such as cyclopentylmethanol, can be synthesized by this means (as shown in Figure 144). 

Like Grignard reagents, organolithium compounds react with formaldehyde to produce a primary alcohol. Figure 14-14 illustrates the reaction of an organolithium reagent with formaldehyde. 

Dibenzocycloheptenone (24-6) also serves as a starting material for the preparation of one of the few medicinal products that contains an acetylenic linkage. Reaction of (24-6) with the Grignard reagent from propargyl bromide leads to the alcohol (27-1). The free proton acetylene is sufficiently acidic for that center to take part in a Mannich reaction. Thus, reaction of (27-1) with formaldehyde and dimethylamine gives the adduct (27-2). Dehydration by means of thionyl chloride completes the synthesis of intriptyline (27-3) [28]. 

The vicinal methylbenzyl alcohols have been prepared in general by the abnormal reaction of the appropriately substituted Grignard reagent with formaldehyde. The present method is preferred because it yields purer products than the Grignard approach. 

The great synthetic utility of the reaction of alkyllithium and Grignard reagents with ketonic functions has been well documented.105 These reactions take place via the intermediacy of alkoxy derivatives formed by addition of the M—C bond across the C=0 function. Hence ketones, aldehydes and formaldehyde will lead to tertiary, secondary and primary alkoxides, respectively. This type of reactivity is known for a number of other carbanionic metal alkyl derivatives, both main group and transition metals, although the synthetic utility of the reactivity has in most cases not been well documented. 

In each part of this problem in which there is a change in the carbon skeleton, disconnect the phenyl group of the product to reveal the aldehyde or ketone precursor that reacts with the Grignard reagent derived from bromobenzene. Recall that reaction of a Grignard reagent with formaldehyde (H2C=0) yields a primary alcohol, reaction with an aldehyde (other than formaldehyde) yields a secondary alcohol, and reaction with a ketone yields a tertiary alcohol. 

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