Acetals, nucleophilic addition

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... 

Chiral acetals can be used as auxiliaries in the diastereoselective reactions of Grignard reagents with acyclic as well as cyclic a-keto acetals. Nucleophilic addition to the monoprotected diketone (69 equation 18) occurs with excellent stereoselectivity to generate the corresponding tertiary alcohol (70) as the major product, usually with greater than 95 5 selectivity. Removal of the ketal yields a-hydroxy ketones of high optical purity. In most examples, enantiomeric excesses of 95% and higher are observed in the resultant keto alcohols. Table 17 represents the results of additions to cyclic and acyclic substrates. 

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... 

An especially interesting case of oxygen addition to quinonoid systems involves acidic treatment with acetic anhydride, which produces both addition and esterification (eq. 3). This Thiele-Winter acetoxylation has been used extensively for synthesis, stmcture proof, isolation, and purification (54). The kinetics and mechanism of acetoxylation have been described (55). Although the acetyhum ion is an electrophile, extensive studies of electronic effects show a definite relationship to nucleophilic addition chemistry (56). 

Unsaturated Hydrocarbons. Olefins from ethylene through octene have been converted into esters via acid-catalyzed nucleophilic addition. With ethylene and propjiene, only a single ester is produced using acetic acid, ethyl acetate and isopropyl acetate, respectively. With the butylenes, two products are possible j -butyl esters result from 1- and 2-butylenes, whereas tert-huty esters are obtained from isobutjiene. The C5 olefins give rise to three j iC-amyl esters and one /-amyl ester. As the carbon chain is lengthened, the reactivity of the olefin with organic acids increases. 

Many other reactions of ethylene oxide are only of laboratory significance. These iaclude nucleophilic additions of amides, alkaU metal organic compounds, and pyridinyl alcohols (93), and electrophilic reactions with orthoformates, acetals, titanium tetrachloride, sulfenyl chlorides, halo-silanes, and dinitrogen tetroxide (94). 

Nucleophilic addition of an alcohol to the carbonyl group initially yields a hydroxy ether called a hemiacetal, analogous to the gem diol formed by addition of water. HcmiacetaJs are formed reversibly, with the equilibrium normally favoring the carbonyl compound. In the presence of acid, however, a further reaction occurs. Protonation of the -OH group, followed by an El-like loss of water, leads to an oxonium ion, R2C=OR+, which undergoes a second nucleophilic addition of alcohol to yield the acetal. The mechanism is shown in Figure 19.12. 

Acetal and hemiacetal groups are particularly common in carbohydrate chemistry. Glucose, for instance, is a polyhydroxy aldehyde that undergoes an internal nucleophilic addition reaction and exists primarily as a cyclic hemiacetal. 

Each of the following substances can be prepared by a nucleophilic addition reaction between an aldehyde or ketone and a nucleophile. Identify the reactants from which each was prepared. If the substance is an acetal, identify the carbonyl compound and the alcohol if it is an imine, identify the carbonyl compound and the amine and so forth. 

The high diastereoselectivity which is found in the nucleophilic addition of Grignard reagents to chiral 2-0x0 acetals can be explained by a chelation-controlled mechanism. Thus, coordination of the magnesium metal with the carbonyl oxygen and the acetal moiety leads to a rigid structure 3A in the transition state with preferred attack of the nucleophile occurring from the S/-side. 

The diastereoselectivity of the nucleophilic addition to nitrone 2 may be rationalized by assuming that magnesium bromide preferentially coordinates with the nitrone oxygen. The Grignard reagent is therefore forced to interact with the acetal oxygen in position 3. 

Davis has described an approach to related 1,3-diol synthons [49] (Eq. 20). Silylation of the -hydroxy ester 129 with diisopropylchlorosilane, followed by fluoride ion-catalyzed intramolecular hydrosilylation generated a 1 1 diastere-omeric mixture of acetals 131. These acetals were shown to undergo diastereo-selective nucleophilic additions vide infra). 

Zincke s aldehyde (61) and cyanomethyltriphenylphosphonium chloride in acetic anhydride at 100 °C gave the salt (62), isolated as the perchlorate, whereas the same reagents in pyridine gave the phosphorane-phosphonium salt (63), presumably via nucleophilic addition of cyanomethylenephos-phorane to the terminal carbon of (62). 

Conversion to acetals is a very general method for protecting aldehydes and ketones against nucleophilic addition or reduction.245 Ethylene glycol, which gives a cyclic dioxolane derivative, is frequently employed for this purpose. The dioxolanes are usually prepared by heating a carbonyl compound with ethylene glycol in the presence of an acid catalyst, with provision for azeotropic removal of water. 

In Entry 5, the carbanion-stabilizing ability of the sulfonyl group enables lithiation and is then reductively removed after alkylation. The reagent in Entry 6 is prepared by dilithiation of allyl hydrosulfide using n-bulyl lithium. After nucleophilic addition and S-alkylation, a masked aldehyde is present in the form of a vinyl thioether. Entry 7 uses the epoxidation of a vinyl silane to form a 7-hydroxy aldehyde masked as a cyclic acetal. Entries 8 and 9 use nucleophilic cuprate reagents to introduce alkyl groups containing aldehydes masked as acetals. 

Alkylisoselenocyanates 339 are also used in the synthesis of 2-methylidene-l,3-selenazolidine derivatives <06T3344>. Nucleophilic addition of the carbanion derived from malononitrile 347 to 339 leads to an intermediate kcten-A, -acetal 348, which reacts with 2-haloacetate ester and 1,2-dibromoethane to provide l,3-selenazolidin-4-ones 350 and 1,3-selenazolidines 352, respectively. 

---