Carbonyl group cyanide addition

Generation of Electrophilic Cations. Complexation of Et2AlCl to ketones and aldehydes activates the carbonyl group toward addition of a nucleophilic alkyl- or allylstannane or allylsilane. Et2AlCl has been used to initiate Beckmann rearrangements of oxime mesylates. The ring-expanded cation can be trapped intermolecularly by enol ethers and cyanide and in-tramolecularly by alkenes (eq 5). ... 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Analogously, aldehydes react with ammonia [7664-41-7] or primary amines to form Schiff bases. Subsequent reduction produces a new amine. The addition of hydrogen cyanide [74-90-8] sodium bisulfite [7631-90-5] amines, alcohols, or thiols to the carbonyl group usually requires the presence of a catalyst to assist in reaching the desired equilibrium product. 

Carbonyl Group Reactions. Mandelonitrile [532-28-5] is formed by the addition of hydrogen cyanide to the carbonyl double bond. 

A cyanohydrin is an organic compound that contains both a cyanide and a hydroxy group on an aUphatic section of the molecule. Cyanohydrias are usually a-hydroxy nitriles which are the products of base-cataly2ed addition of hydrogen cyanide to the carbonyl group of aldehydes and ketones. The lUPAC name for cyanohydrias is based on the a-hydroxy nitrile name. Common names of cyanohydrias are derived from the aldehyde or ketoae from which they are formed (Table 1). 

AH ahphatic aldehydes and most ketones react to form cyanohydrins. The lower reactivity of ketones, relative to aldehydes, is attributed to a combination of electron-donating effects and increased steric hindrance of the second alkyl group in the ketones. The magnitude of the equiUbrium constants for the addition of hydrogen cyanide to a carbonyl group is a measure of the stabiUty of the cyanohydrin relative to the carbonyl compound plus hydrogen cyanide ... 

Predict the product formed by nucleophilic addition of cyanide ion (CN ) to the carbonyl group of acetone, followed by protonalion to give an alcohol ... 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

Tin and HCl reduce out the ben/.ylic OH from (43) in high yield.The Mannich base (45) decomposes to (41) simply on heating. Cyanide addition gives (46) which can be hydrolysed to (40), but a short cut is to hydrolyse to amide (47) and reduce out the carbonyl group by the Clemmensen method (Table T 24.1). Under these conditions the amide is hydrolysed to the acid. Cyclisation to (38) occurs with strong acid, acid anhydrides, or by AlClg-catalysed reaction of the acid chloride. 

Addition of alcohols to lactones results in the formation of orthoacid or orthoester derivatives. Thus, reaction of lactone 95a with potassium cyanide in ethanol led to displacement of the tosyl group by cyanide and addition of ethanol to the lactone carbonyl group, to give the orthoacid derivative 95b, which was isolated as its acetate 95c. Mild deacylation of 95c led back to 95b, but under more vigorous reaction conditions the open-chain methyl aldon-ate was obtained (90). 

Hydrogen cyanide undergoes many important organic reactions forming a variety of industrial products. Probably the most important reaction is the addition of the carbonyl ( =C=0) group. It adds to the carbonyl groups of aldehydes and most ketones forming cyanohydrins ... 

Addition of CN Cyanotrimethylsilane, 87 Sodium cyanide, 185 Addition a to carbonyl groups Chloromethyldiphenylsilane, 74... 

URECH CYANOHYDRIN METHOD. Cyanohydrin formation by addition of alkali cyanide to the carbonyl group in the presence of acetic acid (Urech) or by reaction of the carbonyl compound with anhydrous hydrogen cyanide in the presence of basic catalyst (Ultee). 

An important feature of cyanohydrin formation is that it requires a basic catalyst. In the absence of base, the reaction does not proceed, or is at best very slow. In principle, the basic catalyst may activate either the carbonyl group or hydrogen cyanide. With hydroxide ion as the base, one reaction to be expected is a reversible addition of hydroxide to the carbonyl group ... 

The anion then adds to the carbonyl group of a second molecule of ethanal in a manner analogous to the addition of other nucleophiles to carbonyl groups (e.g., cyanide ion, Section 16-4A). The adduct so formed, 8, rapidly adds a proton to the alkoxide oxygen to form the aldol, 3-hydroxybutanal. This last step regenerates the basic catalyst, OH ... 

There are many addition reactions of a,(3-unsaturated aldehydes, ketones, and related compounds that are the same as the carbonyl addition reactions described previously. Others are quite different and result in addition to the alkene double bond. Organometallic compounds are examples of nucleophilic reagents that can add to either the alkene or the carbonyl bonds of conjugated ketones (see Section 14-12D). Hydrogen cyanide behaves likewise and adds to the carbon-carbon double bond of 3-butene-2-one, but to the carbonyl group of 2-butenal ... 

The acetylacetone carbanion undergoes addition to the imine carbon atom of complex (92) but subsequent cyclization and deacylation processes occur (Scheme 42).212 The apical ammonia group is the most acidic and consequently is favoured to cyclize on to the carbonyl group. In the bis-(1,2-diaminoethane) complex related to the imine chelate (92), the two apical nitrogen atoms are no longer geometrically equivalent. Thus two products are formed when hydrogen cyanide is added to the complex and subsequent cyclization takes place (Scheme 43).213 However, the cyclization reaction is stereoselective. 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

If the protonation were rate determining, then a decrease in electron density at the carbonyl carbon occurs. The p value should be negative. If the second step is rate determining, then nucleophilic addition should result in an increase in electron density at the carbonyl group, the p value should be positive. The data show that the second step is probably rate determining. Moreover the lack of reaction under basic conditions means that the carbonyl group must be activated by protonation for the cyanide to add. Thus the protonation step is probably an equilibrium step. 

The addition of hydrogen cyanide to a carbonyl group of an aldehyde or most ketones produces a cyanohydrin. Sterically hindered ketones, however, don t undergo this reaction. 

The addition of hydrogen cyanide to a carbonyl group results in the formation of an a-hydroxy nitrile, a so-called cyanohydrin (A, Scheme 6.1) [1]. Compounds of this type have in many instances served as intermediates in the synthesis of, e.g., a-hydroxy acids B, a-hydroxy aldehydes C, fS-amino alcohols D, or a-hydroxy ketones E (Scheme 6.1) [1], In all these secondary transformations of the cyanohydrins A, the stereocenter originally introduced by HCN addition is preserved. Consequently, the catalytic asymmetric addition of HCN to aldehydes and ketones is a synthetically very valuable transformation. Besides addition of HCN, this chapter also covers the addition of trimethylsilyl cyanide and cyanoformate to car-... 

The nucleophilic addition involves the addition of a nucleophilic to a molecule. This is a distinctive reaction for ketones and aldehydes and the nucleophile will add to electrophilic carbon atom of the carbonyl group. The nucleophile can be a negatively charged ion like cyanide or hydride, or it can be a neutral molecule like water or alcohol. 

The nucleophilic reaction of the cyanide ion on the carbonyl group is facilitated by protonat-ing the latter to a carboxonium ion. The addition of acid promotes the formation of cyanohydrins, but mainly for a thermodynamic reason. Under acidic conditions cyanohydrins equilibrate with the carbonyl compound and HCN. Under basic conditions they are in equilibrium with the same carbonyl compound and NaCN or KCN. The first reaction has a smaller equilibrium constant than the second, that is, the cyanohydrin is favored. So when cyanohydrins are formed under acidic or neutral (see Figure 9.8) instead of basic conditions, the reversal of the reaction is suppressed. 

This chapter will not concern itself with the topic of hydrogenation of specific functions. Such topics as the hydrogenation of the double bond, the carbonyl group, and the cyanide group have been well covered in recent reviews (5,6,7). It is the authors intention to demonstrate the versatility of Raney nickel by citing the many uses to which it can be put over and above the simple addition of hydrogen to an unsaturated function. No attempt is made, however, to ignore this best-known reaction of Raney nickel, Examples and references are cited where they most aptly fit into the context. 

You met nucleophilic addition to a carbonyl group on p. 114 and 119, where we showed you how cyanide reacts with acetone to give an alcohol. As a reminder, here is the reaction again, with its mechanism. 

The reaction has two steps nucleophilic addition of cyanide, followed by protonation of the anion. In fact, this is a general feature of all nucleophilic additions to carbonyl groups. 

The last nucleophile of this chapter, sodium bisulfite, NaHSC, adds to aldehydes and some ketones to give what is usually known as a bisulfite addition compound. The reaction occurs by nucleophilic attack of a lone pair on the carbonyl group, just like the attack of cyanide. This leaves a positively charged sulfur atom but a simple proton transfer leads to the product. 

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