Unsaturated carbon nucleophilic reactions

When a Br nsted base functions catalytically by sharing an electron pair with a proton, it is acting as a general base catalyst, but when it shares the electron with an atom other than the proton it is (by definition) acting as a nucleophile. This other atom (electrophilic site) is usually carbon, but in organic chemistry it might also be, for example, phosphorus or silicon, whereas in inorganic chemistry it could be the central metal ion in a coordination complex. Here we consider nucleophilic reactions at unsaturated carbon, primarily at carbonyl carbon. Nucleophilic reactions of carboxylic acid derivatives have been well studied. These acyl transfer reactions can be represented by... 

Compound 874, as a representative of derivatives with an electron-withdrawing substituent at C-[1 of the vinyl group, is easily prepared by elimination of one benzotriazole from 2,2-/fo(benzotriazol-l-yl)ethyl methyl ketone 873. The stereoselective elimination catalyzed by NaOH gives exclusively the (E) isomer of derivative 874. Addition of nucleophiles to the double bond of vinyl ketone 874 followed by elimination of benzotriazole leads to a,P unsaturated ketones 875. Amines used as nucleophiles do not need any catalysis, but reactions with carbon and sulfur nucleophiles require addition of a base. The total effect is nucleophilic substitution of the benzotriazolyl group at the i-carbon of orji-iinsaturatcd ketone (Scheme 142) <1996SC3773>. 

There are three possible active sites in a,(3-unsaturated acylzirconocene chlorides with respect to nucleophiles, namely the (3-unsaturated carbon, the acyl carbon, and the Zr—chlorine bond. The reactions of a, (3-unsaturated acylzirconocene chlorides with nucleophiles indicate bimodal reactivity (nucleophilic or electrophilic) at both the acyl and P-carbons (Scheme 5.37) [40],... 

This initial attack of the ozone molecule leads first to the formation of ortho- and para-hydroxylated by-products. These hydroxylated compounds are highly susceptible to further ozonation. The compounds lead to the formation of quinoid and, due to the opening of the aromatic cycle, to the formation of aliphatic products with carbonyl and carboxyl functions. The nucleophilic reaction is found locally on molecular sites showing an electronic deficit and, more frequently, on carbons carrying electron acceptor groups. In summary, the molecular ozone reactions are extremely selective and limited to unsaturated aromatic and aliphatic compounds as well as to specific functional groups. 

If the potential leaving group is attached to unsaturated carbon, as in vinyl chloride or phenyl chloride, attack by nucleophiles is also extremely difficult, and these compounds are very unreactive in Sn2 reactions compared with simple alkyl halides. In these cases, the reason is not so much steric but electrostatic, in that the nucleophile is repelled by the electrons of the unsaturated system. In addition, since the halide is attached to carbon through an 5p -hybridized bond, the electrons in the bond are considerably closer to carbon than in an 5/ -hybridized bond of an alkyl halide (see Section 2.6.2). Lastly, resonance stabilization in the halide gives some double bond character to the C-Hal bond. This effectively strengthens the bond and makes it harder to break. This lack of reactivity is also tme for SnI reactions (see Section 6.2). 

A similar type of acid-catalyzed condensation of aldehydes with 4-methylene-2-oxetanone (diketene), giving 4-oxo-6-methyl-l,3-dioxins, has been patented (73GEP2149650). However, other work has established that <5-hydroxy-/3-keto acids or unsaturated keto acids are formed as the principal products (equation 24) (78CPB3877, 78CL409). The latter reaction probably involves electrophilic attack of the protonated aldehyde on the nucleophilic exocyclic methylene carbon atom of the diketone. A closely related reaction of acetals with diketene, catalyzed by titanium tetrachloride, gives the corresponding <5-alkoxy-/3-keto esters (74CL1189). 

Gas-phase reactions which result in nucleophilic displacement at a saturated, or an unsaturated, carbon centre have been observed in positive and negative ion chemistry. By far, the most widely occurring case is the formal analog of the Sn2 reaction initially reported by Bohme and Young (1970). The experimental determination of rate constants for SN2 reactions has received a great deal of attention as has the mechanistic point of view including the interpretation of the potential energy surface for the gas-phase reaction. 

Nucleophilic displacement reactions are often competitive with other processes promoted by a nucleophile, such as addition-elimination, or proton abstraction and base-induced elimination in which the nucleophile acts as a strong base. This particular situation is especially true in reactions that also involve attack at an unsaturated carbon centre. The delicate interplay between these different mechanisms is in itself a matter of great interest, and as yet it has defied attempts to rationalize it on a quantitative basis. 

The same transition metal systems which activate alkenes, alkadienes and alkynes to undergo nucleophilic attack by heteroatom nucleophiles also promote the reaction of carbon nucleophiles with these unsaturated compounds, and most of the chemistry in Scheme 1 in Section 3.1.2 of this volume is also applicable in these systems. However two additional problems which seriously limit the synthetic utility of these reactions are encountered with carbon nucleophiles. Most carbanions arc strong reducing agents, while many electrophilic metals such as palladium(II) are readily reduced. Thus, oxidative coupling of the carbanion, with concomitant reduction of the metal, is often encountered when carbon nucleophiles arc studied. In addition, catalytic cycles invariably require reoxidation of the metal used to activate the alkene [usually palladium(II)]. Since carbanions are more readily oxidized than are the metals used, catalysis of alkene, diene and alkyne alkylation has rarely been achieved. Thus, virtually all of the reactions discussed below require stoichiometric quantities of the transition metal, and are practical only when the ease of the transformation or the value of the product overcomes the inherent cost of using large amounts of often expensive transition metals. 

Basically two types of reactions can be used for iodinations electrophilic- or nucleophilic iodination at a unsaturated carbon. Iodine attached to a saturated carbon atom is labile and is readily substituted by nucleophiles. For the same reason, radiopharmaceuticals which are labelled at a saturated carbon atom, are quickly metabolised in vivo. 

Nucleophilic reaction — The nucleophilic reaction is found locally on molecular sites showing electronic deficits and, more frequently, on carbons carrying electron-withdrawing groups. The molecular ozone reactions are extremely selective and limited to unsaturated aromatic and aliphatic compounds, as well as to specific functional groups. 

The reaction of a co-ordinated ligand with a nucleophile may be one of two types, which differ both in mechanistic detail and in synthetic consequence. The first type is that which we have already considered in some detail for carbonyl groups in Chapter 3. In these reactions, the nucleophile is added to an unsaturated carbon centre. This results in a change of hybridisation at carbon (Fig. 4-1). Specifically we have only so far discuss-... 

Nucleophilic vinylic substitutions are closely related to nucleophilic aromatic substitutions, as in both the leaving group leaves from an unsaturated carbon atom. However, the vinylic substitution routes are much more diverse, and disclose more of the details of the reaction. Stereochemical study of the reaction can give information on the lifetime of the intermediate and about the structure of the transition state... 

Base-catalyzed hydration of conjugated carbonyls, followed by retro-aldol fragmentation has been a common strategy for studying the reaction cascade (1-4). The kinetically important step in the base-catalyzed hydration of an alpha/beta unsaturated carbonyl is similar to a nucleophilic substitution reaction at carbon 3. The reaction cascade proceeds rapidly from the conjugated carbonyl through its hydration and subsequent fragmentation. 

According to equation (2), A log. K will have the same sign (i. e. the same nucleophilic order will prevail) except for large values of a of equation 3 (a) (very low values of x) i. e. for very hard acids. This is shown by the values of koH-/kF- for reactions at saturated and unsaturated carbon atoms (71), and by the high value of this ratio for the combination of OH-and F- ions with a proton. 

The value of AH is large for reactions at the carbon atom (AH 40 kcal./mole), and hence this determines the reactivity at both saturated and unsaturated carbon atoms. (K 1 and K ->- 1 respectively). The contribution of K A H is much smaller for the reaction at phosphorus, hence the first term determines the relative reactivity in reaction (d), (particularly in the non-polar solvents used in such reactions). These examples are sufficient to illustrate the inadequacy of the SHAB rule when conjugated nucleophiles are considered. 

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