Electrophilic carbon atom

Aryl and vinylic bromides and iodides react with the least substituted and most electrophilic carbon atoms of activated olefins, e.g., styrenes, allylic alcohols, a,p-unsaturated esters and nitriles. 

The use of oximes as nucleophiles can be quite perplexing in view of the fact that nitrogen or oxygen may react. Alkylation of hydroxylamines can therefore be a very complex process which is largely dependent on the steric factors associated with the educts. Reproducible and predictable results are obtained in intramolecular reactions between oximes and electrophilic carbon atoms. Amides, halides, nitriles, and ketones have been used as electrophiles, and various heterocycles such as quinazoline N-oxide, benzodiayepines, and isoxazoles have been obtained in excellent yields under appropriate reaction conditions. 

Risaliti et al. (22), have shown that in the addition of the electrophilic olefins to the enamines of cyclohexanone, the formation of the less substituted enamine is favored when a bulky group is present at the electrophilic carbon atom. For instance, the reaction of (8-nitrostyrene with the morpholine enamine of cyclohexanone gave only the trisubstituted isomer (30) with the substituent in the axial orientation (23). The product on hydrolysis led to the ketone (31) to which erythro configuration was assigned on the grounds illustrated in Scheme 3 (24). 

However, when the bulky substituent is no longer present at the electrophilic carbon atom, the addition of the olefin to the morpholine enamine of cyclohexanone leads largely to the tetrasubstituted isomer. For instance the reaction of this enamine with phenyl vinyl sulfone gave a 1 3 mixture of... 

The preferred formation of the tetrasubstituted isomer with the olefin without any bulky substituent at the electrophilic carbon atom is undoubtedly due to the preponderance of that conformation of the dipolar intermediate in which the substituent is syn to the morpholine group, as shown in (41). The situation is, however, reversed in case of the olefin with... 

Risaliti et al. (2J) have also studied the addition of 2-nitropropene, which also lacks any substituent at the electrophilic carbon atom, to the morpholine enamine of cyclohexanone. The product, as expected, was the tetrasubstituted isomer, the formation of which may be envisioned via the transition state (42). 

First, look at the reaction and identify the bonding changes that have occurred. In this case, a C—Br bond has broken and a C-C bond has formed. The formation of the C-C bond involves donation of an electron pair from the nucleophilic carbon atom of the reactant on the left to the electrophilic carbon atom ol CH Br, so we draw a curved arrow originating from the lone pair on the negatively charged C atom and pointing to the C atom of CH3Br. At the same time the C—C bond forms, the C-Br bond must break so that the octet rule is not violated. We therefore draw a second curved arrow from the C-Br bond to Br. The bromine is now a stable Br- ion. 

We won t study the details of this substitution reaction until Chapter 11 but for now can picture it as happening by the pathway shown in Figure 8.6. The nucleophilic acetylide ion uses an electron pair to form a bond to the positively polarized, electrophilic carbon atom of bromomethane. As the new C-C bond forms, Br- departs, taking with it the electron pair from the former C-Br bond and yielding propyne as product. We call such a reaction an alkylation because a new alkyl group has become attached to the starting alkyne. 

The nucleophilic acetylide anion uses its electron lone pair to form a bond to the positively polarized, electrophilic carbon atom of bromomethane. As the new C-C bond begins to form, the C-Br bond begins to break in the transition state. 

We ll defer a detailed discussion of the mechanisms of these reductions until Chapter 19. For the moment, we ll simply note that they involve the addition of a nucleophilic hydride ion ( H ) to the positively polarized, electrophilic carbon atom of the carbonyl group. The initial product is an afkoxide ion, which is protonated by addition of H 0+ in a second step to yield the alcohol product. 

Like a carbonyl group, a nitrile group is strongly polarized and has an electrophilic carbon atom. Nitriles therefore react with nucleophiles to yield 5p2-hybridized imine anions in a reaction analogous to the formation of an sp3-hybridized alkoxide ion by nucleophilic addition to a carbonyl group. 

When both the carbonyl group and the sulfinyl group of a /J-ketosulfoxide are attached to the same carbon atom of a carbon-carbon double bond, then addition of nucleophiles can occur at the electrophilic -carbon atom (i.e., 1,4-addition, conjugate addition) and/or... 

A nucleophile attacks the electrophilic carbon atom of the polar carbonyl group from a direction approximately perpendicular to the plane of sp hybridised orbitals of carbonyl carbon (Fig. 12.2). The hybridisation of carbon changes from sjf to s f in this process, and a tetrahedral alkoxlde intermediate is produced. This... 

Fig. 8.23 Structure of tienilic acid (A) and an isomeric variant (B) which cause hepatotoxicity by autoimmune and direct mechanisms respectively, following conversion to sulphoxide metabolites and resultant electrophilic carbon atoms.

Scheme 3.28 depicts the proposed reaction mechanism that may happen on these alloys. The first step is the coordination of the ester to the alloy via its oxygen atoms (it is likely that hn favors this coordination due to its electrophilicity). In a second step there is a four-center mechanism where the hydridic hydrogen makes a nucleophilic attack at the electrophilic carbon atom of the carbonyl with forma-... 

Isocyanides are converted, on addition of f-BuLi at the electrophilic carbon atom, to lithioimines—another class of anionic, nitrogen-containing functions which turn out to have good orf/zo-directing ability. The electrophile reacts at both lithium-bearing centres of 129 (Scheme 56). 

Pathway 2 of Scheme 9 corresponds to one of the most interesting developments in the Beckmann rearrangement chemistry. By trapping of the electrophilic intermediate with a nucleophile (Nu ) other than water, an imine derivative 227 is produced that may be used for further transformations. Carbon or heteroatom nucleophiles have been used to trap the nitrilium intermediate. Reducing agents promote the amine formation. More than one nucleophile may be added (for example, two different Grignard reagents can be introduced at the electrophilic carbon atom). Some of the most used transformations are condensed in Scheme 11. 

Among the simplest syntheses of this type are those of tetrahydro-quinolines or -iso-quinolines based on Friedel-Crafts cyclizations. The use of side-chain halides is shown by the synthesis of 1,2,3,4-tetrahydroisoquinolines (158) (71CC799), and of 3,4-dihydroquinol-2-ones (159) (27CB858). Electrophilic carbon atoms can be developed from secondary or tertiary alcohols, or from alkenes or alkynes. In the synthesis of the tetrahydroisoquinoline... 

Furthermore, the structure of microcystin includes an electrophilic carbon atom, (Fig. 7.26), which is part of the Mdha amino acid. If microcystin is ingested from contaminated water, for example, it is taken up into the liver by an organic anion transporter (OAT) system and therefore is concentrated in the liver. The structure of the microcystins means they are able to associate with the enzymes protein phosphatases, such as PP-1, PP-2A, and PP-2B via hydrophobic and ionic interactions. 

The carbonyl group (2a) has an easily polarisahle TT-bond with an electrophilic carbon atom at one end easily attacked by nucleophiles ... 

Steric effects on the rates of quaternization of quinoline are magnified as the size of the alkylating agent is increased in the series methyl, ethyl, and isopropyl iodide. In order to reveal the changing steric effect, it is first necessary to eliminate the reduction in rate that naturally occurs as the electrophilic carbon atom of the alkylating agent undergoes sub-... 

Examples of syntheses in which the heterocyclic ring is generated by cyclization of an exocyclic amine to an electrophilic carbon atom include the preparation of triazolo[4,3-6]triazoles (137) by elimination of alkanethiol from guanidine derivatives 136137 (cf. 132 - 133), and many examples (mostly in patents) of pyrazolo[l,5-a]benzimidazoles prepared according to Eq. (18).138-142... 

Many newer methods for generating cyclohexane derivatives from carbohydrates still depend on the intramolecular attack of nucleophilic carbon species at electrophilic centers, and the range of options is now extensive. Thus, the nucleophiles may be carb-anions stabilized by carbonyl, phosphonate, nitro, or dithio groups, and they may bond to carbonyl carbon atoms, or to those that carry appropriate leaving groups or are contained in epoxide rings, or as jj-centers of a,p-unsaturated carbonyl systems. Otherwise, the nucleophilic activity at the 7-centers of allylsilanes or a-positions of vinyl silanes may be used to react with electrophilic carbon atoms. 

A reaction that appears to have potential for carbohydrate to substituted cyclohexane conversions, and has not been applied to carbohydrate-derived starting materials, involves the intramolecular bonding of the electrophilic carbon atoms of aldehydes and the nucleo-... 

Uncatalyzed hydrolysis of a peptide linkage is very slow with f1/2 at neutral pH and 25°C of 300-600 years.189 Both acids and bases catalyze hydrolysis, but enzymes are needed for rapid digestion. The carbonyl group C=0 is highly polarized, with the resonance form C+-0 contributing substantially to its structure. An attack by a base will take place readily on the electrophilic carbon atom. While the reactivity of the carbonyl group in esters and amides is relatively low... 

A nucleophilic mechanism can be applied in reductions with complex hydrides of highly fluori-nated aliphatic and alicyclic fluoroalkenes with electron-deficient C = C bonds the hydride anion adds as a strong nucleophilic agent to the more electrophilic carbon atom the intermediate anion can then lose a fluoride ion either from the original C = C bond, or from the allylic position finishing an SN2 displacement of the fluorine. Thus, the reductions of vinylic C-F bonds with hydrides proceed by a nucleophilic addition-elimination mechanism. Displacement of fluorine in highly fluorinated aromatic compounds proceeds by the same mechanism ... 

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