Electrophilic regioselectivity

MA Freitas, RAJ O FIair, TD Williams. Gas phase reactions of cysteine with charged electrophiles regioselectivities of the dimethylchlorinium ion and the methoxymethyl cation. J Org Chem 62 6112—6120, 1997. 

Lithiation reactions involving lV-methyl-3-substituted indoles are sometimes useful for introducing electrophiles regioselectively to C2. Comins [77] and Adam [78] reported regioselective C2-lithiations of indole substrates containing... 

Direct Silylation of Heteroarylcarbonyl Compounds. Under ruthenium catalysis vinyltrimethylsilane reacts to ortho silyl-ate heteroaryl carbonyl compounds directly in good yields (eqs 32 and 33). The reaction only works with heteroaromatic systems. The resulting aryltrimethylsilanes can be used to introduce electrophiles regioselectively through electrophilic desilyla-tion. The reaction also works with vinyltriethoxysilane, opening the possibility of silicon-based cross-coupling reactions. 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The synthesis of spiro compounds from ketones and methoxyethynyl propenyl ketone exemplifies some regioselectivities of the Michael addition. The electrophilic triple bond is attacked first, next comes the 1-propenyl group. The conjugated keto group is usually least reactive. The ethynyl starting material has been obtained from the addition of the methoxyethynyl anion to the carbonyl group of crotonaldehyde (G. Stork, 1962 B, 1964A). 

The scheme below shows how the eastern and western parts of a corrin chromo-phore can be combined regioselectively. The western part has a more acidic enamine than the eastern part, whereas the imidic ester of the eastern part is more electrophilic. 

In general alkyl substituents increase the reactivity of a double bond toward elec trophilic addition Alkyl groups are electron releasing and the more electron rich a dou ble bond the better it can share its tt electrons with an electrophile Along with the observed regioselectivity of addition this supports the idea that carbocation formation rather than carbocation capture is rate determining... 

The regioselectivity of addition of HBr to alkenes under normal (electrophilic addi tion) conditions is controlled by the tendency of a proton to add to the double bond so as to produce the more stable carbocatwn Under free radical conditions the regioselec tivity IS governed by addition of a bromine atom to give the more stable alkyl radical Free radical addition of hydrogen bromide to the double bond can also be initiated photochemically either with or without added peroxides... 

The regioselectivity of electrophilic addition is governed by the ability of an aro matic ring to stabilize an adjacent carbocation This is clearly seen m the addition of hydrogen chloride to mdene Only a single chloride is formed... 

Section 11 16 Addition reactions to alkenylbenzenes occur at the double bond of the alkenyl substituent and the regioselectivity of electrophilic addition is governed by carbocation formation at the benzylic carbon See Table 11 2... 

Electrophilic addition (Section 11 16) An aryl group stabilizes a benzylic carbocation and con trols the regioselectivity of addition to a double bond involving the benzylic carbon Markovni kov s rule is obeyed... 

Just as there is a marked difference m how methyl and tnfluoromethyl substituents affect the rate of electrophilic aromatic substitution so too there is a marked difference m how they affect its regioselectivity... 

The regioselectivity of substitution like the rate is strongly affected by the sub stituent In the following several sections we will examine the relationship between the structure of the substituent and its effect on rate and regioselectivity of electrophilic aro matic substitution... 

Why IS there such a marked difference between methyl and trifluoromethyl substituents m their influence on electrophilic aromatic substitution s Methyl is activating and ortho para directing trifluoromethyl is deactivating and meta directing The first point to remember is that the regioselectivity of substitution is set once the cyclohexadienyl cation intermediate is formed If we can explain why... 

The regioselectivity of substitution in furan is explained using a resonance descrip tion When the electrophile attacks C 2 the positive charge is shared by three atoms C 3 C 5 and O... 

Sections How substituents control rate and regioselectivity m electrophilic aro 12 10-12 14 matic substitution results from their effect on carbocation stability An electron releasing substituent stabilizes the cyclohexadienyl cation inter mediates corresponding to ortho and para attack more than meta... 

In view of the overall increased reactivity of furan compared with thiophene it would be anticipated that furan would be less regioselective in its reactions with electrophiles than thiophene. Possible reasons for the high regioselectivity of furan in electrophilic substitution reactions include complex formation between substrates and reagents and the ability of heteroatoms to assist in the stabilization of cationic intermediates (80CHE1195). 

TTie condensation of fluormated carbonyl compounds is a versatile approach to the stereo- and regioselective construction of specifically tluonnated materials It is possible to use fluormated reactants in vanous oxidation states and to utilize them either as the nucleophilic or electrophilic reaction partners Stereocontrol in those processes using the fluormated carbonyl compounds m a nucleophilic fashion has lagged behind the achievement of higher yields... 

The effects of a- vs. P-fluonnation imply that fluoroolefms normally react regioselectively with electrophiles to minimize the number of fluorines p to the electron-deficient carbon in the transition state. Diverse types of electrophilic additions follow this rule (equations 6-8, for example), although there aie exceptions, especially for ionic addiPons of halomethanes to fluoroolefins [124]... 

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