Carbon atoms, electrophilic substitution

If R is an alkyl group, reaction (1) leads to the familiar mechanism of nucleophilic substitution at saturated carbon whilst reaction (2) leads to an electrophilic substitution of saturated carbon. Of course for these mechanisms to be followed it is not necessary for a completely developed carbonium ion or carbanion to be formed, and both nucleophilic and electrophilic substitution at saturated carbon may proceed by mechanisms in which the carbon atom undergoing substitution has a carbonium ion character or a carbanion character respectively. 

When an electrophilic substitution at saturated carbon occurs, either a car-banion is liberated as such or, if no carbanion is actually formed, the carbon atom undergoing substitution has a certain amount of carbanion character . Thus a knowledge of the factors governing the formation and the stability of carbanions might be of help in the understanding of the mechanism of electrophilic substitution at saturated carbon. 

In this mechanism the incoming electrophile and the substrate react in a single bimolecular elementary reaction. There are two main possibilities for the stereochemical course of such a reaction, depending on whether the configuration of the carbon atom undergoing substitution is retained or inverted, viz. 

The substituent effect on the uncatalysed reaction (13) is the same in both solvents (Table 4 added KBr = 0), and indicates that electron-donating substituents aid reaction by increasing the charge density at the carbon atom undergoing substitution and thereby facilitating attack by an electrophile. 

Abraham and Hill22 suggested that the mechanism of acidolysis was that of SE2(cyclic), in which electrophilic attack at the carbon atom undergoing substitution was an important feature the reactivity sequence p-toluidine > cyclo-hexylamine is that of acid strength. A transition state such as (IV) is thus indicated. 

For substitutions proceeding by mechanism SE2(cyclic), it might be expected that substituent effects would reflect, at least in part, the relative importance of electrophilic attack at the carbon atom undergoing substitution compared with nucleophilic attack at the metal atom in the leaving group, i.e. the position of... 

Thus the electrophiles which attack cyanide ion on nitrogen will be the harder ones, and the ones which attack on carbon will be the softer ones. This fits with the reactions illustrated above. As already seen (pp. 38-39) alkyl halides in simple Sn2 reaction are soft electrophiles thus it is appropriate for cyanide to react from the soft end of the ion (32). When a silver ion is present (other Lewis acids like zinc and mercuric ion behave similarly), the halide ion is assisted in leaving the carbon atom, and in the transition state there is now a greater development of charge on the carbon atom undergoing substitution (33). Car-bonium ions are hard electrophiles, and therefore it is again appropriate that on this occasion cyanide ion should react from the harder end of the ion. 

Unimolecular thermal and photochemical reactions Electrophilic attack at heteroatoms Electrophilic attack at carbon atoms Nucleophilic attack at carbon atoms Electrophilic attack on substituents Nucleophilic attack on substituents Nucleophilic substitution Synthesis... 

Strategy For nucleophilic addition, draw Lewis structures with the nucler hile close to the electron-poca- atom where attack will occur (in this case, the carbonyl carbon). For electrophilic substitution, draw Lewis structures with the electrophile close to the site of attack on the benzene ring. Remember that nucleophiles are attracted to and react with electron-poor atoms whereas electrophiles are attracted to and react with electron-rich areas of the molecule. Using this information, and the octet rule, determine which electrons are likely to be involved in the reaction and indicate their repositioning with curved arrows. 

M.o. theory and the transition state treatment In 1942 Wheland proposed a simple model for the transition state of electrophilic substitution in which a pair of electrons is localised at the site of substitution, and the carbon atom at that site has changed from the sp to the sp state of hybridisation. Such a structure, originally proposed as a model for the transition state is now known to describe the (T-complexes which are intermediates in electrophilic substitutions... 

The problem of electrophilic substitution into the anilinium ion has been examined by the methods of m.o. theory. Attempts to simulate the --inductive effect in Hiickel M.o. theory by varying the Coulomb integral of C(j) (the carbon atom to which the NH3+ group is attached) remove 7r-electrons from the o- and -positions and add them to the... 

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. 

Reactivity of A-4-thiazoline-2-thiones and derivatives involves four main possibilities nucleophilic reactivity of exocyclic sulfur atom or ring nitrogen, electrophilic reactivity of carbon 2 and electrophilic substitution on carbon 5. 

Because the carbon atom attached to the ring is positively polarized a carbonyl group behaves m much the same way as a trifluoromethyl group and destabilizes all the cyclo hexadienyl cation intermediates m electrophilic aromatic substitution reactions Attack at any nng position m benzaldehyde is slower than attack m benzene The intermediates for ortho and para substitution are particularly unstable because each has a resonance structure m which there is a positive charge on the carbon that bears the electron withdrawing substituent The intermediate for meta substitution avoids this unfavorable juxtaposition of positive charges is not as unstable and gives rise to most of the product... 

Electrophilic Substitution. The most common mechanism for electrophilic attack at an aromatic system involves the initial attack of an electrophile to give an intermediate containing a tetrahedral carbon atom loss of, usually a proton, from the intermediate, then gives the product ... 

The precise numerical values of the calculated electron densities are unimportant, as the most important feature is the relative electron density thus, the electron density at the pyrazine carbon atom is similar to that at an a-position in pyridine and this is manifest in the comparable reactivities of these positions in the two rings. In the case of quinoxaline, electron densities at N-1 and C-2 are proportionately lower, with the highest electron density appearing at position 5(8), which is in line with the observation that electrophilic substitution occurs at this position. 

The TT-electron density refers to the electron density at a given carbon atom obtained by summing the contributions from all the filled molecular orbitals. Electrophilic attack occurs where this density is highest, and nucleophilic attack where it is lowest tt-electron densities are not dominant in determining the orientation of homolytic substitution. 

An alternative approach is in terms of frontier electron densities. In electrophilic substitution, the frontier electron density is taken as the electron density in the highest filled MO. In nucleophilic substitution the frontier orbital is taken as the lowest vacant MO the frontier electron density at a carbon atom is then the electron density that would be present in this MO if it were occupied by two electrons. Both electrophilic and nucleophilic substitution thus occur at the carbon atom with the greatest appropriate frontier electron density. 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

Since an electron-withdrawing group such as ethoxycarbonyl at the a-carbon atom enhanced the electrophilicity of the )3-carbon atom, the reaction of a-ethoxycarbonyl-)3-ethoxyvinyl ketones (298) with hydroxylamine hydrochloride gave solely 5-substituted isoxazole-4-carboxylates (299) (55JOC1342, 59YZ836). 

The acid-catalyzed additions of bromide and chloride ion to thiiranes occurs readily, with halide preferentially but not exclusively attacking the most substituted carbon atom of the thiirane. The reaction of 1-substituted thiiranes with acetyl chloride shows a slight preference for halide attack at the less substituted carbon atom (80MI50601). For further discussion of electrophilic catalysis of halide ion attack see Section 5.06.3.3.2. The reaction of halogens with thiiranes involves electrophilic attack on sulfur (Section 5.06.3.3.6) followed by nucleophilic attack of halide ion on carbon. 

Both HMO calculations and more elaborate MO methods can be applied to the issue of the position of electrophilic substitution in aromatic molecules. The most direct approach is to calculate the localization energy. This is the energy difference between the aromatic molecule and the n-complex intermediate. In simple Hiickel calculations, the localization energy is just the difference between the energy calculated for the initial n system and that remaining after two electrons and the carbon atom at the site of substitution have been removed from the conjugated system ... 

The silyl group directs electrophiles to the substituted position. That is, it is an ipso-directing group. Because of the polarity of the carbon-silicon bond, the substituted position is relatively electron-rich. The ability of silicon substituents to stabilize carboca-tion character at )9-carbon atoms (see Section 6.10, p. 393) also promotes ipso substitution. The silicon substituent is easily removed from the c-complex by reaction with a nucleophile. The desilylation step probably occurs through a pentavalent silicon species ... 

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). 

During indolization of the 3, 6 and 7-quinolylhydrazones, formation of the new C-C bond occurs between the appropriate carbon atom of the ketone/aldehyde moiety and the 4, 5 and 8 carbon atoms of the quinoline nucleus. It is consistent with the mechanism of formation of the C-C bond during indolization and the direction of electrophilic substitution in the quinoline nucleus. °... 

No example of electrophilic substitution at ring carbon atoms has been reported. 

Phospholes and analogs offer a wide variety of coordination modes and reactivity patterns, from the ti E) (E = P, As, Sb, Bi) through ri -dienic to ri -donor function, including numerous and different mixed coordination modes. Electrophilic substitution at the carbon atoms and nucleophilic properties of the phosphorus atom are well documented. In the ri -coordinated species, group V heteroles nearly acquire planarity and features of the ir-delocalized moieties (heterocymantrenes and -ferrocenes). 

Kinetic studies have been carried out on the displacement reactions of various chloroazanaphthalenes with ethoxide ions and piperi-dine. - 2-Chloroquinoxaline is even more reactive than 2-chloro-quinazoline, thus demonstrating the powerfully electrophilic nature of the -carbon atoms in the quinoxaline nucleus. The ease of displacement of a-chlorine in the quinoxaline series is of preparative value thus, 2-alkoxy-, 2-amino-, - 2-raethylamino-, 2-dimethyl-amino-,2-benzylamino-, 2-mercapto-quinoxalines are all readily prepared from 2-chloroquinoxaline. The anions derived from substituted acetonitriles have also been used to displace chloride ion from 2-chloroquinoxaline, ... 

The mechanism for the conversion of the A -oxide (94) to the o-methylaminophenylquinoxaline (96) involves an initial protonation of the A -oxide function. This enhances the electrophilic reactivity of the a-carbon atom which then effects an intramolecular electrophilic substitution at an ortho position of the anilide ring to give the spiro-lactam (98). Hydrolytic ring cleavage of (98) gives the acid (99), which undergoes ready dehydration and decarboxylation to (96), the availability of the cyclic transition state facilitating these processes. ... 

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