Reactivity substitution reactions

The attack by a reagent of a molecule might be hampered by the presence of other atoms near the reaction site. The larger these atoms and the more are there, the higher is the geometric restriction, the steric hindrance, on reactivity. Figure 3-6e illustrates this for the attack of a nucleophile on the substrate in a nucleophilic aliphatic substitution reaction. 

The results in table 2.6 show that the rates of reaction of compounds such as phenol and i-napthol are equal to the encounter rate. This observation is noteworthy because it shows that despite their potentially very high reactivity these compounds do not draw into reaction other electrophiles, and the nitronium ion remains solely effective. These particular instances illustrate an important general principle if by increasing the reactivity of the aromatic reactant in a substitution reaction, a plateau in rate constant for the reaction is achieved which can be identified as the rate constant for encounter of the reacting species, and if further structural modifications of the aromatic in the direction of further increasing its potential reactivity ultimately raise the rate constant above this plateau, then the incursion of a new electrophile must be admitted. 

The above definition implies that the reactivity of an aromatic compound depends upon the reaction which is used to measure it, for the rate of reaction of an aromatic compound relative to that for benzene varies from reaction to reaction (table 7.1). However, whilst a compoimd s reactivity can be given no unique value, different substitution reactions do generally set aromatic compoimds in the same sequence of relative reactivities. 

The selectivity relationship merely expresses the proportionality between intermolecular and intramolecular selectivities in electrophilic substitution, and it is not surprising that these quantities should be related. There are examples of related reactions in which connections between selectivity and reactivity have been demonstrated. For example, the ratio of the rates of reaction with the azide anion and water of the triphenylmethyl, diphenylmethyl and tert-butyl carbonium ions were 2-8x10 , 2-4x10 and 3-9 respectively the selectivities of the ions decrease as the reactivities increase. The existence, under very restricted and closely related conditions, of a relationship between reactivity and selectivity in the reactions mentioned above, does not permit the assumption that a similar relationship holds over the wide range of different electrophilic aromatic substitutions. In these substitution reactions a difficulty arises in defining the concept of reactivity it is not sufficient to assume that the reactivity of an electrophile is related... 

The ij-arylpalladium bonds in these complexes are reactive and undergo insertion and substitution reactions, and the reactions offer useful methods for the regiospecific functionalization of the aromatic rings, although the reac-... 

The diazonium salts 145 are another source of arylpalladium com-plexes[114]. They are the most reactive source of arylpalladium species and the reaction can be carried out at room temperature. In addition, they can be used for alkene insertion in the absence of a phosphine ligand using Pd2(dba)3 as a catalyst. This reaction consists of the indirect substitution reaction of an aromatic nitro group with an alkene. The use of diazonium salts is more convenient and synthetically useful than the use of aryl halides, because many aryl halides are prepared from diazonium salts. Diazotization of the aniline derivative 146 in aqueous solution and subsequent insertion of acrylate catalyzed by Pd(OAc)2 by the addition of MeOH are carried out as a one-pot reaction, affording the cinnamate 147 in good yield[115]. The A-nitroso-jV-arylacetamide 148 is prepared from acetanilides and used as another precursor of arylpalladium intermediate. It is more reactive than aryl iodides and bromides and reacts with alkenes at 40 °C without addition of a phosphine ligandfl 16]. 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

III. Reactivity of the Selenazole Ring 1. Electrophilic Substitution Reactions... 

The nucleophilic reactivity of 2-halogenothiazoles is strongly affected by the substituent effect, depending on the kind of substitution reaction. Positions 4 and 5 can be considered as meta and para , respectively, with regard to carbon 2 and to groups linked to it consequently, it is possible to correlate the reactivity data with Hammett s relationships. 

This reaction is of synthetic value in that a halo acids are reactive sub strates m nucleophilic substitution reactions... 

Amides are the least reactive caiboxyhc acid deiivative and the only nucleophilic acyl substitution reaction they undeigo is hydrolysis Amides are fanly stable m water but the amide bond is cleaved on heating m the presence of strong acids 01 bases Nomi nally this cleavage produces an amine and a caiboxyhc acid... 

The orbital and resonance models for bonding in arylamines are simply alternative ways of describing the same phenomenon Delocalization of the nitrogen lone pair decreases the electron density at nitrogen while increasing it m the rr system of the aro matic ring We ve already seen one chemical consequence of this m the high level of reactivity of aniline m electrophilic aromatic substitution reactions (Section 12 12) Other ways m which electron delocalization affects the properties of arylamines are described m later sections of this chapter... 

A nitro group behaves the same way m both reactions it attracts electrons Reaction is retarded when electrons flow from the aromatic ring to the attacking species (electrophilic aromatic substitution) Reaction is facilitated when electrons flow from the attacking species to the aromatic ring (nucleophilic aromatic substitution) By being aware of the connection between reactivity and substituent effects you will sharpen your appreciation of how chemical reactions occur... 

Isopentenyl pyrophosphate and dimethylallyl pyrophosphate are structurally sim liar—both contain a double bond and a pyrophosphate ester unit—but the chemical reactivity expressed by each is different The principal site of reaction m dimethylallyl pyrophosphate is the carbon that bears the pyrophosphate group Pyrophosphate is a reasonably good leaving group m nucleophilic substitution reactions especially when as in dimethylallyl pyrophosphate it is located at an allylic carbon Isopentenyl pyrophosphate on the other hand does not have its leaving group attached to an allylic carbon and is far less reactive than dimethylallyl pyrophosphate toward nucleophilic reagents The principal site of reaction m isopentenyl pyrophosphate is the carbon-carbon double bond which like the double bonds of simple alkenes is reactive toward electrophiles... 

Nucleophilicity (Section 8 7) A measure of the reactivity of a Lewis base in a nucleophilic substitution reaction... 

Many of the common electrophilic aromatic substitution reactions can be conducted on indole. CompHcations normally arise either because of excessive reactivity or the relative instabiUty of the substitution product. This is the case with halogenation. 

Substitution Reactions on Side Chains. Because the benzyl carbon is the most reactive site on the propanoid side chain, many substitution reactions occur at this position. Typically, substitution reactions occur by attack of a nucleophilic reagent on a benzyl carbon present in the form of a carbonium ion or a methine group in a quinonemethide stmeture. In a reversal of the ether cleavage reactions described, benzyl alcohols and ethers may be transformed to alkyl or aryl ethers by acid-catalyzed etherifications or transetherifications with alcohol or phenol. The conversion of a benzyl alcohol or ether to a sulfonic acid group is among the most important side chain modification reactions because it is essential to the solubilization of lignin in the sulfite pulping process (17). 

The general reactivity of higher a-olefins is similar to that observed for the lower olefins. However, heavier a-olefins have low solubihty in polar solvents such as water consequentiy, in reaction systems requiting the addition of polar reagents, apparent reactivity and degree of conversion maybe adversely affected. Reactions of a-olefins typically involve the carbon—carbon double bond and can be grouped into two classes (/) electrophilic or free-radical additions and (2) substitution reactions. 

The aminophenols are chemically reactive, undergoing reactions involving both the aromatic amino group and the phenoHc hydroxyl moiety, as weU as substitution on the benzene ring. Oxidation leads to the formation of highly colored polymeric quinoid stmctures. 2-Aminophenol undergoes a variety of cyclization reactions. 

The aromatic ring has high electron density. As a result of this electron density, toluene behaves as a base, not only in aromatic ring substitution reactions but also in the formation of charge-transfer (tt) complexes and in the formation of complexes with super acids. In this regard, toluene is intermediate in reactivity between benzene and the xylenes, as illustrated in Table 2. 

Carbonates undergo nucleophilic substitution reactions analogous to chloroformates except in this case, an OR group (rather than chloride) is replaced by a more basic group. Normally these reactions are cataly2ed by bases. Carbonates are sometimes preferred over chloroformates because formation of hydrogen chloride as a by-product is avoided, which simplifies handling. However, the reactivity of carbonates toward nucleophiles is considerably less than chloroformates. 

Methyl chloride can be converted iato methyl iodide or bromide by refluxing ia acetone solution ia the presence of sodium iodide or bromide. The reactivity of methyl chloride and other aUphatic chlorides ia substitution reactions can often be iacteased by usiag a small amount of sodium or potassium iodide as ia the formation of methyl aryl ethers. Methyl chloride and potassium phthalimide do not readily react to give /V-methy1phtha1imide unless potassium iodide is added. The reaction to form methylceUulose and the Williamson synthesis to give methyl ethers are cataly2ed by small quantities of sodium or potassium iodide. 

In the case of substituted phenazine fV-oxides some activation of substituents towards nucleophilic substitution is observed. 1-Chlorophenazine is usually very resistant to nucleophilic displacements, but the 2-isomer is more reactive and the halogen may be displaced with a number of nucleophiles. 1-Chlorophenazine 5-oxide (56), however, is comparable in its reactivity with 2-chlorophenazine and the chlorine atom is readily displaced in nucleophilic substitution reactions. 2-Chlorophenazine 5,10-dioxide (57) and 2-chlorophenazine 5-oxide both show enhanced reactivity relative to 2-chlorophenazine itself. On the basis of these observations, similar activation of 5- or 6-haloquinoxaline fV-oxides should be observed but little information is available at the present time. 

As in the pyridopyrimidines, selective nucleophilic substitution reactions at reactive ring positions have been a fruitful source of pyridopyridazines. 

These effects can be attributed mainly to the inductive nature of the chlorine atoms, which reduces the electron density at position 4 and increases polarization of the 3,4-double bond. The dual reactivity of the chloropteridines has been further confirmed by the preparation of new adducts and substitution products. The addition reaction competes successfully, in a preparative sense, with the substitution reaction, if the latter is slowed down by a low temperature and a non-polar solvent. Compounds (12) and (13) react with dry ammonia in benzene at 5 °C to yield the 3,4-adducts (IS), which were shown by IR spectroscopy to contain little or none of the corresponding substitution product. The adducts decompose slowly in air and almost instantaneously in water or ethanol to give the original chloropteridine and ammonia. Certain other amines behave similarly, forming adducts which can be stored for a few days at -20 °C. Treatment of (12) and (13) in acetone with hydrogen sulfide or toluene-a-thiol gives adducts of the same type. 

The reactivity of five-membered rings with one heteroatom to electrophilic reagents has been quantitatively compared in a variety of substitution reactions. Table 2 shows the rates of substitution compared to thiophene for formylation by phosgene and iV,AT-dimethylfor-mamide, acetylation by acetic anhydride and tin(IV) chloride, and trifluoroacetylation with trifluoroacetic anhydride (71AHC(13)235). 

Quantitative data are available on the effect on electrophilic substitution reactions of the fusion of a benzene ring to the b face of a furan or thiophene ring. The overall effect is to decrease reactivity this decrease is much more pronounced in the case of fusion to a furan than to a thiophene ring. As a consequence the overall reactivities of benzo[Z)]furan and benzo[Z)]thiophene are approximately equal 71AHC(13)235). 

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). 

It is also of significance that in the dilute gas phase, where the intrinsic orientating properties of pyrrole can be examined without the complication of variable phenomena such as solvation, ion-pairing and catalyst attendant on electrophilic substitution reactions in solution, preferential /3-attack on pyrrole occurs. In gas phase t-butylation, the relative order of reactivity at /3-carbon, a-carbon and nitrogen is 10.3 3.0 1.0 (81CC1177). 

Rate data are also available for the solvolysis of l-(2-heteroaryl)ethyl acetates in aqueous ethanol. Side-chain reactions such as this, in which a delocalizable positive charge is developed in the transition state, are frequently regarded as analogous to electrophilic aromatic substitution reactions. In solvolysis the relative order of reactivity is tellurienyl> furyl > selenienyl > thienyl whereas in electrophilic substitutions the reactivity sequence is furan > tellurophene > selenophene > thiophene. This discrepancy has been explained in terms of different charge distributions in the transition states of these two classes of reaction (77AHC(21)119>. 

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