Substitution reactions, inhibition

The 2-nitrothiazole can be reduced to the corresponding aminothiazole by catalytic or chemical reduction (82, 85, 89). The 5-nitrothiazole can also be reduced with low yield to impure 5-aminothiazole (1, 85). All electrophilic substitution reactions are largely inhibited by the presence of the nitro substituent. Nevertheless, the nitration of 2-nitrothiazoIe to 2,4-dinitrothiazole can be accomplished (see Section IV). 

If (A i[X ]/A 2[Y ]) is not much smaller than unity, then as the substitution reaction proceeds, the increase in [X ] will increase the denominator of Eq. (8-65), slowing the reaction and causing deviation from simple first-order kinetics. This mass-law or common-ion effect is characteristic of an S l process, although, as already seen, it is not a necessary condition. The common-ion effect (also called external return) occurs only with the common ion and must be distinguished from a general kinetic salt effect, which will operate with any ion. An example is provided by the hydrolysis of triphenylmethyl chloride (trityl chloride) the addition of 0.01 M NaCl decreased the rate by fourfold. The solvolysis rate of diphenylmethyl chloride in 80% aqueous acetone was decreased by LiCl but increased by LiBr. ° The 5 2 mechanism will also yield first-order kinetics in a solvolysis reaction, but it should not be susceptible to a common-ion rate inhibition. 

The pyrrole ring is widely distributed in nature. It occurs in both terrestrial and marine plants and animals [1-3]. Examples of simple pyrroles include the Pseudomonas metabolite pyrrolnitrin, a recently discovered seabird hexahalogenated bipyrrole [4], and an ant trail pheromone. An illustration of the abundant complex natural pyrroles is konbu acidin A, a sponge metabolite that inhibits cyclin-dependent kinase 4. The enormous reactivity of pyrrole in electrophilic substitution reactions explains the occurrence of more than 100 naturally occurring halogenated pyrroles [2, 3]. 

On the basis of this argument it is probable that the tris-p-halogen substituted trityl salts will be useful initiators for the polymerisation of isobutylene since their ionisation potentials probably exceed 690 kj mol1 [38], and the p-substitution would inhibit the back-biting reactions which make both trityl and dityl salts unstable [39]. 

The synthesis of polyhalide salts, R4NX , used in electrophilic substitution reactions, are described in Chapter 2 and H-bonded complexed salts with the free acid, R4NHX2, which are used for example in acid-catalysed cleavage reactions and in electrophilic addition reactions with alkenes, are often produced in situ [33], although the fluorides are obtained by modification of method I.I.I.B. [19, 34], The in situ formation of such salts can inhibit normal nucleophilic reactions [35, 36]. Quaternary ammonium chlorometallates have been synthesized from quaternary ammonium chlorides and transition metal chlorides, such as IrClj and PtCl4, and are highly efficient catalysts for phase-transfer reactions and for metal complex promoted reactions [37]. 

The application of phase-transfer catalysis to the Williamson synthesis of ethers has been exploited widely and is far superior to any classical method for the synthesis of aliphatic ethers. Probably the first example of the use of a quaternary ammonium salt to promote a nucleophilic substitution reaction is the formation of a benzyl ether using a stoichiometric amount of tetraethylammonium hydroxide [1]. Starks mentions the potential value of the quaternary ammonium catalyst for Williamson synthesis of ethers [2] and its versatility in the synthesis of methyl ethers and other alkyl ethers was soon established [3-5]. The procedure has considerable advantages over the classical Williamson synthesis both in reaction time and yields and is certainly more convenient than the use of diazomethane for the preparation of methyl ethers. Under liquidrliquid two-phase conditions, tertiary and secondary alcohols react less readily than do primary alcohols, and secondary alkyl halides tend to be ineffective. However, reactions which one might expect to be sterically inhibited are successful under phase-transfer catalytic conditions [e.g. 6]. Microwave irradiation and solidrliquid phase-transfer catalytic conditions reduce reaction times considerably [7]. 

Azide ion is a modest leaving group in An + Dn nucleophilic substitution reactions, and at the same time a potent nucleophile for addition to the carbocation reaction intermediate. Consequently, ring-substituted benzaldehyde g m-diazides (X-2-N3) undergo solvolysis in water in reactions that are subject to strong common-ion inhibition by added azide ion from reversible trapping of an o -azido carbocation intermediate (X-2 ) by diffusion controlled addition of azide anion (Scheme... 

Scheme 22. The rate equation for this mechanism is described in (1). The authors determined that the reaction is first-order in allylic carbonate, aniline and catalyst, and inverse first-order in allylamine product. These results are consistent with the proposed mechanism. Thus, iridium-catalyzed allylic substitution is inhibited by product. In addition, the formation of the allyliridium intermediate is disfavored.

These data also clearly establish that reactions of C-20 alkyl derivatives of deoxydesethyl VBL with soluble MTP or with its polymerized form as microtubules are dissociable events. Whereas the dimethyl- (6) and propyl- (10) substituted compounds inhibited the assembly of microtubules with an IC50 of about 3 x 10 M, they were inactive with steady-state microtubules at 10" M. 

In nitration, halogenation, sulfonation, and acylation, the reactions are easy to control with temperature. The processes deactivate the ring toward further substitution, so the reactions inhibit further reaction. 

An important steric hindrance of the carbon in the a-position to the oxygen (or a bicyclic structure) reduces or even inhibits formation of the phosphoryl group by substitution reaction on this carbon. It must be pointed out that phosphoryl formation occurs, generally, in Arbuzov-type reactions, by a substitution process, but can take place also by a -elimination which is favoured by major steric hindrance. 

The complexes [RuCl4(H20)2] and [RuCl5(H20)]2 were responsible for the catalytic activity. The inhibition by excess chloride ion was attributed to the formation of [RuC16]3. At lower chloride ion concentration the reduction in rate was caused by the formation of neutral or cationic complexes, which are inert to ligand substitution reactions. These reactions could be carried out at normal pressure and slightly raised temperature. 

Two additional substitution reactions of the adamantane nucleus have been studied. Dichlorocarbene is found to insert exclusively and in high yield at the bridgehead position of adamantane. The insertion reaction is strongly inhibited by the presence of electronegative substituents on the substantial positive charge in the transition state of this insertion reaction361). 

The rates of SnI and Sn2 reactions are usually strongly enhanced when atoms with an unshared electron pair are directly attached to the reaction center, as in a-halo-methyl ethers, thioethers, or amines (Scheme 4.30). Only the halogens do not lead to an enhancement of Sn2 reactivity, but to inhibition of bimolecular substitution reactions (Scheme 4.30). In SnI reactions, however, a-halogens can both increase or reduce the rate of substitution [127]. 

Most tropolones give sparingly soluble, yellow or orange sodium salts, green cupric chelates, and colored ferric complexes. Although easily acetyl-ated or methylated and frequently precipitated by picric acid, tropolones only exceptionally react with carbonyl reagents. Electrophilic substitution reactions occur readily however, sulfonation or nitration is inhibited... 

Displacing the Essential Metal Ion in Biomolecules. It is estimated that approximately one third of all enzymes require metal as a cofactor or as a structural component. Those that involve metals as a structural component do so either for catalytic capability, for redox potential, or to confer steric arrangements necessary to protein function. Metals can cause toxicity via substitution reactions in which the native, essential metal is displaced/replaced by another metal. In some cases, the enzyme can still function after such a displacement reaction. More often, however, enzyme function is diminished or completely abolished. For example, Cd can substitute for Zn in the protein famesyl protein transferase, an important enzyme in adding famesyl groups to proteins such as Ras. In this case, Cd diminishes the activity of the protein by 50%. Pb can substitute for Zn in 8-aminolevulinic acid dehydratase (ALAD), and it causes inhibition in vivo and in vitro. ALAD contains eight subunits, each of which requires Zn. Another classic example of metal ions substituting for other metal ions is Pb substitution for Ca in bones. 

Figure 37 Inhibition of substitution reactions on both phenyl groups of diphenyl ether. (From Ref. 162.)...

A comparison of the relative reactivities of norbornane and silanorbor-nane illustrates the point. 1-Halonorbornane derivatives are very resistant to nucleophilic substitution reactions under strenuously applied S l and Sn2 conditions. The low reactivities of these compounds result from the cage structure that prohibits deformation to the planar geometry required for the carbocation intermediates of unimolecular reactions and inhibits the backside attack required for bimolecular substitutions at carbon. 

The ligand-substitution reaction of M(tpps) (M2+ = Zn2+. Cd2+, Pb2+) with N,N -l,2-ethanediylbis[(N-carboxymethyl)glycine] (H4edta) and the acid-dissociation reaction of the metalloporphyrins are inhibited by the presence of 18-Crown (18C6).22 Jhe rate suppression by 18C6 was explttined by the formation of [M(tpps)(18C6)] as a precursor complex. The... 

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