Nucleophilic order

I Nucleophilicity usually increases going down a column of the periodic table. Thus, HS- is more nucleophilic than HO-, and the halide reactivity order is I- > Br- > Cl-. Going down the periodic table, elements have their valence electrons in successively larger shells where they are successively farther from the nucleus, less tightly held, and consequently more reactive. The matter is complex, though, and the nucleophilicity order can change depending on the solvent. 

For Sn2 reactions in solution, there are four main principles that govern the effect of the nucleophile on the rate, though the nucleophilicity order is not invariant but depends on substrate, solvent, leaving group, and so on. 

The following overall nucleophilicity order for Sn2 mechanisms (in protic solvents) was given by Edwards and Pearson RS > ArS >1 >CN > OH > Nj > Br > ArO > Cl > pyridine > AcO > H2O. A quantitative relationship (the Swain-Scott equation) has been worked out similar to the linear free energy equations considered in Chapter 9 ... 

First, the order of ky values in different solvents is quite reasonably interpreted as a nucleophilicity order - e.g. ( 113)280 > HjO CH3NO2 > C2H5OH) and second, the k rate is (as is the k2) greatly reduced by steric crowding . Of course, a nucleophilic attack by solvent is a very likely process, a priori. In any solvent, the solvent itself will be the poorest nucleophile that can be studied since poorer ones will not effectively compete. Thus the k term of equation (21) corresponds to the ki value. The aquo intermediate of scheme (22) has been trapped by using reactions in the presence of OH , a poor nucleophile but good base . ... 

The bulk effect of water as a solvent is rather dramatic since it causes a drastic reduction of the nucleophilicity of 9-methyladenine N1 and even more of 9-methylguanine 06. As a result, there is a reversal of the nucleophilicity order of the purine bases passing from gas phase to aqueous solution. In fact, in solution, methyladenine is more nucleophilic than methylguanine. Moreover, oxygen and N7 nucleophilic centers of 9-methylguanine compete almost on the same footing in solution (Table 2.2) and also the reactivity gap between N1 and N7 of 9-methyladenine is highly reduced in comparison to the gas phase. 

The ease of formation of hydrophobic ion pairs, and hence the rate acceleration, will be determined by the hydrophobic and electrostatic interactions between the anionic and cationic species. Lapinte and Viout (1974) found that the nucleophilic order OH- > CN > C6H50- in water was completely reversed in CTAB micelles hydrophobic phenoxide ion is activated better by the micelle. The micellar binding of phenols and phenoxides was determined by Bunton and Sepulveda (1979). Similarly, hydrophobic hydroxamates are activated much better than their hydrophilic counterparts. In the same vein, the extent of activation correlates approximately with the hydrophobic nature of aqueous aggregates as estimated by Amax of methyl orange (Table 7) and of picrate ion (Bougoin et al., 1975 Shinkai et al., 1978f Table 5). 

Nucleophilicity order for R3X, sign of AS " and existence of 7-coordinated vanadium carbonyls, are consistent with an A mechanism. 

For substitution at a carbonyl carbon, the nucleophilicity order is not the same as it is at a saturated carbon, but follows the basicity order more closely. The reason is presumably that the carbonyl carbon, with its partial positive charge, resembles a proton more than does the carbon at a saturated center. That is, a carbonyl carbon is a much harder acid than a saturated carbon. The following nucleophilicity order for these substrates has been de-termmined 321 Me2C=NO- > EtO" > MeO > OH" > OAr- > N-f > F" > H20 > Br" I". Soft bases are ineffective at a carbonyl carbon.322 In a reaction carried out in the gas phase with alkoxide nucleophiles OR solvated by only one molecule of an alcohol R OH, it was found that both RO and R O" attacked the formate substrate (HCOOR") about equally, though in the unsolvated case, the more basic alkoxide is the better nucleophile.323 In this study, the product ion R"0 was also solvated by one molecule of ROH or R OH. 

The rates for the Sn2 reactions of seven different anionic nucleophiles (Cl-, Br-, I-, OAc-, CN-, SCN- and trifluoromethylacetate-) with methyl / -nitrobenzenesulfonate have been determined in CH2CI2, MeOH, DMSO, and three ionic liquid solvents.122 The reactivity was not correlated with the dielectric constant for the solvents as predicted by the Hughes-Ingold rules and a different nucleophilic order was found in... 

Carbanions are highly reactive species because in them the carbon carrying negative charge is electron rich and can donate its non-bonding pair of electrons to some other group for sharing. Hence, carbanions behave as nucleophiles. Order of reactivity of carbanions is reverse the order of stability. 

According to equation (2), A log. K will have the same sign (i. e. the same nucleophilic order will prevail) except for large values of a of equation 3 (a) (very low values of x) i. e. for very hard acids. This is shown by the values of koH-/kF- for reactions at saturated and unsaturated carbon atoms (71), and by the high value of this ratio for the combination of OH-and F- ions with a proton. 

The term f (0, P) depends on the properties of the O and P atoms leading to a given nucleophilic order for these atoms in the nonconjugat-ed state as discussed in Section 2. 

An interesting feature of these results is that ethanol is less nucleophilic than water toward the adamantyl derivatives, in contrast to the normal nucleophilic order (Bentley et al., 1972). This inverted... 

The stability of onium ions correlates directly with the nucleophilicity of the parent species the nucleophilicity order of heterocyclic monomers as correlated with their basicity is shown is shown in Eq. (44) [59]. Thus, O-based rings which are the least nucleophilic of the four types of pre-... 

It is not possible to construct an invariant nucleophilicity order because different substrates and different conditions lead to different orders of nucleophilicity, but an overall approximate order is NH2 > PhaC > PhNH (aryne mechanism) > ArS > RO > R2NH > ArO > OH > ArNHi > NH3 > 1 > Br > Cl > H2O > ROH. As with aliphatic nucleophilic substitution, nucleophilicity is generally dependent on base strength and nucleophilicity increases as the attacking atom moves down a column of the periodic table, but there are some surprising exceptions, for example, OH, a stronger base than ArO , is a poorer nucleophile. In a series of similar nucleophiles, such as substituted anilines, nucleophilicity is correlated with base strength. Oddly, the cyanide ion is not a nucleophile for aromatic systems, except for sulfonic acid salts and in the von Richter (13-30) and Rosenmund-von Braun (13-8) reactions, which are special cases. 

The nucleophilic order I > SCN > Br > Cl, (Table 21) for a variety of reactions at saturated carbon in protic solvents is well established (Hine, 1962) and has been regarded in the past as strong evidence for polarizability (Edwards and Pearson, 1962) as a factor in determining nucleophilic tendencies towards carbon. However, this series is reversed (Parker 1961a Coniglio et al., 1966 Parker, 1965a) on transfer from methanol to DMF, because log yci-/ y cN- —4-1, log yBr-/ y cN- Is — 2-3, and log y / yscif-1 +0-1 (Table 5). 

Most of the enzyme modification reactions, and hence of the coupling reactions, are nucleophilic reactions, in particular bimolecular nucleophilic substitution reactions following an 5 2-type mechanism. Therefore, the chemical reactivity is basically a function of nucleophilicity of the amino acid side chain. Following the overall nucleophilic order of Edwards and Pearson [22], the sulfhydryl group of cysteine is the most potent nucleophile in the protein, especially in its thiolate form. 

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