Nucleophiles and leaving groups compared

Some rates (relative to that of water = 1) of various nucleophiles towards methyl bromide in ethanol are shown in Table 17.16. 

You have met a similar sequence before in Chapter 10, and it would be useful to review the terms we used then. Nucleophiles like R3P and RS-, the ones that react well with saturated carbon, are referred to as soft nucleophiles and those that are more basic and react well with carbonyl groups referred to as hard nucleophiles. These are useful and evocative terms because the soft nucleophiles are rather large and flabby with diffuse high-energy electrons while the hard nucleophiles are small with closely held electrons and high charge density. When we say hard (nucleophile or electrophile) we refer to species whose reactions are dominated by electrostatic attraction and when we say soft (nucleophile or electrophile) we refer to species whose reactions are dominated by HOMO-LUMO interactions. 

The first of these reactions is assisted by precipitation of NaCi from acetone, which drives the reaction along. 

The 5 2 reaction is different because it does not have an intermediate. Therefore anything that lowers the energy of the transition state will speed up both the forward and the back reactions. We need to consider two results of this the rate of the reaction and which way it will go. 

Iodide ion is one of the best nucleophiles towards saturated carbon because it is at the bottom of its group in the periodic table and its lone-pair electrons are veiy high in energy. This is in spite of the very low basicity of iodide (Table 17.17). It reacts rapidly with a variety of alkyl derivatives and alkyl iodides can be made by displacement of chloride or tosylalc by iodide. 

Just to remind you reactions dominated by electrostatic attraction also need to pass electrons from HOMO to LUMO, but reactions that are dominated by HOMO-LUMO interactions need have no contribution from electrostatic attraction. 

When we say hard (nucleophile or electrophile) we refer to species whose reactions are dominated by electrostatic attraction and when we say soft (nucleophile or electrophile) we refer to species whose reactions are dominated by ffOMO-LUMO interactions. 

In Chapter 10 we expiained that, in a nucleophilic attack on the carbonyl group, a good nucleophile is a bad ieaving group and vice versa. We set you the challenge of predicting which way the foiiowing reaction would go. 

You should by now understand weU that the reaction goes from ester to amide rather than the other way round, because NH3 is a better nucleophile than MeOH and NHj is a worse leaving group than MeO . 

The solvent xylene needs some explanation. Xylene is the trivial name for dimethyl benzene and there are three isomers. Mixed xylenes are isolated cheaply from oil and often used as a relatively high boiling solvent (b.p. about 140 °C) for reactions at high temperature. In this case, the starting materials are soluble in xylene but the product is a salt and conveniently precipitates out during the reaction. Non-polar xylene favours the S 2 reaction (p. 345). 

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Given a particular nucleophile and leaving group, how can we determine whether the equilibrium will favor products in a nucleophilic substitution We can often correctly predict the direction of equilibrium by comparing the basicity of the nucleophile and the leaving group. 

In Fig. 2, the reaction coordinate XR is the difference between the two C-Cl distances, i.e., XR = Rr(C- Cl7) - Wp(C1 - C), where C-Cf is the carbon and leaving group distance and Cl-C is the nucleophilic chloride and carbon distance. The double well potential for an SN2 reaction is clearly characterized by the MOVB method with a binding energy of — 9.7 kcal/mol for the ion-dipole complex.51,52 This may be compared with values of —10.3 kcal/mol from HF/6-31G(d), — 10.5 kcal/mol from the G2(+) model,53 — 10.0 kcal/mol from ab... 

Nucleophilic substitution reactions of unsaturated compounds containing the G=G double bond are well known and are distinguished by the relative location of the double bond and leaving group. Rappoport has recently reviewed the wide and complex nature of nucleophilic vinylic substitutions. The susceptibility of simple vinyl compounds to nucleophilic attack is low and comparable to unactivated halobenzenes. As is the case with aromatic compounds, however, vinylic substrates may be activated by electron-withdrawing substituents conjugated with the reaction centre. 

Pearson and Sweigart have reported one of the first kinetic studies involving substitution at square-planar nickel(n), in Ni"-dithiolate complexes. They discuss nucleophilic reactivity, leaving group, and trans effects, and report that the reactions follow an associative pathway, as expected. The solvent path is not important and, although for Pt" the formation of a five-co-ordinate intermediate may be rate-determining, for Ni" this step is fast compared with subsequent steps. The formation constant of the five-co-ordinate intermediate does, however, markedly affect the overall rates, and it seems that the trans effect for nickel(ii) operates through the stability of this intermediate. 

This reaction is not so different from the reactions we saw earlier in this chapter when we explored hydrogen nucleophiles (NaBH4 and LAH). We saw a similar scenario there the nucleophile attacked, and then the carbonyl group was NOT able to re-form because there was no leaving group. Compare one of those reactions to this reaction ... 

To derive the maximum amount of information about intranuclear and intemuclear activation for nucleophilic substitution of bicyclo-aromatics, the kinetic studies on quinolines and isoquinolines are related herein to those on halo-1- and -2-nitro-naphthalenes, and data on polyazanaphthalenes are compared with those on poly-nitronaphthalenes. The reactivity rules thereby deduced are based on such limited data, however, that they should be regarded as tentative and subject to confirmation or modification on the basis of further experimental study. In many cases, only a single reaction has been investigated. From the data in Tables IX to XVI, one can derive certain conclusions about the effects of the nucleophile, leaving group, other substituents, solvent, and comparison temperature, all of which are summarized at the end of this section. 

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