Substitution nucleophilic, at saturated carbon

The SnI mechanism involves a rate-determining heterolytic cleavage of the alkyl halide bond to yield an intermediate carbocation which undergoes rapid reaction with available electron donors, including solvent  

The typical reactions of carbocation intermediates were discussed in Chapter 7. The solvolysis of alkyl halides is an example of the involvement of carbocations in the SnI mechanism, in other words, where the final outcome is a nucleophilic substitution. The first step is a heterolytic cleavage of the C—X bond. Properties of X which favor heterolytic cleavage, namely electronegativity difference with carbon (the larger, the better) and the degree of overlap of the X orbital with the spn orbital of carbon (the smaller the better), have already been elucidated (Chapter 4). The transition state has partial 

The Sn2 mechanism implies a concerted bimolecular reaction which proceeds with inversion of stereochemistry at the central carbon atom  

Nucleophilicity. A distinction is usually made between nucleophilicity and Lowry-Bronsted basicity [213]. The latter involves specifically reaction at a proton which is complexed to a Lewis base (usually H2O), while the former refers to reactivity at centers other than H. Linear correlations have been shown for gas-phase basicity (proton affinity) and nucleophilicity of nitrogen bases toward CH3I in solution [214] where the solvent is not strongly involved in charge dispersal. In each case, reaction of the base/nucleophile 

Substituent Effects. The overwhelming influence of substituents on the rate of SN2 reactions is steric in nature bulky groups hinder the reaction by preventing the approach of the nucleophile to the central C atom. Nevertheless, one can examine electronic effects of substituents adjacent to the site of substitution on the rate of reaction. Direct elec- 

Let s have a look at why the mechanisms of the two substitutions must be different. Here s a summary of the mechanism of the first reaction. 

In the first step the nucleophile attacks the C=0 jc bond. It s immediately obvious that the first step is no longer possible at a saturated carbon atom. The electrons cannot be added to a 7t bond as the CH2 group is fully saturated. In fact there is no way for the nucleophile to add before the leaving group departs (as it did in the reaction above) because this would give an impossible five-valent carbon atom. 

Instead, two new and different mechanisms become possible. Either the leaving group goes first and the nucleophile comes in later, or the two events happen at the same time. The first of these possibilities you will learn to call the 5, 1 mechanism. The second mechanism, which shows how the neutral carbon atom can accept electrons provided it loses some at the same time, you will learn to call the 8 2 mechanism. You will see later that both mechanisms are possible with this molecule, benzyl chloride. 

If we know which mechanism a compound reacts by, we know what sort of conditions to use to get good yields in substitutions. For example, if you look at a commonly used nucleophilic substitution, the replacement of OH by Br, you ll find that two quite different reaction conditions are used depending on the structure of the alcohol. Tertiary alcohols react rapidly with HBr to give tertiary alkyl bromides. Er/ma/y alcohols, on the other hand, react only very slowly with HBr and are usually converted to primary alkyl bromides with PBrj. The reason is that the first example is an S 1 reaction while the second is an 5 2 reaction by the end of this chapter you will have a clear picture of how to predict which mechanism will apply and how to choose appropriate reaction conditions. 

Before we go any further we are going to look in a bit more detail at these two mechanisms because they allow us to explain and predict many aspects of substitution reactions. The evidence that convinced chemists that there are two different mechanisms for substitution at saturated carbon is kinetic it relates to the rate of reactions such as the displacement of bromide by hydroxide, as shown in the margin. 

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Stereochemical course of the reaction. This kind of information was critical in the elucidation of the SnI and Sn2 pathways for nucleophilic substitution at saturated carbon. 

Alkyl halides can be hydrolyzed to alcohols. Hydroxide ion is usually required, except that especially active substrates such as allylic or benzylic types can be hydrolyzed by water. Ordinary halides can also be hydrolyzed by water, if the solvent is HMPA or A-methyl-2-pyrrolidinone." In contrast to most nucleophilic substitutions at saturated carbons, this reaction can be performed on tertiary substrates without significant interference from elimination side reactions. Tertiary alkyl a-halocarbonyl compounds can be converted to the corresponding alcohol with silver oxide in aqueous acetonitrile." The reaction is not frequently used for synthetic purposes, because alkyl halides are usually obtained from alcohols. 

Carbonyl reactions are extremely important in chemistry and biochemistry, yet they are often given short shrift in textbooks on physical organic chemistry, partly because the subject was historically developed by the study of nucleophilic substitution at saturated carbon, and partly because carbonyl reactions are often more difhcult to study. They are generally reversible under usual conditions and involve complicated multistep mechanisms and general acid/base catalysis. In thinking about carbonyl reactions, 1 find it helpful to consider the carbonyl group as a (very) stabilized carbenium ion, with an O substituent. Then one can immediately draw on everything one has learned about carbenium ion reactivity and see that the reactivity order for carbonyl compounds ... 

The mechanistic aspects of nucleophilic substitutions at saturated carbon and carbonyl centers were considered in Part A, Chapters 4 and 7, respectively. In this chapter we discuss some of the important synthetic transformations that involve these types of... 

Introduction of Functional Groups by Nucleophilic Substitution at Saturated Carbon... 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

Fig. 23 Entropy effects on intramolecular reactions of polymethylene chains. Plot of 9AS (e.u.) against number of single bonds for (O) nucleophilic substitutions at saturated carbon ( ) electron-exchange reactions (A) quenching of benzophenone phosphorescence. The straight line has intercept +30 e.u. and slope —4.0 e.u. per rotor. The right-hand ordinate reports the purely entropic EM s calculated as exp(0AS /J )...

SECTION 3.2. INTRODUCTION OF FUNCTIONAL GROUPS BY NUCLEOPHILIC SUBSTITUTION AT SATURATED CARBON... 

A. Williams, Concerted Organic and Bioorganic Mechanisms, CRC Press, New York, 2000. W. P. Jencks, How Does a Reaction Choose Its Mechanism , Chem. Soc. Rev. 1981,10, 345. J. P. Richard, Simple Relationships between Carbocation Lifetime and the Mechanism for Nucleophilic Substitution at Saturated Carbon, Adv. Carbocation Chem. 1989, 1, 122. T. W. Bentley and G. Llewellyn, Scales of Solvent Ionizing Power, Prog. Phys. Org. Chem. 1990, 17, 121. 

The reaction that usually begins most elementary courses on mechanistic organic chemistry is nucleophilic substitution at saturated carbon. There are two extreme... 

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. 

A. R. Katritzky, B. E. Brycki, Nucleophilic Substitution at Saturated Carbon Atoms. Mechanisms and Mechanistic Borderlines Evidence from Studies with Neutral Leaving Groups, J. Rhys. Org. Chem. 1988, 1, 1-20. 

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