Nucleophiles alkyl halide substitution reactions

Table 10.6 Summary of the Reactivity of Alkyl Halides Substitution Reactions in Nucleophilic...

Two kinds of starting materials have been examined in nucleophilic substitution reactions to this point. In Chapter 4 we saw that alcohols can be converted to alkyl halides by reaction with hydrogen halides and pointed out that this process is a nucleophilic substitution taking place on the protonated fonm of the alcohol, with water serving as the... 

Section 23.4 Aiyl halides aie less reactive than alkyl halides in reactions in which C—X bond breaking is rate-detennining, especially in nucleophilic substitution reactions. 

Chiral oxazolines developed by Albert I. Meyers and coworkers have been employed as activating groups and/or chiral auxiliaries in nucleophilic addition and substitution reactions that lead to the asymmetric construction of carbon-carbon bonds. For example, metalation of chiral oxazoline 1 followed by alkylation and hydrolysis affords enantioenriched carboxylic acid 2. Enantioenriched dihydronaphthalenes are produced via addition of alkyllithium reagents to 1-naphthyloxazoline 3 followed by alkylation of the resulting anion with an alkyl halide to give 4, which is subjected to reductive cleavage of the oxazoline moiety to yield aldehyde 5. Chiral oxazolines have also found numerous applications as ligands in asymmetric catalysis these applications have been recently reviewed, and are not discussed in this chapter. ... 

Mechanistically the reaction can be divided into two steps. Initially the alkyl halide 1 reacts with sodium to give an organometallic species 3, that can be isolated in many cases. In a second step the carbanionic R of the organometallic compound 3 acts as nucleophile in a substitution reaction with alkyl halide 1 to replace the halide ... 

Some organic reactions can be accomplished by using two-layer systems in which phase-transfer catalysts play an important role (34). The phase-transfer reaction proceeds via ion pairs, and asymmetric induction is expected to emerge when chiral quaternary ammonium salts are used. The ion-pair interaction, however, is usually not strong enough to control the absolute stereochemistry of the reaction (35). Numerous trials have resulted in low or only moderate stereoselectivity, probably because of the loose orientation of the ion-paired intermediates or transition states. These reactions include, but are not limited to, carbene addition to alkenes, reaction of sulfur ylides and aldehydes, nucleophilic substitution of secondary alkyl halides, Darzens reaction, chlorination... 

Mechanism 6-1 Allylic Bromination 228 Summary Methods for Preparing Alkyl Halides 229 6-7 Reactions of Alkyl Halides Substitution and Elimination 231 6-8 Second-Order Nucleophilic Substitution The Sn2 Reaction 232 Key Mechanism 6-2 The S j2 Reaction 233 6-9 Generality of the SN2 Reaction 234... 

Alkylation involves treating ammonia or an amine with an alkyl halide. The amine, as a Lewis base with a non-bonding electron pair, is a good nucleophile and displaces the halide ion from the alkyl halide the reaction is nucleophilic substitution with a neutral nucleophile. SN2 reactions are common. Since alkylation tends to continue until four groups are bonded to the nitrogen, it has limited synthetic utility. 

Section 4.11 The conversion of an alcohol to an alkyl halide on reaction with a hydrogen halide is a nucleophilic substitution. Nucleophilic substitutions (Sn) are classihed as S l or 8 2 according to whether the rate-determining step is unimolecular or bimolecular. 

Nucleophilic aromatic substitution often requires metal catalysis, as described above. In contrast, alkyl halides undergo reactions with phosphines directly. Nevertheless, metal-catalyzed cross-couplings of these reactive electrophiles have been developed by activation of the nucleophile. 

We have seen that alkyl halides can undergo four types of reactions Sn2, SnT E2, and El. As a result, you may feel a bit overwhelmed when you are asked to predict the products of the reaction of a given alkyl halide and a nucleophile/base. Let s pause, therefore, to organize what we know about the reactions of alkyl halides to make it a little easier for you to predict their products. Notice, in the following discussion, that HO is called a nucleophile in a substitution reaction (because it attacks a carbon) and it is called a base in an elimination reaction (because it removes a proton). 

HI is also used in organic chemistry to convert primary alcohols into alkyl halides. This reaction is an Sn2 substitution, in which the iodide ion replaces the "activated" hydroxyl group (water). HI is preferred over other hydrogen halides in polar protic solvents because the iodide ion is a much better nucleophile than bromide or chloride, so the reaction can take place at a reasonable rate without much heating. The large iodide anion is less solvated and more reactive in polar protic solvents and thus causes the reaction to proceed faster because of stronger partial bonds in the transition state. This reaction also occurs for secondary and tertiary alcohols, but substitution occurs via the SnI pathway. 

There are many examples where the same reactant is considered sometimes as an agent and sometimes as a substrate. For example, alkyl halides in reactions of nucleophilic substitution and abstraction are considered as substrates, whereas in alkylation reactions of aromatic compoimds they are considered as agents. If both reactants are considered as equivalent, we have to speak about electrophilic-nucleophilic, i.e., heterolytic reactions, in which one reactant is a nucleophile and another is an electrophile. 

N,N,N, N -tetramethyl-l,8,-naph-thalenediamiDe M.P. 51 C. A remarkably strong mono-acidic base (pKg 12-3) which is almost completely non-nucleophilic and valuable for promoting organic elimination reactions (e.g. of alkyl halides to alkenes) without substitution. 

These reactions follow first-order kinetics and proceed with racemisalion if the reaction site is an optically active centre. For alkyl halides nucleophilic substitution proceeds easily primary halides favour Sn2 mechanisms and tertiary halides favour S 1 mechanisms. Aryl halides undergo nucleophilic substitution with difficulty and sometimes involve aryne intermediates. 

When we discussed elimination reactions in Chapter 5 we learned that a Lewis base can react with an alkyl halide to form an alkene In the present chapter you will find that the same kinds of reactants can also undergo a different reaction one m which the Lewis base acts as a nucleophile to substitute for the halo gen substituent on carbon... 

Nucleophilic substitution reactions of alkyl halides are related to elimination reactions m that the halogen acts as a leaving group on carbon and is lost as an anion The... 

Representative Functional Group Transformations by Nucleophilic Substitution Reactions of Alkyl Halides... 

There are very large differences m the rates at which the various kinds of alkyl halides— methyl primary secondary or tertiary—undergo nucleophilic substitution As Table 8 2 shows for the reaction of a series of alkyl bromides... 

The Lewis base that acts as the nucleophile often is but need not always be an anion Neutral Lewis bases can also serve as nucleophiles Common examples of substitutions involving neutral nucleophiles include solvolysis reactions Solvolysis reactions are substitutions m which the nucleophile is the solvent m which the reaction is carried out 8olvolysis m water (hydrolysis) converts an alkyl halide to an alcohol... 

The large rate enhancements observed for bimolecular nucleophilic substitutions m polai aprotic solvents are used to advantage m synthetic applications An example can be seen m the preparation of alkyl cyanides (mtiiles) by the reaction of sodium cyanide with alkyl halides... 

Section 8 13 When nucleophilic substitution is used for synthesis the competition between substitution and elimination must be favorable However the normal reaction of a secondary alkyl halide with a base as strong or stronger than hydroxide is elimination (E2) Substitution by the Sn2 mechanism predominates only when the base is weaker than hydroxide or the alkyl halide is primary Elimination predominates when tertiary alkyl halides react with any anion... 

The reactions of alcohols with hydrogen halides to give alkyl halides (Chapter 4) are nucleophilic substitution reactions of alkyloxonium ions m which water is the leaving group Primary alcohols react by an 8 2 like displacement of water from the alkyloxonium ion by halide Sec ondary and tertiary alcohols give alkyloxonium ions which form carbo cations m an S l like process Rearrangements are possible with secondary alcohols and substitution takes place with predominant but not complete inversion of configuration... 

Anions of acetylene and terminal alkynes are nucleophilic and react with methyl and primary alkyl halides to form carbon-carbon bonds by nucleophilic substitution Some useful applications of this reaction will be discussed m the following section... 

As m other nucleophilic substitution reactions alkyl p toluenesulfonates may be used m place of alkyl halides... 

Unlike elimination and nucleophilic substitution reactions foimation of oigano lithium compounds does not require that the halogen be bonded to sp hybndized carbon Compounds such as vinyl halides and aiyl halides m which the halogen is bonded to sp hybndized carbon react m the same way as alkyl halides but at somewhat slowei rates... 

Nitriles contain the —C=N functional group We have already discussed the two mam procedures by which they are prepared namely the nucleophilic substitution of alkyl halides by cyanide and the conversion of aldehydes and ketones to cyanohydrins Table 20 6 reviews aspects of these reactions Neither of the reactions m Table 20 6 is suitable for aryl nitriles (ArC=N) these compounds are readily prepared by a reaction to be dis cussed m Chapter 22... 

Nucleophilic substitution by azide ion on an alkyl halide (Sections 8 1 8 13) Azide ion IS a very good nucleophile and reacts with primary and secondary alkyl halides to give alkyl azides Phase transfer cata lysts accelerate the rate of reaction... 

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