Synthesis (3) – Reactions of Alkyl Halides

by James

in Alkyl Halides, Organic Chemistry 1, Synthesis

In the last post, we began our discussion of synthesis by starting with the reactions of alkanes. Since we’ve learned only one important class of alkane reactions so far (free-radical halogenation), our “reaction map” was very small. 

Today we will visit the reactions of a much more synthetically versatile functional group: alkyl halides. Using our analogy to airports, if alkanes can be compared to Bozeman, Montana (not exactly a hub), alkyl halides are more like Denver or ORD. There are many connecting flights! 

Here are some of the reactions of alkyl halides we have covered so far, divided by the type of alkyl halide [primary, secondary, and tertiary]. Note that we are excluding alkyl fluorides here, as fluoride is not a good enough leaving group for our purposes.  

1-alkyl halides

Substitution Reactions 

 The SN2 is an extremely versatile reaction from a synthetic standpoint. Primary alkyl halides can be converted into a wide variety of functional groups. Secondary alkyl halides can be used as well, although one has to be careful about competition with elimination reactions if the nucleophile is too basic [a good rule of thumb: species with a pKa higher than 12 will have a strong enough conjugate base to possibly produce E2 products along with SN2 products – that means you will need to pay close attention to the conditions you choose. Low temp, polar aprotic solvents will tend to favor SN2 vs E2. ]. In particular, on the diagram shown below, “strong” bases include hydroxide “HO-“, alkoxide “RO-” and “acetylide” (deprotonated alkyne), although other strong bases [such as NH2] fall into the same category. One prominent exception in many courses is the “bulky” base tert-butoxide [(CH3)3CO-] which generally favors elimination over substitution, even on primary alkyl halies. 

2-sn2

What about the SN1? 

The most useful application of SN1 reactions in synthesis is in “solvolysis” reactions, where the alkyl halide is dissolved in a nucleophilic solvent such as water or an alcohol. This works best for tertiary alkyl halides.  The resulting products are either alcohols (in the case of water as solvent) or ethers (when an alcohol is used as a solvent). If you care about preserving stereochemistry [at this stage, you probably don’t] don’t forget that since the SN1 proceeds through a [flat] carbocation, chiral alkyl halides will form mixtures of stereoisomers. For secondary alkyl halides, keep in mind that carbocations can be prone to rearrangements if a more stable carbocation can form through an alkyl or hydride shift. For this reason (as well as for preserving stereochemistry) it is generally best to avoid incorporating SN1 reactions of secondary alkyl halides into a synthesis unless you are really sure that no other competing products will form. Use SN2 conditions [strong nucleophile, polar aprotic solvent] instead. 

3-sn1 

Elimination Reactions

Elimination reactions are very useful for producing alkenes from alkyl halides. Of the two pathways by which elimination can occur (E1 and E2) the E2 is greatly preferred from a synthetic standpoint since the products of the reaction are much more predictable, it works well with both secondary and tertiary alkyl halides, and is not accompanied by rearrangements. 

 There are always several things to keep in mind with the E2 reaction. 

4-e2

What about E1 reactions? Don’t they get some love? Not from a synthetic standpoint. They go through a carbocation, first of all. From a synthetic standpoint, this is bad for three reasons. Not only can this potentially lead to rearrangements, but since carbocations have a trigonal planar geometry, any hope of controlling the stereochemistry of the elimination reaction is thrown out the window. Furthermore, E1 reactions are almost always accompanied by SN1 byproducts, so it’s not an easy reaction to control. There simply aren’t many situations where the E1 reaction is your best call. Use E2 conditions [strong base, polar protic solvent, heat ] instead. 

This covers the main reactions of alkyl halides so far. There are more to learn,  of course, but we haven’t gotten to them yet! 

What we’ll do now is update the “reaction map” we made in the last post to reflect all the reactions we talked about. 

Ready? Here it is.  

6-new rxn map

In the next post on synthesis we’ll go through the reactions of alkenes.

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{ 2 comments… read them below or add one }

Alex

What does the “rearr” in the 8 and 6 lines of the ‘reactions map’ means? (“rearr possible with….”)

Also, a question , is it true you can make ethers using sn1 AND using sn2 reactions when the substrate is 2-bromo-3-methyl-butane and the nucleophile is NaOCH3 (OCH3-) ?
I don’t see why both types of reactions wouldn’t work with these reagents.
Thanks!

Reply

James

It means “rearrangement”, i.e. a 1,2- hydride or alkyl shift.

Reply

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