Making Alkyl Halides From Alcohols

Making Alkyl Halides From Alcohols

In today’s post we show that treating alcohols with HCl, HBr, or HI (which all fall under the catch-all term “HX” where X is a halide) results in the formation of alkyl halides.

• Primary alcohols tend to proceed through an S_N2 mechanism
• Tertiary alcohols tend to proceed through an S_N1 mechanism
• Watch out for rearrangements in reactions where a secondary carbocation may be formed

Table of Contents

1. Adding Acid To Alcohol Produces A  Good Leaving Group (H2O)
2. Alkyl Halides From Methyl and Primary Alcohols via the SN2 Reaction
3. Alkyl Halides From Tertiary Alcohols Proceeds Through The S_N1 Pathway
4. A Good Rule Of Thumb For Secondary Alcohols With HX: Assume S_N1
5. Rearrangements In The Formation of  Alkyl Halides From Alcohols
6. Rearrangement Example #1: Hydride Shift
7. Rearrangement Example #2: Alkyl Shift
8. Rearrangement Example #3: A Special Case of Alkyl  Shift – Ring Expansion  and Contraction
9. What Doesn’t Work?
10. Summary: Alkyl Halides From Alcohols
11. (Advanced) References and Further Reading

1. Adding Acid To Alcohol Results In A Good Leaving Group

We’ve said many times in this series of posts that alcohols are poor substrates for S_N1 and S_N2 reactions.  That’s because the hydroxyl ion (HO-) is a poor leaving group, and therefore not likely to either 1) depart of its own accord, leaving behind a carbocation (S_N1 pathway) or 2) to be displaced by an incoming nucleophile (which would be an S_N2 reaction).

However we’ve also seen that treating an alcohol with acid leads to an interesting “personality adjustment”: the alcohol (R-OH) is converted to its conjugate acid, (R-OH₂+) which now possesses a decent leaving group (the weak base we know as water, H₂O). (See post: How to Make Alcohols More Reactive)

We saw, in a previous post,  how this allows for formation of (symmetrical) ethers from alcohols, either via S_N2 pathway (with primary alcohols) or an S_N1 pathway (tertiary alcohols).

We might ask: can this be extended to form other functional groups besides ethers?

Absolutely.  Treating alcohols with HCl, HBr, or HI (which all fall under the catch-all term “HX” where X is a halide) results in the formation of alkyl halides.

This occurs in a two step process:

• first, the alcohol is protonated to give its conjugate acid.
• Secondly, a substitution occurs.

Notice how that second step (substitution) was left vague in the diagram above.  That’s because, as we’ve seen,  the type of substitution pathway depends on the substrate.

2. Alkyl Halides From Methyl And Primary Alcohols Via S_N2 Reaction

Knowing how sensitive the S_N2 reaction is to steric hindrance, we should expect that for methyl alcohol and for primary alcohols, the S_N2 pathway dominates. And it does! (See post: The S_N2 Mechanism)

Note how in each case we begin by protonating the alcohol, creating a good leaving group which is then displaced by the conjugate base of the acid. (See post: What Makes a Good Leaving Group?)

Alkyl chlorides, bromides, and iodides can each be made this way.

3. Alkyl Halides From Tertiary Alcohols Proceeds Through The S_N1 Pathway 

Likewise, understanding the trends of carbocation stability, we should expect that conversion of tertiary alcohols to alkyl halides proceeds through an S_N1 pathway. And it does. (See post: The S_N1 Mechanism)

Note in the last example that beginning with a chiral starting material will lead to a mixture of inversion and retention (often called, “racemization“) because it goes through the (flat) intermediate carbocation.

4. A Good Rule of Thumb For Secondary Alcohols With HX: Assume S_N1

Methyl, primary, and tertiary alcohols all represent pretty straightforward cases.

“So what about secondary alcohols?” you might ask. Ah yes. This is where things get interesting – and is, therefore, the stuff of which exam questions are made.

In the lab, treatment of secondary alcohols with HX leads to a mixture of products from S_N1 and S_N2 pathways. For practical purposes it is generally not a useful process, especially if you care about preserving stereochemistry.

However, your introductory textbook and course notes are not “the lab”. The purpose of a course is to introduce you to important concepts in organic chemistry. And from an instructor’s standpoint, it so happens that the conversion of secondary alcohols to secondary alkyl halides by HX is an excellent opportunity to bring up the subject of carbocation rearrangements. This falls under the purview of the S_N1 pathway.

So a good rule of thumb is to assume – for the purposes of your course – that secondary alcohols treated with HX will proceed through an S_N1 mechanism.

5. Rearrangements In The Formation Of Alkyl Halides From Alcohols

We’ve covered rearrangements  (hydride and alkyl shifts)  before in the context of S_N1 reactions. But it’s worth touching on again.

The basic premise is this. Carbocations are unstable, electron-poor species. Their stability generally increases with the number of attached carbons, which serve to donate electron density. Hence, the stability of carbocations increases in the direction methyl < primary < secondary < tertiary.  We also saw that carbocations are stabilized by resonance.

As we saw in a previous series of posts – consult this if you need more hand holding! –  carbocations can undergo 1,2 shifts of C-H and C-C bonds, resulting in new carbocations.

Such rearrangements are most likely to occur if they can result in a more stable carbocation. For example, the rearrangement of a secondary to a tertiary carbocation, is a favoured (energetically “downhill”) process, whereas a rearrangement from a tertiary to a secondary carbocation (energetically “uphill”) is unlikely.

Anytime a reaction proceeds through a carbocation intermediate, we need to be on the lookout to see if it is adjacent to a carbon which can generate a more stable carbocation through a shift of a C-H or C-C bond.

There are three cases in particular to watch out for.

6. Rearrangement Example #1: A  Hydride shift

Look for a secondary alcohol adjacent to a tertiary carbon. Note this common example, where protonation leads to loss of water, followed by a hydride shift and then trapping of the carbocation by the halide ion.

Another example of a favourable rearrangement is when a secondary carbocation is adjacent to an “allylic” or “benzylic” hydrogen. Rearrangement results in a secondary carbon which is stabilized by resonance.

7. Rearrangement Example #2: Alkyl Shift

Look for a secondary alcohol adjacent to a quaternary carbon (i.e. a carbon attached to 4 other carbons). Note how this is essentially the exact same process as the hydride shift above, except that CH₃ is migrating, not H.

8. Rearrangement Example #3:  A Special Case of Alkyl Shifts – Ring Expansions And Contractions

Look for a secondary alcohol that is adjacent to a strained ring (cyclobutane in the classic case).  Once the secondary carbocation is generated, a bond in the strained ring migrates, leading to expansion of the ring by one. This is particularly favourable in the case of cyclobutane to cyclopentane since cyclobutane is highly strained (about 26 kcal/mol) whereas cyclopentane has minimal ring strain.

This type of alkyl shift commonly gives students a hard time, which of course makes it a favourite exam problem of instructors. Although the curved arrow drawn is no different than that for the previous two cases, I think the main difficulty is in mapping the product from the starting material. In this respect I recommend two things:

• Number the carbons (not necessarily IUPAC – just number to keep track of them). For instance here the arrow in Step 3 (the alkyl shift) shows us breaking C2-C3 and forming C1-C3. Applying the rules of curved arrows implies that C1 will then be neutral and C2 will become a carbocation. That’s all that’s happening.  No other bonds are formed or broken in this step. It takes practice to get this right.
• Draw the ugly version first. THEN redraw to make it look good.

Ring contractions are also possible, although are not as favourable as the opening of strained rings. The same principles apply.

9. Alkyl Halides From Alcohols: What Doesn’t Work? 

It’s always helpful to know what doesn’t work in the formation of alkyl halides from alcohols.

First of all, since we’re dealing with substitution reactions here, some familiar rules apply.  Only alkyl alcohols (alcohols on sp³ hybridized carbons) will undergo S_N1 and SN2 reactions. Both the S_N1 and S_N2 pathways involve buildup of positive charge on carbon, and sp² and sp hybridized carbocations are extremely unstable. This attempted S_N1 of phenol, for example, will fail miserably:

You might also wonder if we can use reagents like HCN, HOAc, or HN₃ to convert alcohols to nitriles, esters, and azides respectively. Generally, no. The problem is that each of these are fairly weak acids (pK_a 4 and above)  so these will only give a low concentration of the protonated alcohol. Since the reaction rate is proportional to concentration, formation of these products will be slow. [With azides, there are also potential complications with a different type of rearrangement, but as a curtiusy we’re not going to deal with that schmidt right now : – ) ]

For our purposes, conversion of alcohols to other substitution products using strong acid is limited to HCl, HBr, HI, and the special case of H+/ROH which gives symmetrical ethers. A good rule of thumb is that the conjugate acid of the nucleophile should have a pK_a of 0 or less in order for the reaction to occur.

10. Summary: Making Alkyl Halides From Alcohols

So alcohols can be converted to alkyl halides. You might ask, “why should we care?”. The answer is that, as we said, converting an alcohol (which has a poor leaving group) into an alkyl halide (which has a great leaving group) now allows us to do all kinds of functional group interconversions that were not previously possible. The S_N2 is a very useful and powerful reaction, for example. Once a primary alcohol has been converted to a primary alkyl halide, we can then treat it with all varieties of nucleophiles to make a multitude of functional groups.

However nice it is to be able to do this, though,  it’s far from ideal.  We have to use strong acid, which can often cause complications if we have acid-sensitive functional groups on our molecule. Furthermore, all those pesky rearrangements on secondary carbons are a hassle. They can screw with our stereochemistry and lead to undesired products.  You might ask, “isn’t there some way to get around that?”.

Yes! We’ll talk about a very nice way around this dilemma in the next post!

Next Post – Tosylates And Mesylates

Notes

(Advanced) References and Further Reading

Alkyl chlorides from alcohols:

1. -BUTYL CHLORIDE
   James F. Norris and Alanson W. Olmsted
   Organic Syntheses, Coll. Vol. 1, p.144 (1941); Vol. 8, p.50 (1928).
   DOI: 10.15227/orgsyn.008.0050
   An example of an S_N1 conversion of tert-butanol to t-butyl chloride with HCl. This is from Organic Syntheses, a source of reliable and independently tested organic chemistry experimental procedures.Alkyl iodides from alcohols:
2. Reaction between unsaturated alcohols and potassium iodide in the presence of polyphosphoric acid
   Richard Jones and J. B. Pattison
   J. Chem. Soc. 1969, 1046
   DOI: 10.1039/J39690001046
   This paper uses KI + phosphoric acid to generate HI in situ, which converts alcohols to iodides.
3. 1,6-DIIODOHEXANE
   Herman Stone and Harold Shechter
   Synth. 1951, 31, 31
   DOI: 10.15227/orgsyn.031.0031
   A procedure from Organic Syntheses, a source of reliable and independently tested synthetic organic experimental procedures, for converting alcohols to iodides with KI + PPA (polyphosphoric acid).
4. Synthetic methods and reactions. 63. Pyridinium poly(hydrogen fluoride) (30% pyridine-70% hydrogen fluoride): a convenient reagent for organic fluorination reactions
   George A. Olah, John T. Welch, Yashwant D. Vankar, Mosatomo Nojima, Istvan Kerekes, and Judith A. Olah
   The Journal of Organic Chemistry 1979, 44 (22), 3872-3881
   DOI: 1021/jo01336a027
   Pyridinium poly(hydrogen fluoride), also known as PPHF or “Olah’s reagent” can be used as a Bronsted acid for converting alcohols to iodides, along with KI or NaI.
5. A Simple, Efficient, and General Method for the Conversion of Alcohols into Alkyl Iodides by a CeCl₃7H₂O/NaI System in Acetonitrile
   Milena Di Deo, Enrico Marcantoni, Elisabetta Torregiani, Giuseppe Bartoli, Maria Cristina Bellucci, Marcella Bosco, and Letizia Sambri
   The Journal of Organic Chemistry 2000, 65 (9), 2830-2833
   DOI: 10.1021/jo991894c
   Lewis acids can be used for this reaction instead of a Bronsted acid, allowing for milder reaction conditions.
6. Direct conversion of alcohols into the corresponding iodides
   Reni Joseph, Pradeep S. Pallan, A. Sudalai, T. Ravindranathan
   Tetrahedron Lett. 1995 36 (4), 609-612
   DOI: 10.1016/0040-4039(94)02315-3
   Elemental iodine (I₂) can also be used for directly converting alcohols to iodides.Alcohols can be converted to alkyl bromides with PBr₃:
7. Convenient synthesis of labile optically active secondary alkyl bromides from chiral alcohols
   Robert O. Hutchins, Divakar. Masilamani, and Cynthia A. Maryanoff
   The Journal of Organic Chemistry 1976, 41 (6), 1071-1073
   DOI: 1021/jo00868a034
8. Synthesis of Optically Active Alkyl Halides
   Harry R. Hudson
   Synthesis 1969, 112-119
   DOI: 1055/s-1969-34195
   The main utility of PBr₃ is that it allows the conversion of chiral alcohols to bromides with inversion of configuration without rearrangement, as the above two papers demonstrate. They also illustrate the mechanism of the reaction, going through the intermediate alkyl phosphites.
9. TETRAHYDROFURFURYL BROMIDE
   L. H. Smith
   Org. Synth. 1943, 23, 88
   DOI: 10.15227/orgsyn.023.0088
   This procedure from Organic Synthesis, a source of reliable and independently tested experimental organic chemistry procedures, shows how PBr₃ is compatible with ethers.