Protecting Groups For Alcohols

Alcohol Protecting Groups

• There are many times when it’s useful to mask the reactivity of alcohols since their relatively high acidity interferes with strongly basic reagents like Grignard reagents.
• The most common protecting group for alcohols is silyl ethers.They are easily formed by treating alcohols with R₃SiCl in the presence of base, and then easily removed with a source of fluoride ion F(-) since Si-F bonds are very strong.
• Silyl ethers are inert to Grignard reagents, strong bases, and oxidants (although will be removed with strong acid).
• Tetrahydropyranyl (THP) ethers are also useful protecting groups for alcohols.
• Ordinary ethers are generally not used as protecting groups since their removal requires harsh conditions

Table of Contents

1. When Alcohols Get In The Way
2. Protecting Groups Are Like “Painter’s Tape”
3. What Would Be A Chemical Equivalent of “Painter’s Tape”?
4. One Potential Solution: Ethers (Spoiler: They’re Not Great)
5. A Better Way To Do It: Silyl Ethers
6. A Successful Application of a Silyl Protecting Group Strategy
7. Summary: Protecting Groups For Alcohols
8. Notes
9. (Advanced) References and Further Reading

1. When Alcohols Get In the Way

As we’ve seen in previous posts in this series, alcohols are very versatile functional groups that participate in a variety of reactions. They can be deprotonated with base (making them good nucleophiles in substitution reactions), protonated (making them good leaving groups in substitution and elimination reactions), oxidized to aldehydes or ketones, or transformed into better leaving groups (alkyl halides, or alkyl tosylates) allowing for a host of substitution and elimination reactions.

All this this versatility comes with a drawback, however. Sometimes alcohol functional groups can  get in the way of other reactions we might like to do. Let me show you what I mean.

We’ve seen by now one of the most useful C-C bond forming reactions you learn in Org 1: nucleophilic substitution (S_N2) of alkyl halides with acetylides (the conjugate base of acetylenes)

Since alkynes are like a blank canvas, this reaction can set up the introduction of many different types of functional groups through addition reactions.

Now let’s modify our substrate a bit. We’ll attach a hydroxyl group (OH) to the end of the molecule. Now let’s see what happens.

Look at what happened – we now formed a new O-CH₃ bond instead of a C-C bond. What gives?

The answer, of course, is that our strong base NaNH₂ deprotonated the strongest acid [OH, pK_a of 16 versus acetylide C-H, pK_a of 25] and the resulting alkoxide [R–O^– ] then attacked  CH₃-I, resulting in a substitution reaction with displacement of iodide ion [Note 1]

Here’s another example of the the principle at work. Here, we’d like to perform a substitution reaction of C-Br with C-C . So why does this reaction not lead to formation of a C-C bond?

Same reason! Our acetylide ion is a strong base, and deprotonates the O-H group, which then participates in an S_N2 reaction with the alkyl halide 4 bonds away (forming a five membered ring).

This is a textbook example of what we saw in our last post – an intramolecular S_N2 reaction. [Why doesn’t it do substitution first? Acid-base reactions are fast, relative to substitution reactions].

So how could we have prevented this from occurring?

2. Protecting Groups Are Like Painter’s Tape

It’s reminiscent of a problem anyone who has painted a room would understand. Imagine you’re helping your cousin paint his room in a hideous shade of yellow-green so completely uncool to the untrained eye that only a hipster could appreciate it.  Then you come to one of those annoying wall outlets. You could paint over it of course.

But now it’s useless if your cousin wants to plug in that 1965 Smith-Corona electric typewriter he found at a thrift store that he’s using to write his “novel”. Surely there’s a way to do this that doesn’t destroy our outlet. So what do you do?

Painter’s tape to the rescue!

Cover the outlet with painter’s tape, paint to your heart’s content, then remove the tape. THEN you can plug in the typewriter. Simple!

3. A Chemical Equivalent Of Painter’s Tape

Wouldn’t it be nice if we had a “chemical equivalent” of painter’s tape for alcohols. Something that could

1. mask the reactivity of the OH group
2. be inert to a large set of reaction conditions, and
3. be easily and selectively removed to reveal the OH group once we’re done.

That would allow us to perform a synthesis of our desired molecule (second scheme above). Here I’m using “PG” to stand for “protective group”.

Well, you might have guessed by now that enterprising chemists have developed a solution for this problem. It’s very clever, in fact.

4. One Potential Solution: Ethers

As we’ve discussed earlier, ethers are quite possibly the most boring functional group you can encounter. The only important reaction of ethers you cover in Org 1 is how to cleave them with very strong acid (e.g. with hydroiodic acid, HI). That’s it. Other than that, ethers are inert to pretty much any other reaction condition you can name.

For the chemical equivalent of “painter’s tape”, boring is good! It means that we can “protect” a hydroxyl group as an ether without worrying about it being affected by reactions we might like to do on the rest of the molecule (like addition of an acetylide to an alkyl halide, for example).

There’s just one problem: ethers require very harsh conditions in order to break (hydroiodic acid, HI). That’s like destroying the village in order to save it: such conditions will likely torch whatever other functional groups are on your molecule.

5. A Better Way To Do It: Silyl Ethers

Fortunately a very clever solution has been devised. Instead of making a typical ether (e.g. forming an O-C bond), we form a silyl ether (i.e. make an O-Si bond, not an O–C bond). It’s even easier to form than a “normal” ether, and shares  the property of being inert to many types of reaction conditions. In most introductory courses the most common silyl ether used is trimethylsilyl (TMS) although there are others [Generally, the bulkier the groups around silicon, the harder it is to cleave the O–Si bond]

The main advantage of silyl ethers is that they’re easily cleavable. The Si-F bond is unusually strong – even stronger than Si-O.  Addition of a source of fluoride ion (F-)  will lead to cleavage of Si-O bonds without affecting the rest of the molecule.  A typical source of fluoride ion is the salt tetrabutylammonium fluoride (TBAF).

Are there other protecting groups for alcohols? You betcha. For more information, see Note 2.

6. A Successful Application of A Silyl Ether Protective Group Strategy

So let’s go back to our second example. How could we get this sequence to work? Let’s “protect” the free alcohol as a silyl ether (TMS) and follow along.

There you have it. All we needed to get our desired reaction to work was a way of masking the OH until we were done performing our surgery on the other half of the molecule.

7. Summary: Protecting Groups For Alcohols

This post barely scratches the surface of protecting groups for alcohols. Protecting groups are used for alcohols in a variety of different situations, far beyond the S_N2 examples we covered here. For instance, when we talk about Grignard reagents, we’ll see that they can’t be formed in the presence of alcohols, so we have to protect them. Another example might be if you wanted to selectively oxidize one of two different alcohols in a molecule. We can add more posts on this topic as we go along.

You’ll notice that the vast majority of molecules you encounter in Org 1 and Org 2 have only one important functional group. It’s very rare that you’ll be given a substitution reaction, for example, that has two nucleophiles of comparable strength. Learning how to deal with molecules that have more than one key functional group is, in my opinion, where Org 2 ends and Org 3 begins.

It’s at that point that you need to learn understand the relative reactivity of different functional groups, their compatibility with different reagents, and also how to plan a synthesis such that only one key functional group will participate in the reaction.

Next Post – Thiols And Thioethers

Notes

Note 1. Isn’t it possible that NaNH₂ could have deprotonated a little bit of the alkyne? Sure! But remember that acid base reactions are equilibrium, and the alcohol is a far stronger acid (pK_a ~16 ) than the alkyne (pk_a 25). Even if that acetylide formed, it would be quickly protonated by any spare alcohol R-OH swimming around, giving rise to the alkoxide. [back to article]

Note 2. Two more protecting groups that come up quite frequently are TBS (t-butyldimethylsilyl) and THP (tetrahydropyranyl)  ethers. TBS is installed the exact same way TMS is – by using TBSCl in the presence of a base like NEt₃.

THP ethers are slightly different. They are installed by adding dihydropyran (an “enol ether”) in the presence of strong acid. The enol ether is protonated at carbon by the strong acid, resulting in an oxonium ion, which is then attacked by the alcohol to give the ether. This is actually a special type of ether where two OR groups are attached to the same carbon. It’s a masked ketone, which we refer to as an acetal. We talk about acetals here in this blog post. [back to article]

For even more protecting groups for alcohols,  see this handout by the group of Prof. Andrew Myers at Harvard.  It’s phenomenal.

(Advanced) References and Further Reading

Protection as silyl ethers:

1. Protection of hydroxyl groups as tert-butyldimethylsilyl derivatives
   E. J. Corey and A. Venkateswarlu
   Journal of the American Chemical Society 1972 94 (17), 6190-6191
   DOI: 10.1021/ja00772a043
   The original paper by Nobel Laureate Prof. E. J. Corey (Harvard) describing convenient conditions (TBS-Cl, DMF, imidazole) for the protection of alcohols as TBS-ethers.
2. GENERATION OF NONRACEMIC 2-(t-BUTYLDIMETHYLSILYLOXY)-3-BUTYNYLLITHIUM FROM (S)-ETHYL LACTATE: (S)-4-(t-BUTYLDIMETHYLSILYLOXY)-2-PENTYN-1-OL
   James A. Marshall, Mathew M. Yanik, Nicholas D. Adams, Keith C. Ellis, and Harry R. Chobanian
   Org. Synth. 2005, 81, 157
   DOI: 10.15227/orgsyn.081.0157
   The first step in this synthesis from Organic Syntheses (a source of reliable and reproducible synthetic organic experimental procedures) is O-silylation with TBSCl according to Corey’s procedure.
3. Protection of Hydroxy Groups by Silylation: Use in Peptide Synthesis and as Lipophilicity Modifiers for Peptides
   John S. Davies, Clement L. Higginbotham, E. John Tremeer, Charles Brown, and Richard C. Treadgold
   J. Chem. Soc., Perkin Trans. 1, 1992, 3043-3048
   DOI:1039/p19920003043
   This paper describes a kinetic study of the susceptibility to hydrolysis of various silyl ethers under acidic and basic conditions, and has a convenient table on the first page describing the results.
4. Symmetrical alkoxysilyl ethers. A new class of alcohol-protecting groups. Preparation of tert-butoxydiphenylsilyl ethers
   John W. Gillard, Rejean Fortin, Howard E. Morton, Christiane Yoakim, Claude A. Quesnelle, Sylvain Daignault, and Yvan Guindon
   The Journal of Organic Chemistry 1988 53 (11), 2602-2608
   DOI: 1021/jo00246a038
   This paper describes the use of -SiPh₂OtBu as a protecting group for alcohols which is easier to remove with F^– compared to conventional -TBDPS ethers.
5. Selective Deprotection of Silyl Ethers
   Todd D. Nelson, R. David Crouch
   Synthesis 1996; 1996(9): 1031-1069
   DOI:1055/s-1996-4350
   This review covers the selective removal of silyl ethers in the presence of similar or different silyl ether groups in the same molecule. In organic synthesis, deprotection strategies are just as important as protection strategies!Ethers can also be used for alcohol protection. Two common ether-based protecting groups are THP- (tetrahydropyranyl-) and MOM- (methoxymethyl-).
6. Pyridinium p-toluenesulfonate. A mild and efficient catalyst for the tetrahydropyranylation of alcohols
   Masaaki Miyashita, Akira Yoshikoshi, and Paul A. Grieco
   The Journal of Organic Chemistry 1977, 42 (23), 3772-3774
   DOI: 1021/jo00443a038
   While p-toluenesulfonic acid is generally used as the catalyst for tetrahydropyranylation of alcohols, PPTS (the pyridine salt of p-toluenesulfonic acid) can be used as an even milder catalyst for this reaction. This is of value when trying to protect an alcohol with several other delicate functional groups in the molecule.
7. Total synthesis of (S)-12-hydroxy-5,8,14-cis,-10-trans-eicosatetraenoic acid (Samuelsson’s HETE)
   E. J. Corey, Haruki Niwa, and Jochen Knolle
   Journal of the American Chemical Society 1978, 100 (6), 1942-1943
   DOI: 10.1021/ja00474a058
   This paper demonstrates a synthetic strategy using alcohol protecting groups. One of the -OH in a substrate groups is protected as a THP ether (conditions not mentioned), and later deprotected, using p-TSA in methanol, 1h at RT, 94% yield.
8. Diastereo‐ and Enantioselective Total Synthesis of Stigmatellin A
   Dieter Enders Prof. Dr. Gunter Geibel Dr. Simon Osborne Dr.
   Eur. J. 2000, 16 (8), 1302-1309
   DOI: 10.1002/(SICI)1521-3765(20000417)6:8<1302::AID-CHEM1302>3.0.CO;2-J
   9 -> 3 involves a MOM protection. Interestingly, this is selective for one of the hydroxyl groups in the molecule, since, as the paper says, “the second hydroxyl group is blocked by a hydrogen bond to the carbonyl function in [the] ortho-position”. This shows that the way we commonly draw structures does not always reflect the preferred conformation!
   
   Protecting with the MOM- group is commonly done using MOM-Cl (methoxymethyl chloride). However, due to this compound’s extreme toxicity (it is a powerful alkylating agent and can alkylate proteins and nucleic acids in our bodies), alternative methods for protection are sought, and the following two papers by Nobel Laureate Prof. G. A. Olah give alternative methods for MOM- protection of alcohols without using MOM-Cl.
9. Iodotrimethylsilane-Catalyzed Preparation of Methoxymethyl Ethers of Primary and Secondary Alcohols with Dimethoxymethane
   George A. Olah, Altaf Husain, Subhash C. Narang
   Synthesis 1983, 11, 896-897
   DOI: 10.1055/s-1983-30554
10. Synthesis of terrein, a metabolite of Aspergillus terreus
    Joseph Auerbach and Steven M. Weinreb
    Chem. Soc. Chem. Comm. 1974, 298-299
    DOI: 10.1039/C39740000298
    This paper demonstrates the use of MOM- protection in total synthesis. Two -OH groups are initially protected as MOM ethers by deprotecting to the alkoxides with NaH, followed by MOM-Cl in DMF at RT. At the end of the synthesis, the protecting groups were removed using “a trace of concentrated HCl in MeOH at 62° for 15 min”.