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My textbook does not give a very good explanation of what protecting groups are, how they are made, or how they function in Grignard reactions and others. It just gives a couple of examples of protecting groups and that's all.

So my questions are:

  • How are compounds chosen to be protecting groups? What are the criteria?
  • I noticed that protecting groups tends to be large molecules, is that always the case?
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The term protecting group is not absolutely strictly defined. In general, anything can be a protecting group if it fulfills the following conditions:

  • it is attached somewhat easily and adequatly selectively to certain specific sites
  • it is inert towards a sequence of following reactions which would affect the unprotected site; and
  • it is somewhat easily and adequately selectively removed from those sites to reliberate the original functional groups.

However, the term is sometimes used in an even broader sense meaning when ignoring the first bullet point.

Which functional groups you want to protect and which protecting groups you wish to use for the job depends entirely on your desired sequence. In natural product synthesis, it is very common to transform alcohols into silyl ethers — I would want to argue that this is the most common usage of the term. Alcohols have the disadvantages that they are nucleophilic, weakly acidic, can coordinate metal centres and can even act as bases. If you transform the alcohol into a silyl ether, it is no longer acidic, its ligand properties are substantially impeded and it can no longer attack nucleophilicly. Thus, it is possible to perform reactions, e.g. titanium(IV) catalysed aldol additions, which would not be possible with free alcohols.

Sometimes it is also desireable to introduce different protecting groups to similar sites or to selectively cleave only some protecting groups. For example, you may have two primary alcohols and want to turn only one of them into an aldehyde; by clever choice of your reaction sequence and protecting group strategy you will arrive at a point where only one protecting group is easily removed to give only one of the two free alcohols selectively.

While silyl groups — among them the relatively bulky tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl (TBDPS) and tetraisopropylsilyl (TIPS) groups are exceedingly common, not all protecting groups need be that large. Methoxymethyl (MOM) is a rather small protecting group that enables the alcohol (then acetalic oxygen) to keep its ligand properties. Even smaller is the methyl group used to protect carboxyl functions or, arguably the smallest, the chlorine atom, used by Woodward in his synthesis of 6-demethyl-6-deoxytetracycline.[1]


Reference:

[1]: J. J. Korst, J. D. Johnston, K. Butler, E. J. Bianco, L. H. Conover, R. B. Woodward, J. Am. Chem. Soc. 1968, 90, 439. DOI: 10.1021/ja01004a041.

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Functional groups become protecting groups out of practicality.

I would define an ideal protecting group (PG) as a functional group that is

  • easy to introduce/attach to a given, other functional group (the protection target)
  • stable/non-reactive, i.e. protecting, under a wide range of reaction conditions
  • easy to remove by well-defined and mild reaction conditions
  • with high yields throughout

Clayden/Greeves/Warren/Wothers have referred to PGs as functional groups with an Achilles' Heel.[1] Obviously, the usefulness of a given PG is always dependent on the target molecule and the reactions it will undergo. The "easy" part of the definition also encompasses factors such as price and toxicity.

As a corollary, one can introduce the concept of orthogonal PGs. Since the removal conditions can be very different for different PGs, one can successively attach PGs to, say, the hydroxyl groups of a sugar. By later removing them one by one, a chemist is then able to target them one at a time.[2]

Why do protecting groups tend to be large?

I am not convinced this is entirely the case, because I have seen applications of the methyl group as a PG. However, a larger group can introduce more steric hindrance or a point of attack for the removal that is different from the point of attachment to the protection target.


[1] Clayden, Greeves, Warren, Wothers: Organic Chemistry. Oxford University Press, 2004 (page 635).

[2] Werz, Seeberger, Angew. Chem. Int. Ed., 44, 6135, (2005). DOI:10.1002/anie.200502615.

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A protecting group could, technically, be any functional group. In organic synthesis, if you have a molecule with two or more sites that are reactive to a particular species, but you want to add the new functional group to only one of those sites, then you would add a different functional group to the non-target sites to "block" which ever reaction you want to perform.

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