Therefore any proposed synthesis must be evaluated at each step for possible side reactions that may degrade or otherwise modify the structure in an undesired way. To do this will require an understanding of how variations in structure affect chemical reactivity.
Such understanding is acquired through experience and knowledge of reaction mechanism and reaction stereochemistry. To illustrate the purpose and practice of protecting groups in organic synthesis, let us suppose that the synthesis of cis octene, which we outlined in Section , has to be adapted for the synthesis of 5-octynol.
We could write the following:. However, the synthesis as written would fail because the alkyne is a weaker acid than the alcohol Section , and the alkynide anion would react much more rapidly with the acidic proton of the alcohol than it would displace bromide ion from carbon:.
The hydroxyl group of 4-bromobutanol therefore must be protected before it is allowed to react with the alkynide salt. There are a number of ways to protect hydroxyl groups, but one method, which is simple and effective, relies on the fact that unsaturated ethers of the type are very reactive in electrophilic addition reactions Section An alcohol readily adds to the double bond of such an ether in the presence of an acid catalyst:.
The protected compound is a much weaker acid than the alkyne, and the displacement reaction can be carried out with the alkynide salt without difficulty. Dimethoxytrityl, [bis- 4-methoxyphenyl phenylmethyl] DMT — Removed by weak acid.
Methoxytrityl [ 4-methoxyphenyl diphenylmethyl, MMT — Removed by acid and hydrogenolysis. It is substantially more stable than other acyl protecting groups.
Ethoxyethyl ethers EE — Cleavage more trivial than simple ethers e. Acetyl Ac group is common in oligonucleotide synthesis for protection of N4 in cytosine and N6 in adenine nucleic bases and is removed by treatment with a base, most often, with aqueous or gaseous ammonia or methylamine. Ac is too stable to be readily removed from aliphatic amides. Benzoyl Bz group is common in oligonucleotide synthesis for protection of N4 in cytosine and N6 in adenine nucleic bases and is removed by treatment with a base, most often with aqueous or gaseous ammonia or methylamine.
What gives? The answer, of course, is that our strong base NaNH 2 deprotonated the strongest acid [OH, pKa of 16 versus acetylide C-H, pKa of 25] and the resulting alkoxide [R—O — ] then attacked CH 3 -I, resulting in a substitution reaction with displacement of iodide ion [ note 1 ].
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 N 2 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 SN2 reaction. Acid-base reactions are fast , relative to substitution reactions]. Then you come to one of those annoying wall outlets.
You could paint over it of course. So what do you do? THEN you can plug in the typewriter. Something that could. That would allow us to perform a synthesis of our desired molecule second scheme above.
Well, you might have guessed by now that enterprising chemists have developed a solution for this problem. The only important reaction of ethers you cover in Org 1 is how to cleave them with very strong acid e.
Other than that, ethers are inert to pretty much any other reaction condition you can name. Fortunately a very clever solution has been devised. Instead of making a typical ether e. 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 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. How could we get this sequence to work? 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.
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 N 2 examples we covered here. 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. 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.
Even if that acetylide formed, it would be quickly protonated by any spare alcohol R-OH swimming around, giving rise to the alkoxide. THP ethers are slightly different. 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. This is referred to as an orthogonal protecting group strategy. Not only is selectivity important, but the yields for the protection and deprotection steps must be high to avoid making the reaction sequence inefficient. As a result, chemists in recent years prefer to design synthesis pathways that employ steps conducted under more selective reaction conditions, engineered to affect and convert only the specific desired functional group rather than harsher, less selective conditions that require protection for differentiation.
Another tactic is to employ reaction conditions under which the functional group "protects itself" temporarily, for example as an anion under basic conditions or a cation under acidic conditions. These minimalist approaches can be summarized in the statements that, "the best protective group is no protective group", and "the best protective group is the one that isn't required".
The demands of designing environmentally friendly "green" synthesis pathways, or simply more efficient synthesis pathways with fewer steps and higher overall yields, have resulted in a number of reports of synthetic sequences to produce natural compounds or other synthesis targets that are fully protective group-free.
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