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Selective vs. Specific

Many of the transformations you will encounter have the potential to create multiple products – isomers – from a single starting material. The reactions shown in the drawing, for instance (I’ve left the actual reactants vague) could each form a mixture of constitutional isomers (i.e. regioisomers), diastereomers, or enantiomers.

The potential of these reactions to produce multiple products is both a curse and an opportunity. It’s a curse in that we have the potential to create multiple products, each of which have to be separated from each other. But it’s an opportunity in that if we can develop reactions that can yield one isomer over the other (and vice versa) we have a very useful tool: we can start with a simple starting material – like an alkyne – and transform it into several complex products through a series of selective reactions. That’s extremely powerful.  (For that reason, I like to say that alkynes are like a blank canvas – you can decorate them many, many different ways).

Here comes a part of organic chemistry terminology that can trip people up. We can have selective reactions and specific reactions. Selective means “mostly”, or “almost all”. Specific means “all”. “Selective” implies that there are factors which favor one product over the other, while “specific” is usually a sign that there’s something inherent to the mechanism that leads to only one product.

It might sound like semantics, but there’s some disagreement on where to draw the line for “selective”. For instance, is a reaction that gives you a 99:1 ratio selective or specific? I’m in the camp which believes that 99:1 is merely “highly selective”. Specific reactions are 100:0 .   I am always very careful not to use “specific” where “selective” would suffice. The opinion of your instructor (or textbook) may vary.

Let’s look at some selective reactions:

Regioselective reactions: This is where a starting material forms two (or more) structural isomers, and one predominates. A good example is Markovnikoff addition of water. The major product is where addition has occurred on the most substituted carbon. The mechanism doesn’t rule out a small amount of the minor structural isomer. (Note that this reaction as shown, forms a 50:50 mixture of enantiomers. It is regioselective, but not enantioselective.) Hydroboration is another example of a regioselective reaction: it is highly selective for the less substituted alcohols. Like I said, some instructors might consider this reaction regiospecific, even if it is >99:1. I would make the case that it is merely highly regioselective.

Stereoselective reactions: An example of a stereoselective reaction is shown in the next drawing. In the 2.2.1 bicycle shown, attack of the per-acid from the top face is highly favored, which leads to dominant formation of the epoxide on the left. There is also a small amount of the epoxide on the right.

Stereospecific reactions: A perfect example of a stereospecific reaction is shown in the third drawing. Because the SN2 proceeds through inversion (100%) a given starting material will produce the product with the inverted stereochemistry. The second starting material (the enantiomer of the one above) will produce the enantiomer (100%). Two different isomers go through the same reaction manifold to provide two different enantiomers. There is no “leakage” of one to the other.

There are actually quite a few examples of other stereospecific reactions. The hydroboration reaction is one (cis addition), as is catalytic hydrogenation (gives cis products), addition of bromine to double bonds (anti products), epoxidation, cyclopropanation, the Diels Alder, and more.

There are also reactions which are enantioselective. They aren’t covered as much in Org 1/Org 2, but the 2001 Nobel prize in chemistry was given to Noyori, Sharpless, and Knowles for their development of some key enantioselective reactions. Some of the most cutting-edge organic chemistry going on at the moment is concerned with designing highly enantioselective reactions.

The concept of selectivity is not exclusive to one type of isomer. You can have a regioselective reaction that is not stereoselective (like the Markovnikoff addition of water to alkenes) as well as regioselective reactions that are also stereoselective (like hydroboration. In fact, enantioselective hydroborations have been developed, which are therefore regioselective, stereoselective (for the syn addition product) and enantioselective. It depends on what kind of isomers you can form from your substrate.


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