Acid Base Reactions Are Fast

Acid-Base Reactions Are Generally Faster Than Substitution Or Addition Reactions 

Here is a very common dilemma in organic chemistry as you move through the latter parts of Org 1 and then into Org 2:

When more than one reaction is possible, how do you know which one will happen?

In a steel cage match between an acid base reaction and other types of reactions, which wins?

In this post we postulate a good rule of thumb to keep in mind: acid-base reactions are fast, relative to other reactions. 

Here are three examples – and by the way…  these are common trick questions for exams! 

Table Of Contents

1. Acid-Base vs Nucleophilic Substitution Reactions (S_N2 reactions).
2. Acid-Base Reaction vs Addition To A Carboxylic Acid
3. Grignard Reaction To A Molecule With A Hydroxyl Functional Group
4. Why Acid-Base Reactions Are Fast: The Principle of Least Motion
5. Notes
6. (Advanced) References and Further Reading

1. Acid-Base vs Nucleophilic Substitution Reactions (S_N2 reactions).

Here, note that our nucleophile (the conjugate base of an alkyne, pK_a 25) can remove the proton of an alcohol (pK_a ~15) or perform an S_N2 reaction on the primary alkyl halide.

With a difference of 10 pK_a units between the alkyne and the alcohol, the acid-base reaction between the deprotonated alkyne (“acetylide”, stronger base) to produce a deprotonated alcohol (“alkoxide”, weaker base) is extremely favorable.

And since acid-base reactions are fast, relative to other reactions, the preferred first reaction here is deprotonation of the alcohol to give the conjugate base (“alkoxide“)

Bonus question: what would be the final product of this reaction, after the deprotonation? Answer below [Note 2]

2. Acid-Base Reaction vs Addition To A Carboxylic Acid

Grignard reagents are very good nucleophiles – reacting with carbonyl compounds such as ketones, aldehydes, and esters. But as the conjugate bases of alkanes (pK_a ~ 50) they are also extremely strong bases.

When combined with a carboxylic acid (pK_a ~4 or 5) the result is not an addition to the carbonyl, but an acid base reaction (45 pK_a units makes for a pretty favorable reaction!).

It’s always helpful to remember that carboxylic acids… are acids!

3. Grignard Reaction To A Molecule With A Hydroxyl Functional Group

The same applies for reactions of Grignard reagents with molecules that have hydroxyl groups in addition to  aldehydes or ketones. If merely one equivalent is added, the first thing to happen will be deprotonation of the alcohol, which is faster than addition to the ketone carbonyl carbon.

It’s only after addition of a second equivalent of Grignard that addition to the ketone will occur.

So what’ s going on?

4. Why Acid-Base Reactions Are Fast: The Principle of Least Motion

What’s going on here is an application of a handy principle in chemistry called the Principle of Least Motion. 

Simply stated, it’s this.

Acid-base reactions on “heteroatoms” (that means atoms other than carbon,  such as O, N, and S) generally require very little reorganization of the nuclei in the structure after loss of a proton.

Therefore these reactions are fast, relative to reactions where the nuclei have to move or be reorganized.

Think about removing a proton from an O-H.

After loss of hydrogen, the oxygen gains a new lone pair. But its hybridization doesn’t change – it started as sp³, and it’s still sp³. So the nuclei (other than the H, of course) don’t significantly change positions in these reactions. No extra atomic motion, in other words.

However when bonds are formed or broken at carbon – such as in the S_N2 reaction or in additions to carbonyl carbons – a lot of atomic furniture has to get rearranged.

For instance, the S_N2 proceeds through a backside attack, which means that the geometry of the molecule changes from tetrahedral to trigonal bipyramidal (that’s the  5-coordinate transition state) and then back to tetrahedral.

In addition reactions to carbonyl compounds, we’re changing the hybridization of carbon from sp² to sp³. That requires a shift from trigonal planar to tetrahedral geometry.

Extra atomic motion means it will be a slower reaction, relative to an acid-base reaction.

 Bottom line: acid base reactions on oxygen, sulfur, or nitrogen are fast. So long as the acid base equilibrium is reasonable [How to use a pKa table, a handy rule of thumb for acid-base reactions] do them first.

Next Post: Acid-Base Reactions – What’s The Point?

Notes

Note 1. It’s interesting that Grignard reagents (the conjugate bases of alkanes, pK_a ~50) don’t usually deprotonate the alpha-carbon of aldehydes (pK_a ~18) or ketones (pK_a ~20).

That’s another application of this principle. Removing a proton from an aldehyde or ketone requires breaking a C-H bond, and the resulting base (called an “enolate”) will undergo a change in hybridization from sp³ to sp². Therefore, it’s slow.

Note 2. After the first acid-base reaction, the deprotonated alcohol can then do an S_N2 reaction on the primary alkyl bromide.

(Advanced) References And Further Reading

1. The Principle of Least Nuclear Motion.
   Hine, J.
   Advances in Physical Organic Chemistry, Academic Press, Volume 15, 1977, Pages 1-61.  ISSN 0065-3160.
   DOI: 10.1016/S0065-3160(08)60117-3
   In this book chapter,  Prof. Hine of The Ohio State University reviews the principle of least ncuelar motion. Particularly notable is the graph on page 40, which shows that HCN has the lowest barrier to deprotonation of any carbon-based acid, consistent with a small change in internal geometry.