Identify a Molecule's Most Acidic H

A methodical approach works best. Simply put, you must scan the molecule for acidic functional groups, and then rank the reactivity of these groups. The most acidic functional group usually is holding the most acidic H in the entire molecule.

"Scan and rank" sounds simple, but it conceals several difficulties that are elaborated below.


Scan a molecule for known acidic functional groups

Acidic protons are usually bound to O or N. Therefore, the first step is to look for all OH and NH bonds.

However, as you locate OH and NH bonds, you will need to decide whether these bonded atoms should be lumped into a functional group with neighboring atoms.

The ONLY convenient method for identifying a functional group is to already know some. For example, if you know that ROH, RCO2H, and RSO3H are common acidic functional groups, you'll have no trouble finding acidic groups in the following molecule (the correct groups are marked in red).


Rank OH and NH acidity separately

The pKa values of common OH and NH acids span wide ranges and their ranges overlap. Ranking proceeds more quickly if you rank the OH and NH acids separately, and then compare the top candidates in each category.

The most convenient method for ranking acidic groups is to already know their characteristic pKa values. If you know these values for all of the acidic groups in your molecule, then the group with the lowest pKa contains the most acidic H. Case closed.

If you do not recall pKa values for all of the acidic groups, a few general principles can guide you.

#1 Importance - positively charged acids are stronger than neutral acids. Negatively charged acids are rarely acidic. If you compare pKa values of common OH acids, you will see that ROH2+ acids (which includes H3O+ and R2OH+) are considerably stronger than neutral acids, such as RCO2H, PhOH, and ROH. The only neutral acids that are stronger than ROH2+ are H2SO4 and certain other RSO3H.

The formal charge rule applies even more strongly to NH acids. The difference in pKa between H3O+ and H2O is 18 units, while the difference in pKa between NH4+ and NH3 is a gigantic 26 units.

#2 Importance - look for activating groups, including RSO2, RC=O, and Ph. The following chart shows how each group of atoms activates an OH acid (pKa values range from 16 to -2):

CH3 is considered a spectator group wherever it appears in these molecules. It is nonpolar and does not exert a significant field-inductive effect, and it is incapable of delocalizing charge. Consequently, it is possible to replace CH3 with other spectator groups (for example, H and other R) without affecting reactivity much.

Two additional points should be made concerning activating groups.

First, the groups exert a similar effect on NH acids (and the activating sequence is the same: RSO2 > RC=O > Ph). As it happens, you only need to learn the effect of Ph on NH+ for this course:

Second, the activating groups must be bonded directly to the OH (or NH) group in order to activate it. The following compounds have similar pKa values because the activating groups are not bonded directly to OH: CH3C(=O)CH2OH, PhCH2OH, and CH3CH2OH.

#3 Importance - all things being equal, an OH acid is more acidic than an NH acid. This principle can be very useful if used properly. My concern is that you understand what is meant by "all things being equal." This means that O and N must have the same formal charge (item #1) and must be bonded to the same activating group (item #2). However, differences in spectator groups do not matter.

Some valid comparisons include:

#4 Importance - within a functional group category, use substituent effects to compare acids. Electronegative substituents usually enhance the acidity of a functional group through a combination of field and inductive effects. These effects are enhanced when 1) the substituent is located closer to the acidic group, and 2) there are multiple substituents. Given these principles, we expect the acidity of these carboxylic acids to follow this trend:


Review problems

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