Nucleophilic Addition To Carbonyls

Nucleophilic Addition To Carbonyls

• The most important reaction of the carbonyl group (C=O) is the addition of nucleophiles to the carbonyl carbon, sometimes called, “1,2-addition”.
• Nucleophilic addition changes the hybridization of the carbon from sp² to sp³ and the geometry from trigonal planar to tetrahedral.
• Depending on the basicity of the nucleophile, addition may be irreversible (e.g. with hydride and alkyl groups) or reversible (e.g. with HO- , alcohols, (-)CN).
• The reverse process is elimination, or often, “1,2-elimination”.
• The rate of addition is increased by adjacent electron-withdrawing groups, and decreased by adjacent electon-donating groups.
• The rate is also decreased  by steric factors.

Table of Contents

1. Properties of the Carbonyl Group
2. Nucleophilic Addition (1,2-Addition) To Carbonyls
3. Irreversible Addition With Strong Bases
4. Reversible Addition
5. Factors Affecting The Rate of Addition: Electronic Effects
6. Factors Affecting The Rate of Addition: Steric Effects
7. Addition of Neutral Nucleophiles
8. Summary
9. Notes
10. Quiz Yourself!
11. (Advanced) References and Further Reading

1. Properties of The Carbonyl (C=O) Group

A C=O bond is referred to as a carbonyl group. They are found in aldehydes, ketones, carboxylic acids and their many derivatives.

Due to the significantly higher electronegativity of oxygen (3.5) relative to carbon (2.5), the electrons in the C=O bond are highly polarized towards oxygen.

This is reflected in the partial positive charge found on the carbon and the partial negative charge on oxygen.

Carbonyl groups have a significant resonance form where there is a positive charge on carbon and a negative charge on oxygen.

The resonance form with a negative charge on carbon and a positive charge on oxygen should never be drawn as it represents less than a full octet on oxygen which is very energetically unfavorable.

2. Nucleophilic Addition To Carbonyls

The carbonyl carbon is an excellent electrophile and will undergo reactions with a large variety of nucleophiles.

This reaction is called, “nucleophilic addition”, or sometimes, “1,2-addition”.

In this reaction a C-Nu bond is formed and the C-O pi bond breaks. The geometry of the carbon goes from trigonal planar to tetrahedral. After addition, the oxygen bears a negative formal charge.

For example aldehydes and ketones undergo addition with cyanide ion to give cyanohydrins.

The importance of this mechanism in carbonyl chemistry cannot be stressed enough. Make sure you know how to draw the curved arrows for this reaction!

Click to Flip

It is also possible for the addition product to undergo reversion back to the starting nucleophile and carbonyl.

This reverse process is known as elimination, or “1,2-elimination”. In this mechanistic step, the C-LG bond is broken and a C-O pi bond is formed.

(Remember that a leaving group is essentially just a nucleophile acting in reverse)

Taken together, 1,2-addition and 1,2-elimination are the two most important mechanistic steps in the chemistry of the carbonyl group and they are found in a large number of mechanisms.

3. Irreversible Nucleophilic Addition

Comparing the relative basicity of the starting nucleophile Nu(-)  to that of the negatively charged oxygen on the product can be extremely helpful in determining the position of the equilibrium.

Just as in acid-base reactions, where the favored equilibrium is that where a stronger acid and a stronger base give a weaker acid and a weaker base,  nucleophilic addition reactions that result in the formation of a weaker base will be favored. 

When the nucleophile happens to be a very strong base, addition reactions are essentially irreversible. 

A prime example is the reduction of aldehydes and ketones by sodium borohydride, NaBH₄.

The pK_a of the H₂, the conjugate acid of the hydride ion H(-) is about 36 and the pK_a of ROH, the conjugate acid of the resulting alkoxide is roughly 16.

From an acid-base perspective, this reaction is favored by about 20 pK_a units (10²⁰). The equilibrium runs far to the right. [Note 1]

Another example of an irreversible addition is the addition of Grignard or organolithium reagents to aldehydes and ketones.

The pK_a of carbanions is about 50. So in this case reverse reaction would be disfavored by about 34 pK_a units.

4. Reversible Addition

On the other end of the scale, halide ions such as Cl(-) do not generally add to carbonyls. We can see why by comparing basicities.

The pK_a of HCl, the conjugate acid of Cl(-) is -8. The pK_a of a typical alcohol ROH is in the range of 16-18. Addition of a halide ion would result in the formation of a stronger base from a weaker base, which is energetically unfavorable.

When the basicity of the nucleophile is comparable to the basicity of the product, an equilibrium will result.

This is the case with the addition of hydroxide, alkoxide, and cyanide ions.

What’s meant by comparable? A good rule of thumb is contained in [Note 2]

5. Factors Affecting The Rate Of Nucleophilic Addition. Electronic effects

The rate of addition of nucleophiles to carbonyl compounds is greatly affected by the neighboring substituents.

On one hand, the more electron-poor the carbonyl carbon is, the greater will be its reactivity towards nucleophiles. For example, we should expect the reactivity in the series acetaldehyde versus trichloroacetaldehyde versus trifluoroacetaldehyde to increase with the increasing inductive effects of the substituents.

Click to Flip

Going in the reverse direction, we should expect electron-releasing substituents to have the opposite effect.

You may recall that alkyl groups are activating in electrophilic aromatic substitution because they stabilize adjacent carbocations, relative to hydrogen.

Purely based on this electronic effect we’d therefore expect addition to be faster to aldehydes than to a comparable ketone (and it is!  although steric effects also play a role).

Click to Flip

You could use similar reasoning to predict the relative reactivity of esters, amides, and carboxylates. [Note 3].

6. Factors Affecting The Rate Of Nucleophilic Addition: Steric effects

The rate of addition to carbonyls is also affected by the presence of any group which can block the approach of the incoming nucleophile. These are referred to as steric effects.

One prominent example is the addition of nucleophiles to aldehydes versus ketones. Addition to ketones is considerably slower. [Note 4]

If we bulk our ketone up even more to include, say, adjacent t-butyl groups,  the rate will be even further impeded. [Note 5]

Click to Flip

7. Neutral Nucleophiles

Addition to carbonyls is not limited to negatively charged nucleophiles. Neutral nucleophiles such as alcohols and amines are very much capable of adding to carbonyls.

The arrow-pushing mechanism of nucleophilic addition remains the same.

Note, however, that the product will bear an additional positive formal charge. These reactions are generally reversible and are best described as equilibrium reactions. [Note 6]

Generally speaking, neutral species are poorer nucleophiles than their conjugate bases.

The rate of addition can be increased by using an acid catalyst.

Otherwise, the mechanism for addition remains exactly the same.

Note that acid catalysis only works for nucleophiles that are not destroyed by acid-base reactions!

8. Summary

Nucleophilic addition is the most important reaction of carbonyls. Not just aldehydes and ketones, but also carboxylic acid derivatives in general.

• Carbonyls undergo addition reactions with a large range of nucleophiles.
• Comparing the relative basicity of the nucleophile and the product is extremely helpful in determining how reversible the addition reaction is. Reactions with Grignards and hydrides are irreversible. Reactions with weak bases like halides and carboxylates generally don’t happen.
• Electronic effects (inductive effects, electron donation) have a large impact on reactivity.
• Large groups adjacent to the carbonyl will slow the rate of reaction.
• Neutral nucleophiles can also add to carbonyls, although their additions are generally slower and more reversible. Acid catalysis is sometimes employed to increase the rate of addition.

Notes

Note 1. This is broadly true, but there are some exceptions. The mechanism of the Cannizarro reaction involves a concerted hydride transfer from an aldehyde addition product to give a mixture of an ester and an alcohol.

Note 2. Not precise, but a decent rule of thumb is about 10 pK_a units on either side of the basicity of the alkoxide. The pK_a of HCN is about 9 and the pK_a of alkoxides is in the 16-18 range. On the other end, retro-Claisen reactions are known, and the pK_a of ester enolates is about 25.

Note 3. It may seem strange when you think about it, but if you make a ranked list of activating groups for electrophilic aromatic substitution:
Cl (least activating) < H < alkyl < OR < NH₂, NHR, NR₂ < O(-)  (most activating)
it correlates inversely with the rate of addition of nucleophiles to carbonyls R-C(O)–X.
That is
RCOCl (fastest) > H > alkyl > OR > NH₂, NHR, NR₂< O(-)  (undergoes slowest addition).

Activating groups are very good at stabilizing carbocations. The more electron-density they can donate to a carbocation, the less electron-poor it is.

Think of the carbonyl in its 2nd-best resonance structure as a carbocation with an O(-) attached. The better the group X is at donating electron density, the less reactive towards nucleophiles it will be.

Note 4. H.C. Brown studied the relative rates of reduction of aldehydes and ketones and found aldehydes to be much more reactive. See reference.

Note 5. Although not explicitly discussed here the angle of approach of nucleophiles to carbonyls is about 105°, a value now known as the Burgi Dunitz angle or trajectory. This coincides with the position of the C-O pi* orbital, which accepts the pair of electrons from the nucleophile.

Note 6. The equilibria is subject to several key factors. One obvious one is concentration. By swamping the carbonyl with nucleophile, one can push the addition reaction forward. One way to push condensation reactions (e.g. imine formation) forward is to sequester the H₂O that is formed through the use of a drying agent or distillation. Adding acid increases the rate of addition and can affect the equilibrium. A subtle effect is that of intramolecular reactions, which tend to spontaneously form 5- and 6- membered hemiacetals when possible due to entropic factors. Heat can play a role.

Quiz Yourself!

Become a  MOC member to see the clickable quiz with answers on the back.

Become a  MOC member to see the clickable quiz with answers on the back.

Become a  MOC member to see the clickable quiz with answers on the back.

Become a  MOC member to see the clickable quiz with answers on the back.

Become a  MOC member to see the clickable quiz with answers on the back.

(Advanced) References and Further Reading

1.XCVI.—Reactions involving the addition of hydrogen cyanide to carbon compounds
Arthur Lapworth
J. Chem. Soc., Trans., 1903,83, 995-1005
DOI: 10.1039/CT9038300995

2.CXXII.—Reactions involving the addition of hydrogen cyanide to carbon compounds. Part II. Cyanohydrins regarded as complex acids
Arthur Lapworth
J. Chem. Soc., Trans., 1904,85, 1206-1214
DOI: 10.1039/CT9048501206

Lapworth was among the first to recognize the role of base in catalyzing the addition of HCN to aldehydes and ketones, and also understood that the reaction was reversible.

3. Stereochemistry of reaction paths at carbonyl centres
H.B. Burgi, J.D. Dunitz, J.M. Lehn, G. Wipff,
Tetrahedron, 30(12) 1974, 1563-1572.
DOI: 10.1016/S0040-4020(01)90678-7

A detailed study of crystal structures unveiled a tendency for nucleophiles to approach carbonyl centers at an angle of approximately 105°. This trajectory of the nucleophile towards the C=O bond, which has become known as the Burgi Dunitz trajectory,  is proposed to maximize overlap with the C-O pi* bond and allows for relaxation of the carbonyl carbon to a tetrahedral geometry.

4. Chemical Effects of Steric Strains
H. C. Brown, O. H. Wheeler, K. Ichikawa
Tetrahedron 1 1957, 214-220.
DOI: 10.1016/0040-4020(57)88041-7 
Study on the reaction rates of reduction of various aldehydes and ketones toward sodium borohydride. Spoiler: Aldehydes are much faster.