Nucleophilic Addition Reaction

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NUCLEOPHILIC ADDITION REACTION

Tereochemistry of the Nucleophilic Addition Reaction

Notice that in the course of the nucleophilic addition pictured above, the hybridization of the

carbonyl carbon changes from sp2 to sp3, meaning that the bond geometry changes from

trigonal planar to tetrahedral. It is also important to note that if the starting carbonyl is

asymmetric (in other words, if the two R groups are not equivalent), then a new stereocenter

has been created. The configuration of the new stereocenter depends upon which side of the

carbonyl plane the nucleophile attacks from.

If the reaction is catalyzed by an enzyme, the stereochemistry of addition is tightly controlled,

and leads to one specific stereoisomer - this is because the nucleophilic and electrophilic

substrates are bound in a specific positions within the active site, so that attack must occur

specifically from one side. If, however, the reaction occurs uncatalyzed in solution, then

either side of the carbonyl is equally likely to be attacked, and the result will be a 50:50racemic mixture.

This is the rule for most nonenzymatic reactions, but as with most rules, there are exceptions.

If, for example, the geometry of the carbonyl-containing molecule is constrained in such a

way that approach by the nucleophile is less hindered from one side, a 50:50 racemic mixture

will not necessarily result. Consider camphor, the distinctive-smelling compound found in

many cosmetics and skin creams.


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Upon inspection it is clear that topside attack and bottom side attack by a nucleophile are

nonequivalent in terms of steric hindrance. A relatively simple experiment shows that, when

the incoming nucleophile is a hydride ion from the common synthetic reducing agent sodium

borohydride (a reaction type we will study in a later chapter), the product of bottom side

attack predominates by a ratio of about 6 to 1 (seesection 16.4D for more details on this

experiment). We can infer from this result that approach from the bottom (si) face of thecarbonyl in camphor is less hindered.

Nucleophilic additions to aldehydes and ketones: the general picture

Before we consider in detail the reactivity of aldehydes and ketones, we need to look back

and remind ourselves of what the bonding picture looks like in a carbonyl. Carbonyl carbons

are sp2hybridized, with the three sp2orbitals forming soverlaps with orbitals on the oxygen

and on the two carbon or hydrogen atoms. These three bonds adopt trigonal planar

geometry. The remaining unhybridized 2p orbital on the central carbonyl carbon is

perpendicular to this plane, and forms a side-by-side pbond with a 2p orbital on the

oxygen.

The carbon-oxygen double bond is polar: oxygen is more electronegative than carbon, so

electron density is higher on the oxygen side of the bond and lower on the carbon side.

Recall that bond polarity can be depicted with a dipole arrow, or by showing the oxygen as

holding a partial negative charge and the carbonyl carbon a partial positive charge.

A third way to illustrate the carbon-oxygen dipole is to consider the two main resonance

contributors of a carbonyl group: the major form, which is what you typically see drawn in

Lewis structures, and a minor but very important contributor in which both electrons in the

pbond are localized on the oxygen, giving it a full negative charge. The latter depiction

shows the carbon with an empty 2p orbital and a full positive charge.

The result of carbonyl bond polarization, however it is depicted, is straightforward to predict.

The carbon, because it is electron-poor, is an electrophile: it is a great target for attack by an
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After the carbonyl is attacked by the nucleophile, the negatively charged oxygen has the

capacity to act as a nucleophile. However, most commonly the oxygen acts instead as a base,

abstracting a proton from a nearby acid group in the solvent or enzyme active site.

This very common type of reaction is called a nucleophilic addition. In many biologically

relevant examples of nucleophilic addition to carbonyls, the nucleophile is an alcohol oxygen

or an amine nitrogen, or occasionally a thiol sulfur. In one very important reaction typeknown as an aldol reaction (which we will learn about insection 13.3) the nucleophile

attacking the carbonyl is a resonance-stabilized carbanion. In this chapter, we will

concentrate on reactions where the nucleophile is an oxygen or nitrogen.

Stereochemistry of the nucleophilic addition reaction

Notice that in the course of the nucleophilic addition pictured above, the hybridization of the

carbonyl carbon changes from sp2 to sp3, meaning that the bond geometry changes from

trigonal planar to tetrahedral. It is also important to note that if the starting carbonyl is

asymmetric (in other words, if the two R groups are not equivalent), then a new stereocenterhas been created. The configuration of the new stereocenter depends upon which side of the

carbonyl plane the nucleophile attacks from.
http://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis/Chapter_13%3A_Reactions_with_stabilized_carbanion_intermediates_I/Section_13.3%3A_Aldol_reactionshttp://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis/Chapter_13%3A_Reactions_with_stabilized_carbanion_intermediates_I/Section_13.3%3A_Aldol_reactions


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If the reaction is catalyzed by an enzyme, the stereochemistry of addition is tightly controlled,

and leads to one specific stereoisomer - this is because the nucleophilic and electrophilic

substrates are bound in a specific positions within the active site, so that attack must occur

specifically from one side. If, however, the reaction occurs uncatalyzed in solution, then

either side of the carbonyl is equally likely to be attacked, and the result will be a 50:50racemic mixture.

This is the rule for most nonenzymatic reactions, but as with most rules, there are exceptions.

If, for example, the geometry of the carbonyl-containing molecule is constrained in such a

way that approach by the nucleophile is less hindered from one side, a 50:50 racemic mixture

will not necessarily result. Consider camphor, the distinctive-smelling compound found in

many cosmetics and skin creams.

Upon inspection it is clear that topside attack and bottom side attack by a nucleophile are

nonequivalent in terms of steric hindrance. A relatively simple experiment shows that, when

the incoming nucleophile is a hydride ion from the common synthetic reducing agent sodium

borohydride (a reaction type we will study in a later chapter), the product of bottom side

attack predominates by a ratio of about 6 to 1 (seesection 16.4D for more details on this

experiment). We can infer from this result that approach from the bottom (si) face of the

carbonyl in camphor is less hindered.
http://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis/Chapter_16%3A_Oxidation_and_reduction_reactions/Section_16.4%3A_Hydrogenation%2F%2Fdehydrogenation_reactions_of_carbonyls%2C_imines%2C_and_alcoholshttp://chemwiki.ucdavis.edu/Organic_Chemistry/Organic_Chemistry_With_a_Biological_Emphasis/Chapter_16%3A_Oxidation_and_reduction_reactions/Section_16.4%3A_Hydrogenation%2F%2Fdehydrogenation_reactions_of_carbonyls%2C_imines%2C_and_alcohols

Nucleophilic Addition Reaction

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