Nucleophilic addition - nitrogen nucleophiles

NUCLEOPHILIC ADDITION – NITROGEN NUCLEOPHILES

Key Notes

Imine formation

Primary amines react with aldehydes and ketones to give an imine or Schiff base. The reaction involves nucleophilic addition of the amine followed by elimination of water. Acid catalysis aids the reaction, but too much acid hinders the reaction by protonating the amine.

Enamine formation

Secondary amines undergo the same type of mechanism as primary amines, but cannot give imines as the final product. Instead, a proton is lost from a neighboring carbon and functional groups called enamines are formed.

Oximes, semicarbazones and 2,4-dinitrophenylhydrazones

Aldehydes and ketones can be converted to crystalline derivatives called oximes, semicarbazones, and 2,4-dinitrophenylhydrazones. Such deriva-tives were useful in the identification of liquid aldehydes and ketones.

Imine formation

The reaction of primary amines with aldehydes and ketones do not give the products expected from nucleophilic addition alone. This is because further reaction occurs once nucleophilic addition takes place. As an example, we shall consider the reaction of acetaldehyde (ethanal) with a primary amine – methylamine (Fig. 1). The product contains the methylamine skeleton, but unlike the previous reactions there is no alcohol group and there is a double bond between the carbon and the nitrogen. This product is called an imine or a Schiffbase.

The first stage of the mechanism (Fig. 2) is a normal nucleophilic addition. The amine acts as the nucleophile and the nitrogen atom is the nucleophilic center. The nitrogen uses its lone pair of electrons to form a bond to the electrophilic carbonyl carbon. As this bond is being formed, the carbonyl Ï€ bond breaks with both elec-trons moving onto the oxygen to give it a third lone pair of electrons and a nega-tive charge. The nitrogen also gains a positive charge, but both these charges can be neutralized by the transfer of a proton from the nitrogen to the oxygen (Step 2). 

The oxygen uses up one of its lone pairs to form the new O–H bond and the elec-trons in the N–H bond end up on the nitrogen as a lone pair. An acid catalyst is present, but is not required for this part of the mechanism – nitrogen is a good nucleophile and although the amine is neutral, it is sufficiently nucleophilic to attack the carbonyl group without the need for acid catalysis. The intermediate obtained is the structure one would expect from nucleophilic addition alone, but the reaction does not stop there. The oxygen atom is now protonated by the acid catalyst and gains a positive charge (Fig. 3, Step 3). Since oxygen is electronega-tive, a positive charge is not favored and so there is a strong drive to neutralize the charge. This can be done if the bond to carbon breaks and the oxygen leaves as part of a water molecule. Therefore, protonation has turned the oxygen into a good leaving group. The nitrogen helps the departure of the water by using its lone pair of electrons to form a π bond to the neighboring carbon atom and a pos-itive charged intermediate is formed (Step 4). The water now acts as a nucleophile and removes a proton from the nitrogen such that the nitrogen’s lone pair is restored and the positive charge is neutralized (Step 5).

Overall, a molecule of water has been lost in this second part of the mechanism.

Acid catalysis is important in creating a good leaving group. If protonation did not occur, the leaving group would have to be the hydroxide ion which is a more reactive molecule and a poorer leaving group.

Although acid catalysis is important to the reaction mechanism, too much acid can actually hinder the reaction. This is because a high acid concentration leads to protonation of the amine, and prevents it from acting as a nucleophile.

Enamine formation

The reaction of carbonyl compounds with secondary amines cannot give imines since there is no NH proton to be lost in the final step of the mechanism. However, there is another way in which the positive charge on the nitrogen can be neutralized. This involves loss of a proton from a neighboring carbon atom (Fig. 4). Water acts as a base to remove the proton and the electrons which make up the C–H σ bond are used to form a new π bond to the neighboring carbon. This in turn forces the existing π bond between carbon and nitrogen to break such that both the π electrons end up on the nitrogen atom as a lone pair, thus neutralizing the charge. The final structure is known as an enamine and can prove useful in organic synthesis.

Oximes, semicarbazones and 2,4- dinitrophenyl- hydrazones

The  reaction  of  aldehydes  and  ketones  with  hydroxylamine  (NH₂OH), semicarbazide  (NH₂NHCONH₂)  and  2,4-dinitrophenylhydrazine  takes  place  by  the same mechanism described for primary amines to give oximes, semi- carbazones,  and  2,4-dinitrophenylhydrazones,  respectively  (Fig.  5).  Thesecompounds were frequently synthesized in order to identify a liquid aldehyde or ketone. The products are solid and crystalline, and by measuring their melting points, the original aldehyde or ketone could be identified by looking up melting point  tables  of  these  derivatives.  Nowadays,  it  is  easier  to  identify  liquid aldehydes and ketones spectroscopically.