LAKTAM

This issue of Enamine Product Focus highlights Lactams, cyclic amide building blocks. There are numerous examples of Lactams usage in drug discovery, e.g., β-lactam based antibiotics, oral anticoagulant Rivaroxaban, and anticonvulsant Levetiracetam.

                                       

Rivaroxaban, 2008                                                           Levetiracetam, 2000

The specific features of Lactam building blocks that are of advantage to drug design are summarized in the chart below.

Enamine’s Lactam building block collection is represented by many useful scaffolds, for example, piperidones, piperazinones, (thio)morpholiones, pyrrolidones, and their benzo-fused analogues. From combinatorial chemistry standpoint especially interesting lactams in our collection are those bearing additional functionalities, such as carboxyl, chlorosulfonyl, and amino-groups.

                                                                                     

Piperidones                                                 Piperazinones                                                   Morpholinones

       

Thiomorpholinones               Pyrrolidones                              Dihydroquinoxalinones

The procedures developed for the synthesis of our Lactams allow preparation of highly diverse building blocks on 1–10 g scale. In addition we offer synthesis of novel compounds of the requested structure in 4–8 weeks. Scale-up to 1 kg quantity is performed upon request.

Amines

EN300-14698	EN400-15942	EN300-12374
EN400-15247	EN300-04190	EN300-05878
EN300-27804	EN300-35705	EN300-36103
EN300-14296	EN300-14821	EN300-35764

Sulfochlorides

EN300-13073	EN300-13555	EN300-14981

Carboxylic acids

EN300-42819	EN300-26212	EN300-23517
EN300-13491	EN300-08179	EN300-22965

Other Lactams

EN300-29977	EN300-35893	EN300-12065
EN300-35925	EN300-26962	EN300-23715
EN300-27121	EN300-52210	EN300-62393

When the amide is hydrolyzed in acidic conditions, acid proton of the carbonyl oxygen, increase the susceptibility of the carbonyl carbon to nucleophilic attack. Nucleophilic attack by water on the carbonyl carbon causes the tetrahedral intermediate compound I, which is in equilibrium with form rather than protons, tetrahedral intermediate II. Reprotonasi can occur either at the tetrahedral intermediates of oxygen to reform I ataupada nitrogen to form a tetrahedral intermediate III. Protonation at nitrogen is preferred because the NH2 group is a stronger base than OH groups. Of the two possible groups to go on a tetrahedral intermediate III group (-OH danNH3), NH3 is a weak base, so it is released, forming carboxylic acids as end products. Because the reaction is carried out in acid solution, NH3 be protonated after expelled from the tetrahedral intermediates. This prevents the reverse reaction.

This revelation may be able to answer the question from Mr. Syam, the production amount of carboxylic acid in acidic conditions far more than under base conditions.

PROBLEM

1. why amide does'nt reactive?

2. Why can not hydrolyze amide without a catalyst?

  

  answer :  

1. Amide is a compound that is not reactive, since the protein consists of amino acids linked by amide bonds. Amide does not react with halide ions, ionkarboksilat, alcohol, or water because in each case, the incoming nucleophile is basalemah of the amide group to go. Amide can react with water and alcohol if the reaction mixture was heated dalamsuasana asam.Teori molecular orbitals may explain why the amide is not reactive. Amide resonance memilikikontributor important where one partner shares with karbonkarbonil nitrogen, which contains a lone pair orbital overlap of the vacant orbital overlap guguskarbonil.Keadaan lower-energy one partner is not a base or nucleophilic, and raises the energy of the orbital of the carbonyl group, resulting in less reactive terhadapnukleofil. Amide NH 2 groups can be dehydrated to a nitrile. Reagendehidrasi generally used for this purpose is P₂O₅, POCl₃, and SOCl₃.
2. In the reaction without catalyst, amidatidak protonated. Therefore, the water, a very poor nucleophile, should be neutral menyerangamida far more susceptible to nucleophilic than serangandari amidaterprotonasi. In addition, the group of the tetrahedral intermediate is not protonated in the reaction without a catalyst. Therefore, the-OH group is away from the tetrahedral intermediate, because  -OH is a weak base of the -NH2 amide reform. A amidabereaksi with alcohol under acidic conditions for the same reason will bereaksidengan water under acidic conditions.

                                                                                                   

                                                       I’m sorry if there are mistakes

Preparation of amides:

Amides are generally synthesized in the laboratory in several ways:
1. Anhydride reaction with ammonia

2. Ester reaction with ammonia

3. Reaction of acid chlorides with ammonia

4. Heating ammonium carboxylate salts


Amide hydrolysis:
Amida is very strong / resistant to hydrolysis. But the presence of concentrated acid or base, hydrolysis can occur producing carboxylic acid.