3) Reaction of Isoniazid with benzophenone in the presence of substituted benzoic

acids results in the formation of crystals whose structures were determined by X-

ray crystallography (Cryst. Growth Des. 2018, 18, 8, 4777).

NH₂

NH

Isonicotinic

acid hydrazide

(Isoniazid)

Benzophenone

Modifier

OH

8.

Benzoic acid

co-former

HN-N

Modified Isoniazid/Hydroxybenzoic Acid

Co-Crystal

a) A 1:1:1 ratio (isoniazid: benzophenone: meta-hydroxybenzoic acid) of was

dissolved in methanol. In one case the reagents were reluxed for 3 h, and in a

second experiment they were refluxed for 72 h. Both were then allowed to

crystallize for 7 d by slow evaporation. Therefore, the only substantial change to

the synthetic method was the change in reflux time. However, one crystal

contained a solvate and the other did not. How could this be the case?

b) Which step of the crystallization process was likely affected, nucleation or

growth?

c) In another experiment, isoniazid was reacted with 4-methylbenzophenone and

co-crystallized with meta-hydroxybenzoic acid (mHBA). In one condition, the ratio

of isoniazid/4-methylbenzophenone/mHBA used in the one-pot synthesis was

1:1:1, but in another, a 1:1:1.6 ratio was used, with all other reaction and

crystallizing conditions remaining the same. The result was the formation of two

crystals with different structures, having the same composition but very different

hydrogen-bonding and packing arrangements from each other. How is this

possible?

d) In the experiments described in a or c above, which formed polymorphs (a or c or

both?