Below is the structure of Physostigmine, whose tertiary amines have pKas of 6.12

Question

Below is the structure of Physostigmine, whose tertiary amines have pKas of 6.12 and the secondary amine has a pKa of 12.2. Draw the molecule in its state that would exist at a physiological 7.4. What is the hybridization and geometry of the three nitrogen atoms at this pH? Below is the structure of the nerve agent VE (left), a strong and irreversible Acetylcholineesterase inhibitor, compared to Acetylcholine (right). What are the structural similarities between these two and physostigmine above? What are the differences? What critical structural difference do you think makes VE permanent that physostigmine lacks?

Explanation / Answer

We know that

pH = pKa + log [salt] / [acid]

so In solution, if pH <pKa, then the protonated form of side chain predominates

If if pH > pKa, then the deprotonated form of side chain predominates

(i) For teritary amine pKa < pH (7.4) so the protonated form (R3N+) will predominate

(ii) For secondary amine pKa > pH so the deprotonated from will predominate

In all the cases the hybridisation is sp3

The geometry of secondary amine : trigonal pyramidal

the geometry of tertiary amine : tetrahedral

2) Similarities : presence of amino group

Presence of O-C=O linkage in physostigmine and acetylcholine

Differences: physostigmine is aromatic with benzene ring

While the other two are not aromatic as they lack the benzene ring

The difference in polarity of bonds present

(phophate linkage is highly polar, which makes molecules VE more polar than other two]

The presence of phosphate linkage makes it permanent. The presence of sulphur bond also makes it strong.

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