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15.8: Cation-pi interactions and the stabilization of carbocation intermediates

As an experienced student of chemistry, you are already very familiar with several different kinds of non-covalent interactions between chemical groups that are exceedingly important in organic structure and reactivity - hydrogen bonds, hydrophobic interactions, dipole-dipole interactions, etc.    The isoprenoid cyclization reactions covered in section 15.7B offer an excellent example of one more type of non-covalent interaction that we have not yet discussed.  Consider again the pentalanene synthase reaction.  The figure below shows the carbon skeleton of pentalenene, along with red dots to show the location of positive charges at various points in the cyclization mechanism.

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Carbocations are potent electrophiles, and thus the enzyme must be able to protect each carbocation intermediate from unwanted nucleophilic attack by solvent water molecules.  In order to do this, the reaction must take place in a water-free pocket deep inside the enzyme, the walls of which are made up mainly of hydrophobic residues (the substrate for the reaction is, after all, highly hydrophobic). This presents the enzyme with a dilemma: a hydrophobic environment is an inherently unfriendly place for a charged species like a carbocation!  How can an active site be hydrophobic and 'water-proof', while at the same time be capable of stabilizing a carbocation?

It turns out that the aromatic amino acids are perfect for this job.  The side chains of phenylalanine and tryptophan are certainly hydrophobic.  However, aromatic rings are also able to form relatively strong interactions with positive charges.  Recall (section 2.1C) that an aromatic ring has regions of pi-electron density directly above and below the plane of the ring.  Positively charged species are attracted to these regions of aromatic electron density, and thus will bind strongly to either face of an aromatic group such as the benzene ring of phenylalanine. 

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This has been termed the 'cation-pi interaction' (see Science 1996, 271, 163 for a very interesting discussion of cation-pi interactions). 

In the past few decades, scientists have become increasingly aware of the importance of cation-π interactions in enzymatic reaction mechanisms. The aromatic amino acids phenylalanine, tyrosine, and tryptophan are very effective at stabilizing positively charged reaction substrates or intermediates that are bound deep in the hydrophobic core of the enzyme.  The aromatic side chains are both hydrophobic and cation-stabilizing - two attributes that would appear at first to be mutually exclusive.  The x-ray crystal structure of pentalenene synthase shows that active-site phenylalanine and tryptophan side chains are well-positioned to stabilize positive charges that develop at different carbons during the cyclization reaction.

Another interesting example of a cation-pi interaction is provided by the acetylcholine esterase enzyme described in section 12.4C (this is the enzyme, located in neuron synapses, which is affected by sarin nerve gas).  X-ray crystal structures show that the enzyme binds the positively charged trimethylammonium group of the neurotransmitter acetylcholine in an 'aromatic gorge' lined with aromatic residues (Science 1991, 253, 872).  Until this crystal structure was published, it was presumed that the enzyme must bind the cationic trimethylammonium group in a pocket lined by negatively charged residues.

 

 

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