Amides: Humble But Useful

A heartfelt thank-you to Chemjobber and See Arr Oh for helpful discussions!

CENtral Science’s benevolent overlord, Rachel Pepling, has organized a blog carnival around the theme of “your favorite chemical reaction”. For the Haystack’s contribution, I thought it would be appropriate to write about a reaction medicinal chemists might find familiar. So I re-read See Arr Oh’s post about which types of reactions were really the most common in the med-chem toolkit. I decided on amide formation, which sits just about at the top of the list. I’m not sure it’s my favorite chemical reaction; I’ve got a special place in my heart for the Heck reaction (or Mizoroki-Heck reaction), though I’ve already blogged extensively about it. But every amide bond formation I ran in grad school worked. That’s justification enough for me!

If this necklace represented a peptide or protein, amide bonds would be the little metal links. (Shutterstock)

Amides are the chemical ties that bind amino acids together to form peptides and proteins. Amides also turn up in a variety of other small molecules that nature makes. So it’s not surprising that amides are frequently found in drugs. Take a look at University of Arizona chemist Jón T. Njarðarson’s poster of top brand name drugs and marvel at the amide-y goodness.

Amide bond formation isn’t accomplished by a single, archetypical chemical reaction– far from it. I thought I’d provide a brief overview of some classic chemistry in this area and then move into a selection of modern-day additions to the amide-construction toolkit.

The endgame of Sheehan's penicillin synthesis

At first glance, it looks like all that’s needed to make an amide is to combine a carboxylic acid and an amine. But to make those two components come together, chemists have had to grease the wheels a bit by activating the carboxylic acid. Converting the carboxylic acid into an acid chloride or acid anhydride are among the oldest of the old-school methods for this. In 1955, MIT chemist John C. Sheehan reported a different idea—use of a coupling reagent, dicyclohexylcarbodiimide (DCC).

Classics in Total Synthesis notes that in its time, DCC was “an important advance in the state of the art for forming amide bonds.” In fact, Sheehan used it, along with the base potassium hydroxide, in the critical final step of the first total synthesis of penicillin– construction of the beta-lactam ring of the molecule.

However, separation of byproducts from the desired amide can be a limitation of DCC, according to the Haystack’s intrepid guest blogger See Arr Oh. Today, “O-chemists have newer, sexier reagents,” See Arr Oh adds.

Those reagents include N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC), a next-generation version of DCC that’s water soluble, and other classes of activating reagents including uronium and phosphonium reagents. John Pokorsi, a student in Karl Scheidt’s research group at Northwestern, prepared an excellent overview of how these reagents work back in 2004. (Thanks to Chemjobber for this reference.) The various coupling reagents are easy to find in pharma company patents—this site links to patents from AstraZeneca, Roche, and Pfizer.

The Bode team's amide formation

See Arr Oh notes that drugmakers also have a few options outside the coupling reagent box. For instance, the ETH chemist Jeffrey Bode developed a synthesis of amides from α-keto carboxylic acids and N-alkyl hydroxylamines. The reaction occurs selectively in the presence of amines and carboxylic acids, the traditional amide ligation partners. It proceeds in water without catalysts or other reagents, with byproducts of water and carbon dioxide. Bode also developed an organocatalytic amide-making approach. Though this is by no means a comprehensive list, other amide-formation advances include a coupling between alcohols and amines from David Milstein at Israel’s Weizmann Institute, and organocatalytic approaches (one notably using the word “magic” in the journal article title) from Robert Waymouth’s group at Stanford.

That’s certainly quite a few reactions. (Sorry, Rachel, I couldn’t pick one favorite!) With the ubiquity of the amide group in pharmaceuticals, researchers are no doubt working on even better options. If you’ve got a favorite amide bond formation I didn’t mention (since I certainly left many out!) please feel free to comment.

Author: Carmen Drahl

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3 Comments

  1. Great post! If you haven’t already read it I would heartily recommend Sheehan’s memoir “The Enchanted Ring” with the title naturally referring to the penicillin beta lactam ring. In it Sheehan has very interesting anecdotes about his accidental discovery of DCC as well as about his wartime work with Merck.

    Amide bond formation is also a great device for teaching the distinction between kinetics and thermodynamics. This also leads us to contemplate the remarkable evolutionary success of the amide bond since thermodynamically the reverse hydrolysis reaction is preferred by many kcal/mol. Gratifyingly, kinetics wins and a typical dipeptide has an aqueous half-life of several years.

  2. Nice to see such a useful little disconnect receiving its time in the limelight. Hope this inspires all you casual readers to try your hand at blogging about your faves, too!

  3. “Sorry, Rachel, I couldn’t pick one favorite!”

    I’ll let it go. This time. (That’s me being benevolent.)