In the modern age of accessible quantum mechanics (DFT and so on), teaching hybridization can be anticlimactic. However, simple concepts continue to be empowering. In the past, I mentioned the “rabbit ear” view of carbonyl oxygen’s lone pairs. Despite the documented existence of n-to-π* interactions that cannot be adequately described using hybridization models, there are many cases where the good old bonding arguments hold and help understand molecular structure.

Today I want to talk about the often overlooked Bent’s rule. By the way, there is a great review by Professor Igor Alabugin of Florida State University in the J. Phys. Org. Chem. on this subject (see the link below). Bent’s rule states that “s-character concentrates in orbitals directed toward electropositive substituents or, alternatively, that atoms direct hybrid orbitals with more p-character towards more electronegative elements”. Here is a practical demonstration of its utility from Igor’s paper. Consider the molecule of difluoromethane. Chemical intuition based on electron repulsion might suggest that the F-C-F angle should be larger than the H-C-H angle. In reality, the opposite is true, which is a direct consequence of Bent’s rule. This is a fantastic example.

http://onlinelibrary.wiley.com/doi/10.1002/poc.3382/abstract

I have been travelling extensively, which is the reason for not being able to write any posts. Now the summerly pace is settling in and I am back in Toronto. Not too long ago, my graduate student Sean Liew brought up an interesting JACS manuscript to my attention. I asked Sean to sum it up and here is his take:

“When we consider the fundamental properties of water, hydride formation to furnish H^– and HO⁺ is not the first thing that comes to mind. Prof. Benjamin Stokes at UC Merced just published a creative strategy for transfer hydrogenation of alkenes using water in the presence of palladium and tetrahydroxydiboron. The authors propose a mechanism in which the oxidative addition product of palladium and tetrahydroxydiboron allows for the recruitment of water molecules to the Lewis acidic boron ligands. This zwitterionic Pd-B-O-H complex can be likened to that of the very well known Pd-C-C-H moiety that is notorious for β-hydride elimination chemistry. The reaction appears to proceed through generation of boric acid and the active palladium hydride species that recruits the alkene or alkyne for migratory insertion. Repeat the water recruitment process with the other boron centre followed by reductive elimination provides the hydrogenated product. So why is this so intriguing? H-O⁺-B^–-Pd species is just being deprotonated, but by way of the unique reactivity of this short-lived intermediate, water’s proton is turned into a hydride through an entirely “inorganic” β-hydride elimination process.”

http://pubs.acs.org/doi/full/10.1021/jacs.6b02132

You might have noticed a certain trend in contemporary approaches to mechanistic investigations using computation: the (over)use of water. It is curious that 10 years ago people rarely considered water and now it is the fixture of almost every other paper, seemingly to patch holes in mechanistic arguments.

Jokes aside, molecular-level involvement of adventitious molecules is an interesting topic. Of course, experiment is the “real deal” and I pay attention to studies that reveal strange rate laws that hint at solvent involvement in transition state assemblies. Several days ago I came back from Halifax, Nova Scotia, where I heard a great talk by Joseph Moran of the University of Strasbourg. He described a system that reveals the enabling role of nitromethane in catalysis (http://pubs.acs.org/doi/abs/10.1021/jacs.5b06055). While listening to his talk, I took note of a peculiar paper by Berkessel, which is not something I was familiar with. In this work, there is experimental evidence for the involvement of 3 HFIP molecules in the rate-limiting step of olefin epoxidation. This reminds me of Ryan Hili’s studies of aziridine aldehyde dimers, where we always noted an important role of trifluoroethanol. However, our kinetic work has not allowed us to conclude that something remarkable was happening on a “molecular level”. In the Berkessel case, the kinetics clearly point at the involvement of 3 molecules of HFIP in the transition state. Do let me know if you are aware of other interesting cases that implicate adventitious molecules in rate-limiting steps.

The central role of heterocycles in modern chemical synthesis cannot be overestimated. Last week, I had a chance to appreciate the role of some of the fathers of modern approaches to heterocycle use and construction. As part of a trip to Germany (superbly organized by Professor Herbert Mayr) I visited the Ludwigs Maximilian University in Munich. The highlight of this trip was a meeting with the two gentlemen featured on the picture below. On my right hand side is Professor Wolfgang Steglich, the discoverer of DMAP (among many other things), while on my left side is Professor Rolf Huisgen. As the founder of dipolar cycloaddition chemistry, Professor Huisgen needs no introduction and I really want to wish him a happy 96^th birthday, which will be celebrated on June 13.

My host, Professor Mayr (a former PhD student of Huisgen), continues to push the boundaries of chemical reactivity. I already mentioned his work in the past and I am glad that he continues to educate the chemistry community on how one can predict selective reactions between various functional groups. With the help of my students, we will soon be collaborating with Professor Mayr to better understand the reactivity trends of our  own molecules. The Mayr scale has served as the go-to tool in teaching organic reactivity. The following contribution features what I call “the real rule of 5” and I enjoy discussing it with my students.

http://pubs.rsc.org/en/Content/ArticleLanding/2012/SC/c2sc00883a#!divAbstract

When one embarks on the treacherous journey in organic chemistry research, proper planning of experiments is of utmost important. Nothing is more dreadful than going from one experiment to the next while changing two different parameters at a time. If you are a chemistry professor mentoring graduate students, I am sure that you wholeheartedly agree with me and may recall cases when this happened to beginning students in your lab (for example, an attempt to concurrently change a concentration and temperature in a reaction). The core of our work is to ensure that we take a rational approach to incremental learning, which is based on looking for cause/effect correlations while focusing on one variable at a time.

The idea of incremental changes goes beyond running experiments and affects our reasoning by implying that additivity should be the guiding light in reaching sound conclusions. I will provide evidence where being too dogmatic about additivity is counterproductive. As you can see, Klebe and co-workers make an excellent point: if you modify the inhibitor on the top left with a methyl group, you will get a molecule, whose binding affinity to thermolysin is improved only marginally (2.2 kcal / mol gain). If you then modify the same starting point with a carboxylic acid, again there is nothing remarkable (1 kcal / mol gain). But if you now do both of these changes (methyl and acid) at the same time, the result is profoundly better than the starting point (6.7 kcal / mol gain). While the underlying reasons for this sort of behavior are complex, this set of examples speaks to the non-additivity of functional groups and suggests that it is wrong to think about molecules as Lego-like agglomerates of functional groups. Every molecule is in its own class and simple functional group additivity is not always a sound guiding principle. You might then ask: does this imply that the vast majority of medicinal chemistry research is misguided? I don’t know. Maybe it is.

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201200206/abstract

Remote control of chemical reactivity ranks among the most fascinating aspects of chemistry, particularly if a network of non-covalent interactions is involved. During a recent discussion, one of my graduate students, Joanne Tan, presented an interesting paper detailing one such effect. I asked Joanne to write a summary for my blog, so here it is:

“Ever since my undergraduate years, I have always been turned off by carbohydrate chemistry. It is difficult to functionalize a carbohydrate at a specific hydroxyl group without the need for extensive protecting group manipulations. That is why I like reading about methods that allow one to perform regioselective modification of carbohydrates.

A recent JACS paper by Richard R. Schmidt and coworkers describes “the cyanide effect” – a method for the regioselective O-acylation of carbohydrates. In a typical acylation of a carbohydrate-derived diol, equatorial hydroxyl reacts preferentially. However, in the presence of cyanide anion, the axial OH is acylated instead, furnishing the kinetic product. On the basis of an NMR study, cyanide anion appears to hydrogen bond to the more acidic axial –OH, which increases its nucleophilicity. Particularly interesting is the double hydrogen bonding from the equatorial hydroxyl group to the axial oxygen atom, which serves to stabilize the resulting anion upon deprotonation by cyanide.”

http://pubs.acs.org/doi/abs/10.1021/jacs.6b02454

Every now and then I pause and wonder about the role of unnatural amino acids in chemical biology and drug discovery. Apart from obvious gains in accessible molecular diversity of peptide collections, the structural value of some of the commonly used unnatural amino acids it is not immediately clear, at least to me. While diversity is an extremely important consideration, one has to wonder about the molecular-level significance of, say, cyclohexyl alanine. Apart from general hydrophobicity, what would the cyclohexane chair “glued” to a peptide chain impart when thrown into the medley of more mundane amino acids? How will it fare?

I was surprised to find out that the chair I just mentioned does just fine when it comes to stacking. In a thought-provoking study, Gunaydin
 and Bartberger point out excellent stacking abilities of cyclohexane. It appears that unsaturated rings found in drugs may be replaced with their saturated counterparts without losing potency even when it comes to stacking interactions with the side chains of aromatic residues. This should give us a lot of food for thought. What about asymmetric catalysis? Recall the importance of stacking interactions there. When we consider some widely used partially hydrogenated BINOL ligands, invoking stacking interactions in transition state assemblies might not be that outlandish if we think about Gunaydin
 and Bartberger’s eloquent study in structural biology.

http://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.6b00099