Organic chemists are used to breaking and forming all sorts of chemical bonds; it’s what we do. But to do that we have to mess around with the energetics, because many (most!) of these processes don’t happen fast enough or selectively enough on their own. (In fact, the fundamental idea of “click” reactions, as introduced by Sharpless, was the search for the relatively few reactions that actually will happen quickly and selectively between otherwise unreactive species). Selective changes in rate constants, that’s the business of organic synthesis, and we accomplish that by all sorts of ways.
But they pretty much all come down to changing activation energies: the gap between the energies of the starting materials for any given step and the transition state, which is the highest-energy “hump” that the reactants have to pass through on their way to becoming reaction products. It’s all very well to determine the free energy changes between starting materials and products, but if that activation energy barrier in the middle is too high, you’re still not going anywhere. If you think of the energy landscape as a two-dimensional sheet, it’s full of valleys and ridges, sinkholes and odd sudden peaks and mesas. From a thermodynamic standpoint, a chemist’s job is to move stuff from one low point (the stable low-energy state of your starting materials) across various mountain passes and trails to where they can descend to another deeper valley, the energy state of the products. Along any particular trail from one valley to another, the highest point in the mountain pass, the exact place where a step in any direction takes you either back down towards the starting materials or on down towards the products, is the transition state.
If that point is too high, or if the trail sends you towards the wrong valleys, then it’s time to reach in and see if you can change the topography of the landscape. That’s where the hiking-map analogy breaks down, because in chemistry we really can alter the map. Adding a new reagent or catalyst can perform the equivalent of yanking down on the sheet from underneath and opening entirely new pathways – take them away, and it all twangs back to the forbidding territory you had before.
That mental picture prepares a person for this paper, which addresses a change to a chemical bond’s energy landscape that you don’t see used so often: mechanical stress. The authors attach an amide-bonded unit between the tip of an atomic force microscope and a substrate, and start pulling. This sort of work has shown some interesting effects, and in this case, there’s a dramatic change once a certain level of force is reached. At 0.6 nanoNewtons, the tether lasts for about 30 seconds, but at 0.8 nN, it lasts for only a tenth of a second. Control species localize the break point to the amide bond in the middle, but amide bonds had already been predicted to be relatively insensitive to that sort of thing. Apparently not!
In amide hydrolysis, the first thing that happens is (formally) the attack of a hydroxide ion on the carbonyl, which gives you a tetrahedral species, which then can fall back to the original amide (by losing hydroxide) or fall apart to an acid and an amine (I’m skipping a couple of fast proton transfers). What seems to be going on is a lowering of the transition state energy for the second step (TS2) – the energy landscape alters so that the path to making those two products becomes a lot easier to cross. A lot easier: just sitting around in water, amide bonds can have lifetimes of years to decades (or longer), so this sort of acceleration (nine orders of magnitude!) is at the level provided by enzyme catalysis.The breaking of the C-N bond in that second step seems to be almost parallel to the applied force; it’s perfectly set up to be weakened by what is not a very strong pull.
This makes a person wonder if this sort of thing is actually performed by some enzymes, at least in part. The authors say “In view of our findings, it would be surprising if nature had not used mechanical activation to increase enzymatic efficiency. . .” I look forward to someone finding an example of it!