Using BDE for C-H activation prediction (or for example to identify the weakest bond likely to be targetted by CYP450-mediated metabolism) makes perfect sense.

My question was already lengthy, but I was asking because in an enzyme-catalysed reaction, I (believe) I was seeing a thermodynamically uphill reaction, ie converting an alkyl ester of the ligand to the weaker phenol ester of a tyrosine residue on the enzyme, which by all intuition (pKa of phenol vs alkyl alcohol, delocalisation of charge by phenol, etc) should not occur.

Thinking along the lines of Hess’s law, I was hoping by using the BDE of all formed/broken bonds to get an idea of how unfavorable the delta enthalpy is (as enthalpy is path invariant), which could provide insights into the catalytic driving force. This is of course, all heterolytic cleavage and in water (easier to separate charges), but the correction factors for the homolytic BDE (Acc Chem Res, 2003) should be roughly the same for each bond-breaking/forming step.

A further wrinkle is that some of the products/reactants are cyclic, which has made predicting BDE’s unusual (usually you calculate the energy of the neutral radical fragments, but homolytic cleavage of a ring gives you one product, not two).

I was hoping to estimate the enthalpy of the reaction in the usual way (bonds formed minus broken) using BDEs, which for the acrylic analogues of the ester to phenyl ester (tyrosine) transesterification is +5.7 kcal/mol. There’s an entropy component (a small group is cleaved, ie 1 reactant -> 2 products), so I’m trying to get a rough idea of whether this transesterification is possible, perhaps a different residue is involved (serine/threonine), or perhaps I’m way off.

If using BDE values to validate/invalidate my hypothesis is a fool’s errand, please let me know! I’m in a synthetic/biology focused lab, not really physical organic, so I can’t quite tell if there is any utility to estimating the thermodynamics of the reaction, especially through BDE estimations.

Hi Grant – sorry for late reply.

BDE’s are extremely useful when planning free-radical reactions. One example would be C-H oxidations of alkanes. One time we were planning a late-stage C-H oxidation on a carbon adjacent to an amide and in order to choose a proper oxidant it was helpful to compare its BDE with those of C-H bonds that underwent oxidation with various oxidants.

For a transesterification reaction, the mechanism will be heterolytic. Under basic conditions, your best proxy for deciding which ester is easiest to cleave will be the pKa of the corresponding alcohol. The more acidic the alcohol, the less basic its conjugate base will be, which will give you a fair idea of its ability to stabilize negative charge and thus act as a leaving group.

To give a simple exanple, it is much easier to cleave phenolic esters than it is to cleave the corresponding aliphatic ester. Even more so if the phenolic ester has attached electron-withdrawing groups that can help to stabilize negative charge.

So to answer your question, I would say, no, the BDE of the O-H bond is not going to tell you very much.

For example, if I was considering a transesterification reaction in water between para-cresyl acetate (CAS 140-39-6) and a benzyl acetate (CAS 140-11-4) and I know the BDE for the phenyl ester and alkyl ester (and the BDE of phenol/akyl deprotonation), would the BDE give me an idea of the favorability of the reaction? Is it possible for the reaction to reverse in this example where I tried to keep all else equal? Can it reverse in general? I get that reactions in solution may be different than breaking the lowest BDE-bond, but if we know the BDE of phenol vs alkyl O-H, can we assume this is the same? I’m also interested to know–in non/polar a/protic solvents, or for example, in the varied nonpolar and polar microenvironments of an enzyme–can we use BDE to compare a transesterification like the above or get any insight from the BDE?

I’m asking many questions ultimately to try to clarify my main question: is BDE comparison to polar/heterolytic reactions acceptable (ceteris paribus), limited, useless, or outright misleading? I did read the article (Acc Chem Res, 2003, p255) and while I get that it’s problematic/more work needs to be done, I don’t think it addresses my main question.

It’s hard to give a good answer without seeing a picture of the reaction. What solvent are you using? Do you have a good leaving group present that might ionize?

I had a friend who was doing a reaction in a photobox with near-UV radiation and the solvent was CH2Cl2. Weird things happened. Turns out the light was generating HCl from CH2Cl2 and it was causing all kinds of polar reactions. Fun times