Strain energy for days: an in silico study of xinghaiamine A

SeeArrOh (via Twitter) reminded me of something I’ve been wanting to check out since this paper surfaced.

The paper in question features a supposed natural product, named “xinghaiamine A,” with some pretty wonky bonding.  Readers at Just Like Cooking and In the Pipeline brought up some issues regarding the evidence for this compound’s existence.  And rightly so; there appears to be something off about the supplemental data¹.  But, ignoring the (very real) issues readers have brought up with the supporting info for this paper, just look at this structure:

Oh dear

One half of the proposed compound.

At first glance, there’s some serious strain going on in there.  I figured I’d take a look at what xinghaiamine A looks like in 3D-space.  Getting it to behave in Spartan was a challenge on its own.  Chiefly, that bicyclo[2.2.0]hexane system was quite problematic.  Initial geometry optimizations at the semi-empirical level of theory produced some odd results.  I ended up settling on MMFF geometry optimization, which gave me the reasonably acceptable structure shown below²:

MMFF geometry optimization

MMFF geometry optimization of the xinghaiamine A “monomer”

Check out that bowl-shaped aromatic system.  That thing is supposed to be planar.

Check out that torsion angle: 40 degrees!

A torsion angle of 40 degrees.  And how!

The next logical step is to figure out exactly how much strain energy is in this thing.  This was done by taking the MMFF optimized geometry of xinghaiamine A and using it as a starting point for Spartan’s “T1 thermochemical recipe.”³  The T1 recipe is a post-Hartree-Fock method which consists of:

  • A quick and dirty HF/6-31G* geometry optimization
  • MP2 single point energy calculation with expanded basis set

This set of calculations yielded a heat of formation for xinghaiamine A of 1098.65 kJ/mol

Now, if we break that C-C bond joining the acenaphthalene and the bicyclo[2.2.0]hexane systems, repeat the calculations, and compare the results we can get a pretty decent idea of how much strain energy this proposed structure contains:

That planar acenaphthalene system looks so much happpier

That planar acenaphthalene system looks so much happpier

The answer is: a lot.

Breaking that one bond liberates quite a bit of energy.  But that’s not what makes this structure so implausible.  No, as others have pointed out, some of the motifs in this molecule have never been seen in a natural product.  And if you’re going to propose something never-before-seen, you best have the evidence to back it up.

Which raises the question: did the authors think the chemistry community would look at that structure and collectively go “yup, looks good to me, moving on then”?

  1. Something that rhymes with “fata dabrication”
  2. Note: the published structure is a dimer.  I’ve modeled it as a monomer, with a methyl R-group for computational simplicity
  3. Not a shill for Spartan, I promise