The concept of complementarity between enzyme and substrate, especially the transition state for reactions at the substrate, is a key element of Pauling’s model for enzymatic activity. Koshland’s “induced fit” modification suggests that the enzyme might change its structure during the binding process to either destabilize the reactant or help stabilize the TS. These concepts are now tested in a very nice model by Stoddart, Siegel and coworkers.¹

Stoddart recently reported the host compound ExBox⁴⁺ 1 and demonstrated that it binds planar polycyclic aromatic hydrocarbons.² (I subsequently reported DFT computations on this binding.) The twist in this new paper is the binding of corranulene 2 inside ExBox⁴⁺ 1. Corranulene is bowl-shaped, with a bowl inversion barrier of 11.5 kcal mol^-1 (10.92 kcal mol^-1 at B97D/Def2-TZVPP).

The corranulene bowl is too big to fit directly into 1 without some distortions. The x-ray structure of the complex of 1 with 2 inside shows the width of 1 expanding by 0.87 Å and the bowl depth of 2 decreasing by 0.03 Å. The B97D/Def2-TZVPP optimized geometry of this complex (shown in Figure 1) shows similar distortions – the width of 1 increases by 0.37 Å (gas) or 0.29 Å (acetone solution), while the bowl depth of 2 decreases by 0.03 Å (gas) or 0.02 Å (solution).

ground state

transition state

Figure 1. B97D/Def2-TZVPP optimized geometries of the complex of 2 inside 1 (a) ground state and (b) transition state.

The calculated structure of the bowl inversion transition state of 2 inside of 1 is shown in Figure 1. 2 is planar at the TS. The experimental inversion barrier (determined by variable temperature NMR line shift analysis) is 7.88 kcal mol^-1, while the calculated barrier is 8.77 kcal mol^-1. The reduction in the bowl inversion barrier of 2 inside of 1 is therefore about 2.5 kcal mol^-1. The authors argue that this barrier reduction can be attributed to about 0.5 kcal mol^-1 of destabilization of the ground state of 2 along with 2 kcal mol^-1 of stabilization of the transition state afforded by the host. This study thus confirms the notions of a host reducing a barrier (through both transition state stabilization and ground state destabilization) and induced fit.

References

(1) Juríček, M.; Strutt, N. L.; Barnes, J. C.; Butterfield, A. M.; Dale, E. J.; Baldridge, K. K.; Stoddart, J. F.; Siegel, J. S. "Induced-fit catalysis of corannulene bowl-to-bowl inversion," Nat. Chem. 2014, 6, 222-228, DOI: 10.1038/nchem.1842.

(2) Barnes, J. C.; Juríček, M.; Strutt, N. L.; Frasconi, M.; Sampath, S.; Giesener, M. A.; McGrier, P. L.; Bruns, C. J.; Stern, C. L.; Sarjeant, A. A.; Stoddart, J. F. "ExBox: A Polycyclic Aromatic Hydrocarbon Scavenger," J. Am. Chem. Soc. 2012, 135, 183-192, DOI: 10.1021/ja307360n.

(3) Bachrach, S. M. "DFT Study of the ExBox·Aromatic Hydrocarbon Host–Guest Complex," J. Phys. Chem. A 2013, 117, 8484-8491, DOI: 10.1021/jp406823t.

InChIs

1: InChI=1S/C48H40N4/c1-2-38-4-3-37(1)33-49-25-17-45(18-26-49)41-9-11-43(12-10-41)47-21-29-51(30-22-47)35-39-5-7-40(8-6-39)36-52-31-23-48(24-32-52)44-15-13-42(14-16-44)46-19-27-50(34-38)28-20-46/h1-32H,33-36H2/q+4
InChIKey=ZMELWAYDWQWNOQ-UHFFFAOYSA-N

2: InChI=1S/C20H10/c1-2-12-5-6-14-9-10-15-8-7-13-4-3-11(1)16-17(12)19(14)20(15)18(13)16/h1-10H
InChIKey=VXRUJZQPKRBJKH-UHFFFAOYSA-N

Hong and Tantillo¹ report a real tour de force computational study of multiple pathways along the routes towards synthesis of a variety of sesquiterpenes. The starting point is the bisabolyl cation 1, and a variety of rearrangements, cyclizations, proton and hydride transfers are examined to convert it into such disparate products as barbatene 2, widdradiene 3, and champinene 4. The pathways are explored at mPW1PW91/6-31+G(d,p)//B3LYP/6-31+G(d,p). Some new pathways are proposed but the main points are the sheer complexity of the C₁₅H₂₅⁺ potential energy surface and the interconnections between potential intermediates.

References

(1) Hong, Y. J.; Tantillo, D. J. "Branching Out from the Bisabolyl Cation. Unifying Mechanistic Pathways to Barbatene, Bazzanene, Chamigrene, Chamipinene, Cumacrene, Cuprenene, Dunniene, Isobazzanene, Iso-γ-bisabolene, Isochamigrene, Laurene, Microbiotene, Sesquithujene, Sesquisabinene, Thujopsene, Trichodiene, and Widdradiene Sesquiterpenes," J. Am. Chem. Soc. 2014, 136, 2450-2463, DOI: 10.1021/ja4106489.

InChIs

1: InChI=1S/C15H25/c1-12(2)6-5-7-14(4)15-10-8-13(3)9-11-15/h6,8,15H,5,7,9-11H2,1-4H3/q+1
InChIKey=YKHXORRQMGBNFI-UHFFFAOYSA-N

2: InChI=1S/C15H24/c1-11-6-9-13(2)10-12(11)14(3)7-5-8-15(13,14)4/h6,12H,5,7-10H2,1-4H3/t12-,13-,14+,15-/m0/s1
InChIKey=RMKQBFUAKZOVPQ-XQLPTFJDSA-N

3: InChI=1S/C15H24/c1-12-6-7-13-14(2,3)9-5-10-15(13,4)11-8-12/h6-7H,5,8-11H2,1-4H3/t15-/m0/s1
InChIKey=SJUIWFYSWDVOEQ-HNNXBMFYSA-N

4: InChI=1S/C15H24/c1-11-6-9-15-10-12(11)14(15,4)8-5-7-13(15,2)3/h6,12H,5,7-10H2,1-4H3/t12-,14-,15-/m1/s1
InChIKey=XRDHEPAYTVHOPC-BPLDGKMQSA-N

Organocatalysis affected by proline is an extremely active research area, and computational chemists have made considerable contributions (see Chapter 5.3 of my book – and this is expanded on in the 2^nd edition which should be out in just a few months). Most importantly, the Houk-List model¹ for the catalysis was largely developed on the basis of computations.

Recent experiments have indicated cocatalysts that can hydrogen bond to proline may increase the catalytic effect, including the enantioselectivity. Xue and co-workers have examined a series of potential cocatalysts for their ability to enhance the acidity of proline.² This is important in that a proton transfer is a component to the key step of the Houk-List model.

The cocatalysts examined included such compounds as 1–6. The deprotonation energy of proline with the associated cocatalysts was compared with that of proline itself. The energies were computed at M06-2x/6-311++G(2df,2p)//B3LYP/6-31+G(d) with the SMD treatment of five solvents. The structure of 5 with proline is shown in Figure 1.

5 with proline

5 with proline conjugate base

Figure 1. M06-2x/6-311++G(2df,2p)//B3LYP/6-31+G(d) optimized structure of 5 with proline and its conjugate base.

The effect of the cocatalysts is striking. In the gas phase, these additives decrease the pK_a of proline by 15 – 70 pK_a units, with 2 showing the largest effect. In solvent, the effect of the cocatalyst is attenuated, especially in more polar solvents, but still a considerable decrease in the pK_a is seen (as much as a 12 pK_a unit increase in acidity). Further exploration of potential cocatalysts seems fully warranted.

References

(1) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.-Y.; Houk, K. N. "Theory of Asymmetric Organocatalysis of Aldol and Related Reactions:  Rationalizations and Predictions," Acc. Chem. Res. 2004, 37, 558-569, DOI: 10.1021/ar0300524.

(2) Xue, X.-S.; Yang, C.; Li, X.; Cheng, J.-P. "Computational Study on the pK_a Shifts in Proline Induced by Hydrogen-Bond-Donating Cocatalysts," J. Org. Chem. 2014, 79, 1166–1173, DOI: 10.1021/jo402605n.

InChIs

1: InChI=1S/CH4N2O/c2-1(3)4/h(H4,2,3,4)
InChIKey=XSQUKJJJFZCRTK-UHFFFAOYSA-N

2: InChI=1S/CH5N3/c2-1(3)4/h(H5,2,3,4)/p+1
InCiKey=ZRALSGWEFCBTJO-UHFFFAOYSA-O

3: InChI=1S/C4H4N2O2/c5-1-2(6)4(8)3(1)7/h5-6H2
InChIKey=WUACDRFRFTWMHE-UHFFFAOYSA-N

4: InChI=1S/C13H12N2S/c16-13(14-11-7-3-1-4-8-11)15-12-9-5-2-6-10-12/h1-10H,(H2,14,15,16)
InChIKey=FCSHMCFRCYZTRQ-UHFFFAOYSA-N

5: InChI=1S/C20H14O2/c21-17-11-9-13-5-1-3-7-15(13)19(17)20-16-8-4-2-6-14(16)10-12-18(20)22/h1-12,21-22H
InChIKey=PPTXVXKCQZKFBN-UHFFFAOYSA-N

6: InChI=1S/C7H13N3/c1-3-8-7-9-4-2-6-10(7)5-1/h1-6H2,(H,8,9)/p+1
InChIKey=FVKFHMNJTHKMRX-UHFFFAOYSA-O

Proline: InChI=1S/C5H9NO2/c7-5(8)4-2-1-3-6-4/h4,6H,1-3H2,(H,7,8)/t4-/m0/s1
InChIKey= ONIBWKKTOPOVIA-BYPYZUCNSA-N