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C1---C3 distance (pm)
C1-
--C2
dist
ance
(pm
)
TS1
TS2
NH
NH
NH
NH
NH
NH
!
Paton Research Group Computational Organic Chemistry
[email protected] http://paton.chem.ox.ac.uk
Chemistry Research Laboratory, Office 11 first floor
Introduction
Computation has played a major role in shaping our understanding of organic chemistry. More than ever before, computational and theoretical approaches are in widespread use to gain insight into chemical structure, reactivity and selectivity. Research in the Paton group is based on solving problems in organic and bio-organic chemistry using theoretical and computational methods. In particular, our research seeks to gain chemical insight into catalytic processes and hopefully to make testable predictions: we work in close collaboration with synthetic and crystallographic groups in Oxford and beyond. We are supported by state-of-the-art facilities in the Chemistry Research Laboratory and the Oxford Supercomputer Centre. Of particular interest are the factors controlling reactivity, mechanism and selectivity. Some of our ongoing research themes are described in this poster.
Understanding Organic Reactivity
We use calculations to gain insight into the factors that control selectivity in synthesis. We have developed a new way to understand regioselective nucleophilic addition to substituted benzynes. We were able to predict poor selectivity of 5,6-indolynes and the high selectivity of 6,7-indolynes prior to experiment. Key papers on Reactivity and Selectivity: Angew. Chem. Int. Ed. 2011, early view Recent Publications: Angew. Chem. Int. Ed. 2012, 51, 2758-2762. Angew. Chem. Int. Ed. 2011, 50, 10366-10368. J. Am. Chem. Soc. 2010, 133, 1267-1269.
X'
X
X'
X
Nuc
NucX'
Increased Ring Distortion
Decreased Ring Distortion
NucX
X'
XNuc
H
X'
XH
Nucpre-distorted aryne
δ+δ-
C-H activation
Pd-catalyzed so-called “direct” arylation provides an efficient, chemically benign alternative to traditional C-C bond forming reactions. Our work focuses on understanding factors governing the mechanism and site-selectivity of arylation for heterocycles such as indole. We have examined competing SE3, Heck-type C arbopa l ladat ion and Concer ted Meta l l at ion Deprotonation (CMD) mechanistic pathways. Our calculations also address the question of which ligands are bound to the Palladium under phosphine-free conditions. The computed free energy profile for the reaction is compared against experimental kinetic isotopic data. Recent Publications: Angew. Chem. Int Ed. 2012, 51, 10448–10450.
Biocatalysis & Baldwin’s Rules
The search for efficient biomass conversion methods to produce useful, green and sustainable products has gained much ground in recent years. However, a major obstacle has been that the main components of biomass - namely cellulose and l ignin - are tough polymers that do not break down easily. In collaboration with sc ient ists the US National Renewable Energy Laboratory, we are interested in homogeneous catalysis of lignin depolymerization.
Catalysis of Biofuel Production
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Me H H HH
Me CHO
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brevetoxin B
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Funding and equipment is gratefully acknowledged from:
Computed transition states show that oxidative insertion into the C-O bond is rate-limiting, whilst reduction by silane is relatively facile. Recent Publications: J. Phys. Chem. Lett. 2011, 2, 2846–2852.
!
Dynamics of Named Reactions
A key aspect to exploiting the reactivity of indoles in order to prepare molecules for medicine and biology is a clear understanding of mechanism and selectivity. We have investigated the mechanism of the Pictet-Spengler reaction, calculating the shape of the potential energy surface (PES) to understand the competing formation of five- and six-membered rings.
We have also studied the Diels-Alder reactions of strained dienophiles, in the context of the distortion-interaction model, which partitions the activation barrier of states into a combination of reactant distortion and intermolecular interaction terms. The distortion energy term in this expression correlates well with the overall barrier, and thus allows us to rank substrate reactivity without calculating the full reaction profile.
The exquisite control achieved by enzymes in the biosynthesis of natural product molecules is an ongoing source of interest. The mechanism of biosynthesis of polyether natural products from their polyepoxide precursors is particularly intriguing since nature often catalyzes such transformations selectively, giving products that are not seen in the same reaction in solution. We are currently col laborating with crystallographers to understand how the enzymatic synthesis of polyethers proceeds via a six-endo process in the active site, contrary to the five-exo reaction that occurs in solution. Recent Publications: Nature 2012, 483, 355-358.
Acknowledgements
CMD Carbopalladation SE3
Ar-Pd(II)-X!
RT, DMF!
Scan For More Info
0.0
8.0
23.0
8.6
25.2 25.6
14.6
-15.9
-5.2
PdPh
O
R
OH
R = DMFPhPdOAc -DMFPhPdOAc
TS1
3.9 3.9
10.4 10.3
Ph-H Pd-arylcomplex
CMD-TS
Diarylated Pd
RE-TS
Ph-Ph
PdO
R
HOTS2
23.025.2
27.128.6
21.824.7
26.5
14.625.6
15.825.2
17.228.1
20.4
wB97XD
M062X
B3LYP+DFTF3
CEPA
TS1 TS2method
Basis set: 6-311+G(d,p) for C, H, N, OLANL2TZ(f) for Pd
