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Theoretical modeling of metal- and enzyme catalyzed transformations
Stockholm University, Faculty of Science, Department of Organic Chemistry. (Jan-E. Bäckvall)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is focused on describing and predicting catalytic reactions. The major part of the work is based on density functional theory (DFT). In some cases where the size of the investigated system precluded the use of more accurate methods molecular dynamics was employed. In several cases the proposed mechanism was later tested in the laboratory. A few examples where the predictions were confirmed are:

  • The formation of an acyl intermediate in the activation of a ruthenium catalyst used for racemizing alcohols. This intermediate was observed by both NMR and in situ FT-IR.
  • The improvement of the substrate specificity and catalytic activity of Candida antarctica lipase A by modifying amino acids close to the active site.
  • The improved specificity of Candida antarctica lipase B toward δ-substituted secondary alcohols by an enzyme variant where the alanine in position 281 was exchanged for a serine.

In other cases experimental results were complemented with a theoretical investigation, for example:

  • The observed second order rate constant for a ruthenium based catalyst used for water oxidation was explained and a novel intramolecular mechanism based on a high valent ruthenium dimer was suggested.
  • The effects of electron withdrawing/donating axial ligands on the performance of ruthenium catalyzed water oxidation were addressed.
  • Mechanisms of H2 activation by Lewis acid/Lewis base adducts were rationalized. One example of the predictive power of computational chemistry is the mechanism of hydrogen uptake by phosphanylboranes; the potential energy barrier for the transition state could be predicted within a few kcal/mol based on the orbital energies of the starting material.
Place, publisher, year, edition, pages
Stockholm: Department of Organic Chemistry, Stockholm University , 2010. , 96 p.
Keyword [en]
density functinal theory, computational chemistry, directed evolution, enzyme, mechanistic studies, catalysis, ruthenium, hydrogen transfer, racemization, artificial photosynthesis, frustrated lewis pairs, hydrogen storage
National Category
Organic Chemistry
Research subject
Organic Chemistry
Identifiers
URN: urn:nbn:se:su:diva-38344ISBN: 978-91-7447-063-5 (print)OAI: oai:DiVA.org:su-38344DiVA: diva2:309828
Public defence
2010-05-12, Magnelisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Submitted. Paper 8: In press.Available from: 2010-04-20 Created: 2010-04-08 Last updated: 2010-05-28Bibliographically approved
List of papers
1. CO Assistance in ligand exchange of a ruthenium racemization catalyst: identification of an acyl intermediate
Open this publication in new window or tab >>CO Assistance in ligand exchange of a ruthenium racemization catalyst: identification of an acyl intermediate
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2009 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 131, no 27, 9500-9501 p.Article in journal (Refereed) Published
Abstract [en]

An acyl intermediate in the activation of eta(5)-(Ph(5)Cp)Ru(CO)(2)Cl by t-BuOK was identified by means of in situ FT-IR measurements and NMR spectroscopy. This strongly supports the conclusion that the ligand exchange takes place via CO assistance, i.e., that the activation occurs via nucleophilic attack by tert-butoxide on one of the CO ligands. The tert-butoxycarbonyl intermediate shows stretching vibrations at 1933 and 1596 cm(-1), corresponding to the CO and COOt-Bu groups, respectively. In the (13)C NMR spectrum, the CO group appears at 209.5 ppm and the COOt-Bu group at 208.7 ppm. The NMR assignments were confirmed by density functional theory calculations. The subsequent alcohol-alkoxide exchange is also thought to take place via CO assistance. However, no intermediate in that step could be detected.

Place, publisher, year, edition, pages
American Chemical Society, 2009
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29966 (URN)10.1021/ja9038455 (DOI)000268239400016 ()
Available from: 2009-09-24 Created: 2009-09-24 Last updated: 2017-12-13Bibliographically approved
2. Highly Active Mononuclear Ru Catalysts for Water Oxidation: O-O Bond Formation via Direct Radical Coupling
Open this publication in new window or tab >>Highly Active Mononuclear Ru Catalysts for Water Oxidation: O-O Bond Formation via Direct Radical Coupling
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(English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:su:diva-38340 (URN)
Available from: 2010-04-08 Created: 2010-04-08 Last updated: 2017-12-12
3. Enantioselective Kinetic Resolution of p-Nitrophenyl 2-Phenylpropanoate by a Variant of Candida antarctica Lipase A Developed by Directed Evolution
Open this publication in new window or tab >>Enantioselective Kinetic Resolution of p-Nitrophenyl 2-Phenylpropanoate by a Variant of Candida antarctica Lipase A Developed by Directed Evolution
2010 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 132, no 20, 7038-7042 p.Article in journal (Refereed) Published
Abstract [en]

A variant of Candida antarctica lipase A (CalA) was developed for the hydrolysis of α-substituted p-nitrophenyl esters by directed evolution. The E values of this variant for 7 different esters was 45−276, which is a large improvement compared to 2−20 for the wild type. The broad substrate scope of this enzyme variant is of synthetic use, and hydrolysis of the tested substrates proceeded with an enantiomeric excess between 95−99%. A 30-fold increase in activity was also observed for most substrates. The developed enzyme variant shows (R)-selectivity, which is reversed compared to the wild type that is (S)-selective for most substrates.

Place, publisher, year, edition, pages
American Chemical Society, 2010
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-38337 (URN)10.1021/ja100593j (DOI)
Available from: 2010-04-08 Created: 2010-04-08 Last updated: 2017-12-12Bibliographically approved
4. Evolution of O2 in a seven-coordinate RuIV dimer complex with a [HOHOH]- bridge: A computational study
Open this publication in new window or tab >>Evolution of O2 in a seven-coordinate RuIV dimer complex with a [HOHOH]- bridge: A computational study
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2010 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 49, no 10, 1773-1777 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2010
Keyword
density functional calculations; O-O bond formation; redox chemistry; ruthenium
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-38330 (URN)10.1002/anie.200906439 (DOI)000275388300008 ()20155772 (PubMedID)
Available from: 2010-04-08 Created: 2010-04-08 Last updated: 2017-12-12Bibliographically approved
5. Influence of delta-functional groups on the enantiorecognition of secondary alcohols by Candida antarctica lipase B
Open this publication in new window or tab >>Influence of delta-functional groups on the enantiorecognition of secondary alcohols by Candida antarctica lipase B
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2008 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 9, no 12, 1968-1974 p.Article in journal (Refereed) Published
Abstract [en]

The selectivity of acetylation of delta-functionalized secondary alcohols catalyzed by Candida antarctica lipase B has been examined by molecular dynamics. The results from the simulation show that a delta-alcohol functionality forms a hydrogen bond with the carbonyl group of Thr 40. This interaction stabilizes the tetrahedral intermediate and thus leads to selective acetylation of the R enantiomer. A stabilizing interaction of the delta-(R)-acetoxy group with the peptide NH of alanine 282 was also observed. No stabilizing interaction could be found for the delta-keto functionality, and it is proposed that this is the reason for the experimentally observed decrease in enantioselectivity. From these results, it was hypothesized that the enantioselectivity could be restored by mutating the alanine in position 281 for serine. The mutation was made experimentally, and the results show that the E value increased from 9 to 120.

Identifiers
urn:nbn:se:su:diva-14702 (URN)doi:10.1002/cbic.200800036 (DOI)000258586600018 ()
Available from: 2009-01-02 Created: 2009-01-02 Last updated: 2017-12-13Bibliographically approved
6. "Frustration" of orbital interactions in Lewis base/Lewis acid adducts: a computational study of H2 uptake by phosphanylboranes R2P=BR'2
Open this publication in new window or tab >>"Frustration" of orbital interactions in Lewis base/Lewis acid adducts: a computational study of H2 uptake by phosphanylboranes R2P=BR'2
2009 (English)In: European Journal of Inorganic Chemistry, ISSN 1434-1948, E-ISSN 1099-1948, no 19, 2759-2764 p.Article in journal (Refereed) Published
Abstract [en]

The reaction of mol. hydrogen with phosphanylboranes R2P:BR'2 (1) is systematically studied by d. functional theory calcns. and second order Moller-Plesset perturbation theory. The potential energy barriers and the exothermicity of H2 uptake are reported for a series of phosphanylboranes with different electron-donating and -withdrawing groups bound to phosphorus and boron. Systematic MO anal. reveals that the "frustration" between boron and phosphorus can be increased by modifying the substituents, and thus, AO interactions could be exploited in order to increase the reactivity of 1. Addnl., authors found a correlation between the potential energy barrier for H2 uptake and the energy of the HOMO of the P:B complex, which could be relevant for the prediction of the properties of candidate compds. for H2 activation and therefore useful for the development of such systems. [on SciFinder(R)]

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2009
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29965 (URN)10.1002/ejic.200900311 (DOI)000267915100002 ()
Note
CAPLUS AN 2009:789341(Journal)Available from: 2009-09-24 Created: 2009-09-24 Last updated: 2017-12-13Bibliographically approved
7. On the possibility of catalytic reduction of carbonyl moieties with tris(pentafluorophenyl)borane and H2: a computational study
Open this publication in new window or tab >>On the possibility of catalytic reduction of carbonyl moieties with tris(pentafluorophenyl)borane and H2: a computational study
2009 (English)In: Dalton Transactions, ISSN 1477-9226, E-ISSN 1477-9234, no 29, 5780-5786 p.Article in journal (Refereed) Published
Abstract [en]

The study thoroughly examines the Gibbs free energy surfaces of a new mechanism for redn. of ketones/aldehydes by tris(pentafluorophenyl)borane (1) and H2. Key elements of the proposed mechanism are the proton and the hydride transfer steps similar to Stephan's catalytic redn. of imines by 1. The proton is transferred to the ketone/aldehyde in the process of H2 cleavage by the carbonyl-borane couple and the hydride is transferred in a nucleophilic attack on the carbonyl carbon by the hydridoborate in the ionic pair, [HOCRR']+[HB(C6F5)3]-. The in solvent Gibbs free energy barriers of H2 splitting by adducts of B(C6F5)3 with acetone, acetophenone and benzaldehyde are predicted to be in the range of 24.5 ± 2.5 kcal mol-1, which corresponds to potential energy barriers in the range of 17.0 ± 2.0 kcal mol-1. Significantly lower barrier of H2 activation is predicted in cases of bulky ketones such as 2,2,4,4-tetramethylpentan-3-one. With respect to the hydridoborate intermediate, the nucleophilic attack on the activated carbon is predicted to have a relatively low barrier for the sterically unhindered substrates, while this barrier is considerably higher for the sterically encumbered substrates. Since the formation of the hydridoborate intermediates is found to be endothermic, the transition state of the nucleophilic attack is the highest point of the computed energy profile for all tested substrates. Overall, according to in solvent d. function calcns. the proposed redn. of "compact" ketones/aldehydes by 1 and H2 is allowed both thermodynamically and kinetically at elevated temp., but it is expected to be slower and more substrate specific than the corresponding redn. of imines. [on SciFinder(R)]

Place, publisher, year, edition, pages
The Royal Society of Chemistry, 2009
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-30237 (URN)10.1039/b905137f (DOI)000267981000024 ()
Note
CAPLUS AN 2009:849255 (Journal)Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2017-12-13Bibliographically approved
8. Hydrogenation of carbon-heteroatom unsaturated bonds: An assessment of consistency of density functional methods
Open this publication in new window or tab >>Hydrogenation of carbon-heteroatom unsaturated bonds: An assessment of consistency of density functional methods
2010 (English)In: Journal of Molecular Catalysis A: Chemical, ISSN 1381-1169, E-ISSN 1873-314X, Vol. 324, no 1-2, 97-103 p.Article in journal (Refereed) Published
Abstract [en]

Hydrogenation of unsaturated carbon-heteroatom bonds, C = X, is the general process for which we assess consistency of quantum chemical calculations in the context of B(C6F5)3-catalyzed reduction of imines with H2. According to the mechanism of the reaction, computational uncertainty of energies of hydrogenation of imines, i.e. the difference between results obtained with different methods, contributes to method related uncertainties of the computed relative energies of key H2-activating species. For this reason, it is desirable to know the magnitude of methodological dependence/uncertainty of energies of hydrogenation. Calculations were performed with a number of different density functionals, such as M05-2X, M06-2X, B3LYP, B3PW91, BH&HLYP, MPW1K, MPW1PW91, HCTH407 and PBE, on a number of relevant imines and ketones/aldehydes. Additionally, second order Møller-Plesset perturbation theory was also evaluated. The results quantitatively reveal the manner in which the form of a method affects the calculated energy change and that there is substantial difference between results obtained with different methods even for structurally simple species.

Place, publisher, year, edition, pages
Elsevier B.V., 2010
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-39541 (URN)10.1016/j.molcata.2010.03.001 (DOI)000278823100014 ()
Available from: 2010-05-26 Created: 2010-05-26 Last updated: 2017-12-12Bibliographically approved
9. Racemization of alcohols catalyzed by [RuCl(CO)25-pentaphenylcyclopentadienyl)] – Mechanistic insights from theoretical modeling
Open this publication in new window or tab >>Racemization of alcohols catalyzed by [RuCl(CO)25-pentaphenylcyclopentadienyl)] – Mechanistic insights from theoretical modeling
2009 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 15, no 21, 5220-5229 p.Article in journal (Refereed) Published
Abstract [en]

Two possible pathways of inner-sphere racemization of sec-alcohols by using the [RuCl(CO)(2)(eta(5)-pentaphenylcyclopentadienyl)] catalyst (1) have been thoroughly investigated by means of density function calculations. To be able to racemize alcohols, catalyst 1 needs to have a free coordination site on the metal. This can be achieved either by a eta(5)-->eta(3) ring slippage or by dissociation of a carbon monoxide (CO) ligand. The eta(5)-->eta(3) ring-slip pathway was found to have a high potential energy barrier, 42 kcal mol(-1), which can be explained by steric congestion in the transition state. On the other hand, CO dissociation to give a 16-electron complex has a barrier of only 22.6 kcal mol(-1). We have computationally discovered a mechanism involving CO participation that does not require eta(5)-->eta(3) ring slippage. The key features of this mechanism are 1) CO-assisted exchange of chloride for alkoxide, 2) alcohol-alkoxide exchange, and 3) generation of an active 16-electron complex through CO dissociation with subsequent beta-hydride elimination as the racemization step. We have found a low-energy pathway for reaction of 1 with potassium tert-butoxide and a pathway for fast alkoxide exchange with interaction between the incoming/leaving alcohol and one of the two CO ligands. We predict that dissociation of a Ru-bound CO ligand does not occur in these exchange reactions. Dissociation of one of the two Ru-bound CO ligands has been found necessary only at a later stage of the reaction. Though this barrier is still quite high, our results indicate that it is not necessary to cross the CO dissociation barrier for the racemization of each new alcohol. Thus, the dissociation of a CO ligand is interpreted as a rate-limiting reaction step in order to create a catalytically active 16-electron complex.

Place, publisher, year, edition, pages
Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA, 2009
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-29969 (URN)10.1002/chem.200900291 (DOI)000266419600010 ()
Available from: 2009-09-24 Created: 2009-09-24 Last updated: 2017-12-13Bibliographically approved
10. Directed evolution of Candida antarctica lipase A using an episomaly replicating yeast plasmid
Open this publication in new window or tab >>Directed evolution of Candida antarctica lipase A using an episomaly replicating yeast plasmid
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2009 (English)In: Protein Engineering Design & Selection, ISSN 1741-0126, E-ISSN 1741-0134, Vol. 22, no 7, 413-420 p.Article in journal (Refereed) Published
Abstract [en]

We herein report the first directed evolution of Candida antarctica lipase A (CalA), employing a combinatorial active-site saturation test (CAST). Wild-type CalA has a modest E-value of 5.1 in kinetic resolution of 4-nitrophenyl 2-methylheptanoate. Enzyme variants were expressed in Pichia pastoris by using the episomal vector pBGP1 which allowed efficient secretory expression of the lipase. Iterative rounds of CASTing yielded variants with good selectivity toward both the (S)- and the (R)-enantiomer. The best obtained enzyme variants had E-values of 52 (S) and 27 (R).

Place, publisher, year, edition, pages
Oxford University Press, 2009
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-30458 (URN)10.1093/protein/gzp019 (DOI)000267226800004 ()
Available from: 2009-10-15 Created: 2009-10-15 Last updated: 2017-12-12Bibliographically approved

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