Thomas Hansen

Thomas Hansen
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Thomas verified their affiliation via an institutional email.
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Thomas verified their affiliation via an institutional email.
Vrije Universiteit Amsterdam | VU · Department of Chemistry and Pharmaceutical Sciences

Ph.D.
Decoding Organic Chemistry!

About

93
Publications
18,709
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1,427
Citations
Introduction
Thomas Hansen (ORCID ID: 0000-0002-6291-1569) obtained his M.Sc. (2015, summa cum laude) and Ph.D. (2020, cum laude) in Chemistry from Leiden University. He is currently an Assistant Professor in the Synthetic Organic Chemistry & Catalysis group (Prof. Ruijter). His research interests lie at the intersection between organic and computational chemistry, striving to understand chemical reactivity at the molecular level.
Additional affiliations
August 2021 - August 2022
University of Barcelona
Position
  • PostDoc Position
Description
  • Supervision: Prof. Rovira; Subject: Catalytic mechanisms of enzymes; Keywords: QM/MM metadynamics, DFT, MD, X-ray crystallography.
September 2022 - present
Vrije Universiteit Amsterdam
Position
  • Professor (Assistant)
Description
  • Supervision: Prof. Eelco Ruijter; Field: Organic Chemistry, Catalysis, Computational Chemistry.
August 2019 - July 2021
Vrije Universiteit Amsterdam
Position
  • PostDoc Position
Description
  • Supervision: Prof. Bickelhaupt and Hamlin; Field: Computational Chemistry, Theoretical Chemistry; Subject: Theory-driven organic synthesis.
Education
August 2015 - July 2019
Leiden University
Field of study
  • Organic Chemistry, Computational Chemistry
September 2013 - September 2015
Leiden University
Field of study
  • Chemistry, Chemical Biology

Publications

Publications (93)
Article
Full-text available
The α‐effect is a term used to explain the dramatically enhanced reactivity of α‐nucleophiles (R−Y−X:⁻) compared to their parent normal nucleophile (R−X:⁻) by deviating from the classical Brønsted‐type reactivity‐basicity relationship. The exact origin of this effect is, however, still heavily under debate. In this work, we have quantum chemically...
Article
Full-text available
We have quantum chemically investigated how solvation influences the competition between the SN2 and E2 pathways of the model F– + C2H5Cl reaction. The system is solvated in a stepwise manner by going from the gas phase, then via microsolvation of one to three explicit solvent molecules, then last to bulk solvation using relativistic density functi...
Article
Full-text available
The development of small‐molecule covalent inhibitors and probes continuously pushes the rapidly evolving field of chemical biology forward. A key element in these molecular tool compounds is the “electrophilic trap” that allows a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively trap th...
Article
Full-text available
The traditional and widespread rationale behind the stability trend of alkyl-substituted carbocations is incomplete. Through state-of-the-art quantum chemical analyses, we quantitatively established a generally overlooked driving force behind the stability...
Article
Full-text available
Nucleophilic substitution reactions are elementary reactions in organic chemistry that are used in many synthetic routes. By quantum chemical methods, we have investigated the intrinsic competition between the backside SN2 (SN2‐b) and frontside SN2 (SN2‐f) pathways using a set of simple alkyl triflates as the electrophile in combination with a syst...
Article
Full-text available
Based on the successful application of a nitroaryl transfer cascade reaction in the total synthesis of various monoterpene indole alkaloids proceeding via fused bicyclic intermediate, we investigated analogous cascade reactions involving spiro, bridged, and alternatively fused bicyclic intermediates. Unfortunately, none of these was found to afford...
Article
Full-text available
We present an Ugi multicomponent approach to explore the chemical space around Aspidosperma‐type monoterpene indole alkaloids. By variation of the isocyanide and carboxylic acid inputs we demonstrate the rapid generation of molecular diversity and the possibility to introduce handles for further modification. The key Ugi three‐component reaction sh...
Article
Full-text available
Minimal structural differences in the structure of glycosyl donors can have a tremendous impact on their reactivity and the stereochemical outcome of their glycosylation reactions. Here, we used a combination of systematic glycosylation reactions, the characterization of potential reactive intermediates, and in-depth computational studies to study...
Article
Full-text available
We have quantum chemically studied the influence of ring strain on the competition between the two mechanistically different SN2 and E2 pathways using a series of archetypal ethers as substrate in combination with a diverse set of Lewis bases (F⁻, Cl⁻, Br⁻, HO⁻, H3CO⁻, HS⁻, H3CS⁻), using relativistic density functional theory at ZORA‐OLYP/QZ4P. The...
Preprint
Full-text available
Minimal structural differences in the structure of glycosyl donors can have a tremendous impact on their reactivity and the stereochemical outcome of their glycosylation reactions. It can be exceedingly hard to adequately account for the observed differences and our current understanding of the nature of different reactive intermediates and the rea...
Article
Full-text available
Herein, we described the first synthesis of the pentasaccharide and decasaccharide of the A. baumannii ATCC 17961 O‐antigen for developing a synthetic carbohydrate‐based vaccine against A. baumannii infection. The efficient synthesis of the rare sugar 2,3‐diacetamido‐glucuronate was achieved using our recently introduced organocatalytic glycosylati...
Article
Herein, we described the first synthesis of the pentasaccharide and decasaccharide of the A. baumannii ATCC 17961 O‐antigen for developing a synthetic carbohydrate‐based vaccine against A. baumannii infection. The efficient synthesis of the rare sugar 2,3‐diacetamido‐glucuronate was achieved using our recently introduced organocatalytic glycosylati...
Article
Full-text available
Oxocarbenium ions are key reactive intermediates in organic chemistry. To generate a series of structure‐reactivity‐stereoselectivity principles for these species, we herein investigated the bimolecular electrophilic substitution reactions (SE2′) between allyltrimethylsilane and a series of archetypal six‐membered ring oxocarbenium ions using a com...
Article
Full-text available
The reactivity of the acceptor alcohol can have a tremendous influence on the outcome of a glycosylation reaction, both in terms of yield and stereoselectivity. Through a systematic survey of 67 acceptor alcohols in glycosylation reactions with two glucosyl donors we here reveal how the reactivity of a carbohydrate acceptor depends on its configura...
Article
Full-text available
The iron‐catalyzed oxidative addition of C(spⁿ)−X bonds (n=1–3 and X=H, CH3, Cl) in archetypal model substrates H3C−CH2−X, H2C=CH−X and HC≡C−X to Fe(CO)4 was investigated using relativistic density functional theory at ZORA‐OPBE/TZ2P. The C(spⁿ)−X bonds become substantially stronger going from C(sp³)−X to C(sp²)−X to C(sp)−X, whereas the oxidative...
Cover Page
Full-text available
The traditional and widespread rationale behind the stability trend of alkyl-substituted carbocations is incomplete.
Article
Full-text available
Acetal substitution reactions of α‐halogenated five‐ and six‐membered rings can be highly stereoselective. Erosion of stereoselectivity occurs as nucleophilicity increases, which is consistent with additions to a halogen‐stabilized oxocarbenium ion, not a three‐membered‐ring halonium ion. Computational investigations confirmed that the open‐form ox...
Article
Full-text available
Uronic acids are carbohydrates carrying a terminal carboxylic acid and have a unique reactivity in stereoselective glycosylation reactions. Herein, the competing intramolecular stabilization of uronic acid cations by the C‐5 carboxylic acid or the C‐4 acetyl group was studied with infrared ion spectroscopy (IRIS). IRIS reveals that a mixture of bri...
Article
Full-text available
Acetal substitution reactions of α‐halogenated five‐ and six‐membered rings can be highly stereoselective. Erosion of stereoselectivity occurs as nucleophilicity increases, which is consistent with additions to a halogen‐stabilized oxocarbenium ion, not a three‐membered‐ring halonium ion. Computational investigations confirmed that the open‐form ox...
Article
Full-text available
We have quantum chemically explored the competition between the SN2 and SN2' pathways for X− + H2C=CHCH2Y (X, Y = F, Cl, Br, I) using a combined relativistic density functional theory and coupled-cluster theory approach. Bimolecular nucleophilic substitution reactions at allylic systems, i.e., Cy=Cb–Ca–Y, bearing a leaving-group at the a-position,...
Article
Full-text available
The stereoselective introduction of glycosidic bonds is of paramount importance to oligosaccharide synthesis. Among the various chemical strategies to steer stereoselectivity, participation by either neighboring or distal acyl groups is used particularly often. Recently, the use of the 2,2-dimethyl-2-(ortho-nitrophenyl)acetyl (DMNPA) protection gro...
Article
Full-text available
The C−X bond activation (X = H, C) of a series of substituted C(n°)−H and C(n°)−C(m°) bonds with C(n°) and C(m°) = H3C− (methyl, 0°), CH3H2C− (primary, 1°), (CH3)2HC− (secondary, 2°), (CH3)3C− (tertiary, 3°) by palladium were investigated using relativistic dispersion‐corrected density functional theory at ZORA‐BLYP‐D3(BJ)/TZ2P. The effect of the s...
Article
Full-text available
We have quantum chemically studied the iron‐mediated C–X bond activation (X = H, Cl, CH3) by d8‐FeL4 complexes using relativistic density functional theory at ZORA‐OPBE/TZ2P. We find that by either modulating the electronic effects of a generic iron‐catalyst by a set of ligands, that is, CO, BF, PH3, BN(CH3)2, or by manipulating structural effects...
Article
Full-text available
We have studied the palladium‐mediated activation of C(spⁿ)−X bonds (n = 1–3 and X = H, CH3, Cl) in archetypal model substrates H3C−CH2−X, H2C=CH−X and HC≡C−X by catalysts PdLn with Ln = no ligand, Cl⁻, and (PH3)2, using relativistic density functional theory at ZORA‐BLYP/TZ2P. The oxidative addition barrier decreases along this series, even though...
Preprint
Full-text available
The targeted application of multiple helicenes in photo-optical applications requires their rational design. Toward this goal, we report on the synthesis of pyrene-based triple helicene 1 and investigate the positional effect of extension of the π-conjugated system on the photo-chemical and chiro-optical properties of triple helicenes. The conforma...
Preprint
Full-text available
The physico-chemical properties of chiral propeller-shaped PAHs (propellerenes) are strongly dependent on their conformational behavior. A sound, physical model to understand why propellerenes exhibit a conformation preference for either a C2 or D3 conformation that moves beyond a phenomenological explanation is needed. We have therefore performed...
Cover Page
Full-text available
The α-effect is a “reactivity booster” that affords the less basic peroxide (HOO⁻) the edge over hydroxide (HO⁻) in the Grand Prix of SN2 Reactivity! In their Research Article (DOI: 10.1002/anie.202106053), Trevor A. Hamlin et al. equip researchers with two criteria that α-nucleophiles need to fulfill to exhibit an α-effect: (i) a small HOMO lobe o...
Cover Page
Full-text available
Der α‐Effekt ist ein „Reaktivitäts‐Booster“, der dem weniger basischen Peroxid (HOO−) den Vorteil gegenüber Hydroxid (HO−) im Grand Prix der SN2‐Reaktivität verschafft! In ihrem Forschungsartikel (DOI: 10.1002/ange.202106053) stellen Trevor A. Hamlin et al. zwei Kriterien auf, die α‐Nucleophile erfüllen müssen, um einen α‐Effekt zu zeigen: (i) ein...
Article
Full-text available
The α‐effect is a term used to explain the dramatically enhanced reactivity of α‐nucleophiles (R–Y–X:– ) compared to their parent normal nucleophile (R–X:– ) by deviating from the classical Brønsted‐type reactivity–basicity relationship. The exact origin of this effect is, however, still heavily under debate. In this work, we have quantum chemicall...
Article
Full-text available
Anthracyclines are effective drugs in the treatment of various cancers, but their use comes with severe side effects. The archetypal anthracycline drug, doxorubicin, displays two molecular modes of action: DNA double-strand break formation (through topoisomerase IIα poisoning) and chromatin damage (via eviction of histones). These biological activi...
Article
Full-text available
The mechanism of the Lewis base F– catalyzed 1,3-dipolar cycloaddition between CO2 and nitrilimines is interrogated using DFT calculations. F– activates the nitrilimine, not CO2 as proposed in the literature, and imparts a significant rate enhancement for the cycloaddition. The origin of this catalysis is in the strength of the primary orbital inte...
Article
Full-text available
We have quantum chemically studied the Lewis acid-catalyzed epoxide ring-opening reaction of cyclohexene epoxide by MeZH (Z = O, S, and NH) using relativistic dispersion-corrected density functional theory. We found that the reaction barrier of the Lewis acid-catalyzed epoxide ring-opening reactions decreases upon ascending in group 1 along the ser...
Chapter
(Stereo)electronic effects dictate the outcome of a glycosylation reaction. This article documents how these effects impact the properties, reactivity, and structure of the donor, reactive intermediates, and acceptor glycosides. It is discussed how the reactivity of carbohydrate donors can be tuned through the protection groups, allowing the develo...
Thesis
Full-text available
This thesis describes the use of a combined approach of computational and experimental techniques to gain novel insights to understand the glycosylation reaction and its reactive intermediates. The research in this thesis shows that glycosyl cations can act as reactive intermediates in glycosylation reactions for the introduction of glycosidic link...
Article
Full-text available
The assembly of complex bacterial glycans presenting rare structural motifs and cis‐glycosidic linkages is significantly obstructed by the lack of knowledge of the reactivity of the constituting building blocks and the stereoselectivity of the reactions in which they partake. We here report a strategy to map the reactivity of carbohydrate building...
Article
Full-text available
We have quantum chemically analyzed the competition between the bimolecular nucleophilic substitution (S N 2) and base-induced elimination (E2) pathways for F − + CH 3 CH 2 Cl and PH 2 − + CH 3 CH 2 Cl using the activation strain model and Kohn−Sham molecular orbital theory at ZORA-OLYP/QZ4P. Herein, we correct an earlier study that intuitively att...
Article
Full-text available
The concepts of nucleophilicity and protophilicity are fundamental and ubiquitous in chemistry. A case in point is bimolecular nucleophilic substitution (SN2) and base‐induced elimination (E2). A Lewis base acting as a strong nucleophile is needed for SN2 reactions, whereas a Lewis base acting as a strong protophile (i.e., base) is required for E2...
Cover Page
Full-text available
The inherent competition between the bimolecular nucleophilic substitution (SN2) and base‐induced elimination (E2) reactions is depicted in the cover image. This work reports a physically sound and intuitive model to elucidate why strong Lewis bases act as protophiles (E2), while weak Lewis bases behave as nucleophiles (SN2). The general concepts o...
Article
Full-text available
The assembly of complex bacterial glycans presenting rare structural motifs and cis ‐glycosidic linkages is significantly obstructed by the lack of knowledge of the reactivity of the constituting building blocks and the stereoselectivity of the reactions in which they partake. We here report a strategy to map the reactivity of carbohydrate building...
Article
Full-text available
We have quantum chemically analyzed the ring‐opening reaction of the model non‐symmetrical epoxide 2,2‐dimethyloxirane under basic and acidic conditions using density functional theory at OLYP/TZ2P. For the first time, our combined activation strain and Kohn–Sham molecular orbital analysis approach have revealed the interplay of physical factors th...
Article
Full-text available
The inverse electron demand Diels–Alder pyridazine elimination reaction between tetrazines and allylic substituted trans‐cyclooctenes (TCOs) is a key player in bioorthogonal bond cleavage reactions. Determining the rate of elimination of alkylamine substrates has so far proven difficult. Here, we report a fluorogenic tool consisting of a TCO‐linked...