Trevor A. Hamlin

Vrije Universiteit Amsterdam | VU · Division of Theoretical Chemistry

Understanding chemical reactivity through the use of state-of-the-art computational techniques enables chemists to both predict reactivity and rationally design novel reactions. This protocol aims to provide chemists with the tools to implement a powerful and robust method for analyzing and understanding any chemical reaction using PyFrag 2019. The...

ConspectusOrganic chemistry has undoubtedly had a profound impact on humanity. Day in and day out, we find ourselves constantly surrounded by organic compounds. Pharmaceuticals, plastics, fuels, cosmetics, detergents, and agrochemicals, to name a few, are all synthesized by organic reactions. Very often, these reactions require a catalyst in order...

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...

A reagent-controlled stereodivergent carbocyclisation of aryl aldimine-derived, photocatalytically-generated, α-amino radicals possessing adjacent conjugated alkenes, affording either bicyclic or tetracyclic products, is described. Under net reductive conditions using commercial Hantzsch ester, the α-amino radical species underwent a single stereos...

The first metal-free catalytic intermolecular enantioselective Michael addition to unactivated α,β-unsaturated amides is described. Consistently high enantiomeric excesses and yields were obtained over a wide range of alkyl thiol pronucleophiles and electrophiles under mild reaction conditions, enabled by a novel squaramide-based bifunctional imino...

Tropone is an unreactive diene in normal electron demand Diels- Alder reactions, but it can be activated via carbonyl umpolung by using hydrazone ion analogs. Recently, the higher reactivity of hydrazone ion analogs was ascribed to a raised HOMO energy induced by antiaromaticity (Org. Lett., 2020, 22, 7083). We show that this is incorrect, and that...

Herein, we describe the convergent enantioselective total synthesis of himalensine A in 18 steps, enabled by a highly enantio- and diastereoselective construction of the morphan core via a palladium/hydroxy proline co-catalyzed desymmetrization of vinyl-bromide-tethered cyclohexanones. The reaction pathway was illuminated by density functional theo...

We have quantum chemically studied activation of H n A–AH n bonds (AH n = CH 3 , NH 2 , OH, F) by PdL n catalysts with L n = no ligand, PH 3 , (PH 3 ) 2 , using relativistic density functional theory at ZORA-BLYP/TZ2P. The activation energy associated with the oxidative addition step decreases from H 3 C–CH 3 to H 2 N–NH 2 to HO–OH to F–F, where th...

Boron‐boron multiple bonds, such as those found in diborenes and diborynes, are typically stabilized by σ‐donor ligands that furnish electron density to these otherwise electron‐deficient species. These compounds are not only of fundamental importance in the study of chemical bonding, but can also activate small molecules in a chemistry reminiscent...

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...

We have quantum chemically analyzed the nature and the origin of the directionality of pnictogen (PnB), chalcogen (ChB), and halogen bonds (XB) in archetypal FmZ•••F– complexes (Z = Pn, Ch, X), using relativistic density functional theory (DFT) at ZORA‐M06/QZ4P. Quantitative Kohn‐Sham MO and energy decomposition analyses (EDA) show that all these i...

Recently, Sowlati-Hashjin et al.1 have used the exchange-correlation interaction collectivity index (ICIXC; ICIXC  [0,1]) to conclude that the nature of the Li–C chemical bond in LiCF3 differs significantly from that in LiCPh3 (Ph = phenyl). Whereas the Li–C bond of LiCF3 is classified as a conventional two-center two-electron bond (ICIXC = 0.910,...

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 oxidat...

We have quantum chemically studied the base‐catalyzed Diels‐Alder (DA) reaction between 3hydroxy‐2‐pyrone and N‐methylmaleimide using dispersion‐corrected density functional theory. The uncatalyzed reaction is slow and is preceded by the extrusion of CO2 via a retro‐DA reaction. Base catalysis, e.g., by triethylamine, lowers the reaction barrier up...

The traditional and widespread rationale behind the stability trend of alkyl-substituted carbocations is incomplete.

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...

An iron‐catalysed carbene transfer reaction of diazo compounds to isocyanides is developed. The resulting ketenimines are trapped in situ with various bisnucleophiles to access a range of densely functionalized heterocycles (i.e., pyrimidinones, dihydropyrazolones, 1H‐tetrazoles) in a one‐pot process. The electron‐rich Hieber anion ([Fe(CO)3NO]−) f...

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 for a covalent linkage with the target enzyme. The reactivity of this entity needs to be well balanced to effectively tra...

Hierarchical, convergent ab initio benchmark computations were performed followed by a systematic analysis of DFT performance for five pericyclic reactions comprising Diels-Alder, 1,3-dipolar cycloaddition, electrocyclic rearrangement, sigmatropic rearrangement, and double group transfer prototypes. Focal point analyses (FPA) extrapolating to the a...

The 1,3‐dipolar cycloaddition (1,3‐DCA) reaction, conceptualized by Rolf Huisgen in 1960, has proven immensely useful in organic, material, and biological chemistry. The uncatalyzed, thermal transformation is generally sluggish and unselective, but the reactivity can be enhanced by means of metal catalysis or by the introduction of either predistor...

We have quantum chemically investigated how methyl substituents affect the stability of alkyl radicals Me m H 3‐m C • and the corresponding Me m H 3‐m C–X bonds (X = H, CH 3 , OH; m = 0 ‐ 3) using density functional theory at M06‐2X/TZ2P. The state‐of‐the‐art in physical organic chemistry is that alkyl radicals are stabilized upon an increase in th...

We have quantum chemically investigated how methyl substituents affect the stability of alkyl radicals Me m H 3‐m C • and the corresponding Me m H 3‐m C–X bonds (X = H, CH 3 , OH; m = 0 ‐ 3) using density functional theory at M06‐2X/TZ2P. The state‐of‐the‐art in physical organic chemistry is that alkyl radicals are stabilized upon an increase in th...

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,...

Invited for the cover of this issue are Pascal Vermeeren, Trevor A. Hamlin, and F. Matthias Bickelhaupt of the TheoCheM group at the Vrije Universiteit Amsterdam. The cover art depicts how ionizing the dienophile lowers the Diels–Alder reaction barrier between 1,3‐butadiene and acrylaldehyde by reducing the destabilizing steric Pauli repulsion and...

Ionization of the dienophile is an effective method to enhance the Diels–Alder reaction between buta‐1,3‐diene and acrylaldehyde. The origin of this ionization catalysis is both a reduction in steric Pauli repulsion and simultaneous enhancement of the orbital interactions between the reactants. Our work demonstrates the similarities and differences...

We have quantum chemically studied the palladium‐mediated activation of C(spn)–X bonds (n = 1–3; X = F, Cl, Br, I) in the archetypal model substrates H3C–CH2–X, H2C=CH–X, and HC≡C–X by a model bare palladium catalyst, using relativistic density functional theory at ZORA‐BLYP/TZ2P. The bond activation reaction barrier decreases, for all sp‐hybridize...

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. We pinpoint the eff...

We have studied the catalytic effect of ionization on the Diels‐Alder reaction between 1,3‐butadiene and acrylaldehyde using relativistic density functional theory (DFT). Removal of an electron from the dienophile, acrylaldehyde, significantly accelerates the Diels‐Alder reaction and shifts the reaction mechanism from concerted asynchronous for the...

Invited for this month's cover are the groups of Célia Fonseca Guerra at the Vrije Universiteit Amsterdam and Leiden University, Giampaolo Barone from the Università degli Studi di Palermo, and F. Matthias Bickelhaupt at Vrije Universiteit Amsterdam and Radboud University Nijmegen. The cover picture shows the four primary interaction components (hy...

The front cover provided by the TheoCheM group from Vrije Universiteit Amsterdam shows the four primary interaction components (hydrogen bonding, cross-terms, base stacking, and solvation) that determine the stability of B-DNA duplexes. Quantum chemical analyses identify an interplay between the stabilizing hydrogen bonds between nucleotides that d...

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...

We have quantum chemically analyzed the influence of nucleotide composition and sequence (that is, order) on the stability of double-stranded B-DNA triplets in aqueous solution. To this end, we have investigated the structure and bonding of all 32 possible DNA duplexes with Watson–Crick base pairing, using dispersion-corrected DFT at the BLYP-D3(BJ...

The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered β,β′-disubstituted nitroolefin. This key carbon–carbon bond forming reaction efficiently constructed a chiral bicycli...

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...

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...

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...

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...

The front cover artwork is provided by the TheoCheM group of the Vrije Universiteit Amsterdam. The image shows that guanine quadruplexes have a stronger binding affinity for divalent cations than monovalent cations. Read the full text of the Article at 10.1002/cphc.202100529. “In their contribution, Fonseca Guerra, Hamlin, and co‐workers report a u...

The Front Cover shows that guanine quadruplexes have a stronger binding affinity for divalent cations than monovalent cations. More information can be found in the Article by Trevor A. Hamlin, Célia Fonseca Guerra and co‐workers.

Atom size, not electronegativity difference, determines C−X bond strength, which weakens from X=F to I. In their Communication (DOI: 10.1002/chem.202103544), M. Bickelhaupt et al. reveal that, as the atom size increases, it is the increase in steric Pauli repulsion that weakens the C−X bond, and not the weakening of the orbital interaction (which,...

The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered β,β’-disubstituted nitroolefin. This key carbon–carbon bond forming reaction efficiently constructed a chiral bicycli...

The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered β,β’-disubstituted nitroolefin. This key carbon–carbon bond forming reaction efficiently constructed a chiral bicycli...

We have quantum chemically analyzed element-element bonds of archetypal HnX-YHn molecules (X, Y = C, N, O, F, Si, P, S, Cl, Br, I), using density functional theory. One purpose is to obtain a set of consistent homolytic bond dissociation energies (BDE) for establishing accurate trends across the periodic table. The main objective is to elucidate th...

The concept of dipolar repulsion has been widely used to explain several phenomena in organic chemistry, including the conformational preferences of carbonyl compounds. This model, in which atoms and bonds are viewed as point charges and dipole moment vectors, respectively, is however oversimplified. To provide a causal model rooted in quantitative...

The catalytic effect of various Lewis acids (LAs) on the ene reaction between propene (ene) and but‐3‐en‐2‐one (enophile) was studied quantum chemically using density functional theory and with coupled‐cluster theory. The studied LAs efficiently accelerate the ene reaction by lowering the reaction barrier up to 12 kcal mol–1 compared to the uncatal...

Asynchronicity in Diels-Alder reactions plays a crucial role in determining the height of the reaction barrier. Currently, the origin of asynchronicity is ascribed to the stronger orbital interaction between the diene and the terminal carbon of an asymmetric dienophile, which shortens the corresponding newly formed C–C bond and hence induces asynch...

The reactivity of phenothiazine ( PS ), phenoselenazine ( PSE ), and phenotellurazine ( PTE ) with different reactive oxygen species (ROS) has been studied using density functional theory (DFT) in combination with the QM‐ORSA (Quantum Mechanics‐based Test for Overall Free Radical Scavenging Activity) protocol for an accurate kinetic rate calculatio...

The formation of guanine quadruplexes (GQ) in DNA is crucial in telomere homeostasis and regulation of gene expression. Pollution metals can interfere with these DNA superstructures upon coordination. In this work, we study the affinity of the internal GQ channel site towards alkaline earth metal (Mg 2+ , Ca 2+ , Sr 2+ , and Ba 2+ ), and (post-)tra...

Brønsted acid‐catalyzed inverse‐electron demand (IED) aza‐Diels‐Alder reactions between 2‐aza‐dienes and ethylene were studied using quantum chemical calculations. The computed activation energy systematically decreases as the basic sites of the diene progressively become protonated. Our activation strain and Kohn‐Sham molecular orbital analyses tr...

A reagent‐controlled stereodivergent carbocyclisation of aryl aldimine‐derived, photocatalytically‐generated, α‐amino radicals possessing adjacent conjugated alkenes, affording either bicyclic or tetracyclic products, is described. Under net reductive conditions using commercial Hantzsch ester, the α‐amino radical species underwent a single stereos...

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...

Some nitrile‐boron halide adducts exhibit a double‐well potential energy surface with two distinct minima: a “long bond” geometry (LB, a van der Waals interaction mostly based on electrostatics, but including a residual charge transfer component) and a “short bond” structure (SB, a covalent dative bond). This behavior can be considered as a “weak”...

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...

We have analyzed the structure and stability of archetypal pnictogen-bonded model complexes D3PnA- (Pn = N, P, As, Sb; D, A = F, Cl, Br) using state-of-the-art relativistic density functional calculations at the ZORA-M06/QZ4P level. We have accomplished two tasks: (i) to compute accurate trends in pnictogen-bond strength based on a set of consisten...

An iridium-catalyzed reductive generation of both stabilized and unstabilized azomethine ylides and their application to functionalized pyrrolidine synthesis via [3 + 2] dipolar cycloaddition reactions is described. Proceeding under mild reaction conditions from both amide and lactam precursors possessing a suitably positioned electron-withdrawing...