The clinical translation of polysarcosine (pSar) as polyethylene glycol (PEG) replacement in the development of novel nanomedicines creates a broad demand of polymeric material in high-quality... Show moreThe clinical translation of polysarcosine (pSar) as polyethylene glycol (PEG) replacement in the development of novel nanomedicines creates a broad demand of polymeric material in high-quality making high-purity sarcosine N-carboxyanhydride (Sar-NCA) as monomer for its production inevitable. Within this report, we present the use of triethyloxonium tetrafluoroborate in Sar-NCA synthesis with focus on amino acid and chloride impurities to avoid the sublimation of Sar-NCAs. With a view towards upscaling into kilogram or ton scale, a new methodology of monomer purification is introduced by utilizing the Meerwein's Salt triethyloxonium tetrafluoroborate to remove chloride impurities by covalent binding and converting chloride ions into volatile products within a single step. The novel straightforward technique enables access to monomers with significantly reduced chloride content (<100 ppm) compared to Sar-NCA derived by synthesis or sublimation. The derived monomers enable the controlled-living polymerization in DMF and provide access to pSar polymers with Poisson-like molecular weight distribution within a high range of chain lengths (Xn 25-200). In conclusion, the reported method can be easily applied to Sar-NCA synthesis or purification of commercially available pSar-NCAs and eases access to well-defined hetero-telechelic pSar polymers. Show less
A single acyloxy group at C-2 can control the outcome of nucleophilic substitution reactions of pyran-derived acetals, but the extent of the neighboring-group participation depends on a number of... Show moreA single acyloxy group at C-2 can control the outcome of nucleophilic substitution reactions of pyran-derived acetals, but the extent of the neighboring-group participation depends on a number of factors. We show here that neighboring-group participation does not necessarily control the stereochemical outcome of acetal substitution reactions with weak nucleophiles. The 1,2-trans selectivity increased with increasing reactivity of the incoming nucleophile. This trend suggests the intermediacy of both cis-fused dioxolenium ions and oxocarbenium ions in the stereochemistry-determining step. In addition, as the electron-donating ability of the neighboring group decreased, the preference for the 1,2-trans products increased. Computational studies show how the barriers for the ring-opening reaction on the dioxolenium ions and the transition states to provide the oxocarbenium ions change with the electron-donating capacity of the C-2-acyloxy group and the reactivity of the nucleophile.Neighboring-group participation by C-2 acyloxy groups can control the 1,2-trans stereoselectivity of acetal substitution reactions with the employment of strong nucleophiles. 1,2-Trans selectivity increases with decreased electron-donating ability of the acyloxy groups at C-2.image. Show less
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... Show moreOxocarbenium 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 combined density functional theory (DFT) and coupled-cluster theory approach. These reactions preferentially proceed following a reaction path where the oxocarbenium ion transforms from a half chair (3H4 or 4H3) to a chair conformation. The introduction of alkoxy substituents on six-membered ring oxocarbenium ions, dramatically influences the conformational preference of the canonical 3H4 and 4H3 conformers, and thereby the stereochemical outcome of the SE2' reaction. In general, we find that the stereoselectivity in the reactions correlates to the "intrinsic preference" of the cations, as dictated by their shape. However, for the C5-CH2OMe substituent, steric factors override the "intrinsic preference", showing a more selective reaction than expected based on the shape of the ion. Our SE2' energetics correlate well with experimentally observed stereoselectivity, and the use of the activation strain model has enabled us to quantify important interactions and structural features that occur in the transition state of the reactions to precisely understand the relative energy barriers of the diastereotopic addition reactions. The fundamental mechanistic insight provided in this study will aid in understanding the reactivity of more complex glycosyl cations featuring multiple substituents and will facilitate our general understanding of glycosylation reactions. Show less
Uronic acids are carbohydrates carrying a terminal carboxylic acid and have a unique reactivity in stereoselective glycosylation reactions. Herein, the competing intramolecular stabilization of... Show moreUronic 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 bridged ions is formed, in which the mixture is driven towards the C-1,C-5 dioxolanium ion when the C-5,C-2-relationship is cis, and towards the formation of the C-1,C-4 dioxepanium ion when this relation is trans. Isomer-population analysis and interconversion barrier computations show that the two bridged structures are not in dynamic equilibrium and that their ratio parallels the density functional theory computed stability of the structures. These studies reveal how the intrinsic interplay of the different functional groups influences the formation of the different regioisomeric products. Show less
Uronic acids are carbohydrates carrying a terminal carboxylic acid and have a unique reactivity in stereoselective glycosylation reactions. Herein, the competing intramolecular stabilization of... Show moreUronic 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 bridged ions is formed, in which the mixture is driven towards the C-1,C-5 dioxolanium ion when the C-5,C-2-relationship is cis, and towards the formation of the C-1,C-4 dioxepanium ion when this relation is trans. Isomer-population analysis and interconversion barrier computations show that the two bridged structures are not in dynamic equilibrium and that their ratio parallels the density functional theory computed stability of the structures. These studies reveal how the intrinsic interplay of the different functional groups influences the formation of the different regioisomeric products. Show less
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 ... Show moreThe 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 trap the desired enzyme, while not being attacked by off-target nucleophiles. We here investigate the intrinsic reactivity of substrates containing a class of widely used electrophilic traps, the three-membered heterocycles with an N- (aziridine), P- (phosphirane), O- (epoxide) and S-atom (thiirane) as heteroatom. Using quantum chemical approaches, we studied the conformational flexibility and nucleophilic ring-opening reaction of a series of model substrates, in which these electrophilic traps are mounted on a cyclohexene scaffold (C6H10Y with Y = NH, PH, O, S). It is revealed that the activation energy of the ring-opening reaction does not necessarily follow the trend that is expected from C-Y leaving-group bond strength, but steeply decreases from NH, to PH, to O, to S. We illustrate that the HOMONu-LUMOSubstrate interaction is an all-important factor for the observed reactivity. In addition, we show that the activation energy of aziridines and phosphiranes can be tuned far below that of the corresponding epoxides and thiiranes by the addition of proper electron-withdrawing ring substituents. Our results provide mechanistic insights to rationally tune the reactivity of this class of popular electrophilic traps and can guide the experimental design of covalent inhibitors and probes for enzymatic activity. Show less
The amino groups of thio- and selenoamides can act as stronger hydrogen-bond donors than of carboxamides, despite the lower electronegativity of S and Se. This phenomenon has been experimentally... Show moreThe amino groups of thio- and selenoamides can act as stronger hydrogen-bond donors than of carboxamides, despite the lower electronegativity of S and Se. This phenomenon has been experimentally explored, particularly in organocatalysis, but a sound electronic explanation is lacking. Our quantum chemical investigations show that the NH2 groups in thio- and selenoamides are more positively charged than in carboxamides. This originates from the larger electronic density flow from the nitrogen lone pair of the NH2 group towards the lower-lying π*C=S and π*C=Se orbitals than to the high-lying π*C=O orbital. The relative energies of the π* orbitals result from the overlap between the chalcogen np and carbon 2p atomic orbitals, which is set by the carbon-chalcogen equilibrium distance, a consequence of the Pauli repulsion between the two bonded atoms. Thus, neither the electronegativity nor the often-suggested polarizability but the steric size of the chalcogen atom determines the amide's hydrogen-bond donor capability. Show less
Hansen, T.; Sun, X.; Dalla Tiezza, M.; Zeist, W.J.; Poater, J.; Hamlin, T.A.; Bickelhaupt, F.M. 2022
We have studied the palladium-mediated activation of C(sp(n))-X bonds (n = 1-3 and X = H, CH3, Cl) in archetypal model substrates H3C-CH2-X, H2C=CH-X and HC equivalent to C-X by catalysts PdLn with... Show moreWe have studied the palladium-mediated activation of C(sp(n))-X bonds (n = 1-3 and X = H, CH3, Cl) in archetypal model substrates H3C-CH2-X, H2C=CH-X and HC equivalent to C-X by catalysts PdLn with L-n = 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 the strength of the bonds increases going from C(sp(3))-X, to C(sp(2))-X, to C(sp)-X. Activation strain and matching energy decomposition analyses reveal that the decreased oxidative addition barrier going from sp(3), to sp(2), to sp, originates from a reduction in the destabilizing steric (Pauli) repulsion between catalyst and substrate. This is the direct consequence of the decreasing coordination number of the carbon atom in C(sp(n))-X, which goes from four, to three, to two along this series. The associated net stabilization of the catalyst-substrate interaction dominates the trend in strain energy which indeed becomes more destabilizing along this same series as the bond becomes stronger from C(sp(3))-X to C(sp)-X. Show less
Fluorescent labeling of biomacromolecules enjoys increasing popularity for structural, mechanistic, and microscopic investigations. Its success hinges on the ability of the dye to alternate between... Show moreFluorescent labeling of biomacromolecules enjoys increasing popularity for structural, mechanistic, and microscopic investigations. Its success hinges on the ability of the dye to alternate between bright and dark states. Forster resonance energy transfer (FRET) is an important source of fluorescence modulation. Photo-induced electron transfer (PET) may occur as well, but is often considered only when donor and acceptor are in van der Waals contact. In this study, PET is shown between a label and redox centers in oxidoreductases, which may occur over large distances. In the small blue copper protein azurin, labeled with ATTO655, PET is observed when the label is at 18.5 angstrom, but not when it is at 29.1 angstrom from the Cu. For Cu-II, PET from label to Cu occurs at a rate of (4.8 +/- 0.3) x 10(4) s(-1) and back at (0.7 +/- 0.1) x 10(3) s(-1). With Cu-I the numbers are (3.3 +/- 0.7) x 10(6) s(-1) and (1.0 +/- 0.1) x 10(4) s(-1). Reorganization energies and electronic coupling elements are in the range of 0.8-1.2 eV and 0.02-0.5 cm(-1), respectively. These data are compatible with electron transfer (ET) along a through-bond pathway although transient complex formation followed by ET cannot be ruled out. The outcome of this study is a useful guideline for experimental designs in which oxidoreductases are labelled with fluorescent dyes, with particular attention to single molecule investigations. The labelling position for FRET can be optimized to avoid reactions like PET by evaluating the structure and thermodynamics of protein and label. Show less
