Leveraging Limited Experimental Data with Machine Learning: Differentiating a Methyl from an Ethyl Group in the Corey-Bakshi-Shibata Reduction.

We present a case study on how to improve an existing metal-free catalyst for a particularly difficult reaction, namely, the Corey-Bakshi-Shibata (CBS) reduction of butanone, which constitutes the classic and prototypical challenge of being able to differentiate a methyl from an ethyl group. As there are no known strategies on how to address this challenge, we leveraged the power of machine learning by constructing a realistic (for a typical laboratory) small, albeit high-quality, data set of about 100 reactions (run in triplicate) that we used to train a model in combination with a key-intermediate graph (of substrate and catalyst) to predict the differences in Gibbs activation energies ΔΔ of the enantiomeric reaction paths. With the help of this model, we were able to select and subsequently screen a small selection of catalysts and increase the selectivity for the CBS reduction of butanone to 80% enantiomeric excess (ee), the highest possible value achieved to date for this substrate with a metal-free catalyst, thereby also exceeding the best available enzymatic systems (64% ee) and the selectivity with Corey's original catalyst (60% ee).

Lipid-related ion suppression on the herbicide atrazine in earthworm samples in ToF-SIMS and matrix-assisted laser desorption ionization mass spectrometry imaging and the role of gas-phase basicity.

In mass spectrometry imaging (MSI), ion suppression can lead to a misinterpretation of results. Particularly phospholipids, most of which exhibit high gas-phase basicity (GB), are known to suppress the detection of metabolites and drugs. This study was initiated by the observation that the signal of an herbicide, i.

Preparation and Spectroscopic Identification of the Cyclic CO Dimer 1,2-Dioxetanedione.

We report the preparation and infrared spectroscopic identification of 1,2-dioxetanedione, which is one of the two possible cyclic dimers of carbon dioxide. We prepared this hitherto experimentally incompletely characterized species in a solid nitrogen matrix at 3 K from the reaction of oxalyl dichloride with the urea·hydrogen peroxide complex. Surprisingly, irradiation at 254 nm does not lead to its dissociation into carbon dioxide but rather yields cyclic carbon trioxide.

Machine Learning for Bridging the Gap between Density Functional Theory and Coupled Cluster Energies.

Accurate electronic energies and properties are crucial for successful reaction design and mechanistic investigations. Computing energies and properties of molecular structures has proven extremely useful, and, with increasing computational power, the limits of high-level approaches (such as coupled cluster theory) are expanding to ever larger systems. However, because scaling is highly unfavorable, these methods are still not universally applicable to larger systems.

Machine Learning of Coupled Cluster (T)-Energy Corrections via Delta (Δ)-Learning.

Accurate thermochemistry is essential in many chemical disciplines, such as astro-, atmospheric, or combustion chemistry. These areas often involve fleetingly existent intermediates whose thermochemistry is difficult to assess. Whenever direct calorimetric experiments are infeasible, accurate computational estimates of relative molecular energies are required.

Breaking the Symmetry of a Compound by Isotopic Substitution: Synthesis and Stereochemical Assignment of Monodeuterated -Perhydroazulene.

We report the synthesis and absolute configuration of monodeuterated -perhydroazulene (-), which is a rare example of an isotopically chiral hydrocarbon whose synthesis and stereochemical analysis are known to be particularly difficult. The synthesis features nickel-boride-catalyzed deuteration that allowed formation of the diastereomerically pure -fused bicyclic system in -. The vibrational circular dichroism results are in excellent agreement with the computed spectrum at ωB97XD/aug-cc-pVTZ, allowing unambiguous assignment of the absolute configuration of -.

Soil water solutes reduce the critical micelle concentration of quaternary ammonium compounds.

Quaternary alkyl ammonium compounds (QAACs) are produced in large quantities for use as surfactants and disinfectants and also found in soils, sediments, and surface waters, where they are potentially involved in the selection of antibiotic resistance genes. Micelle formation influences fate and effects of QAACs. The critical micelle concentration (CMC) of six homologs of benzylalkylammonium chlorides (BAC) was determined in deionized water, 0.

Absolute Configuration of -Perhydroazulene.

We present the absolute configuration (AC) determination of an alkane, -perhydroazulene (), that displays the naturally very common trans fused [5,7] ring system. We outline the first synthesis yielding enantiopure and the application of optical rotatory dispersion (ORD) and vibrational circular dichroism (VCD) techniques. The spectroscopic results are in excellent agreement with the computed ORD at B3LYP/6-311++G(2d,2p) and the computed VCD spectrum at B3LYP/6-311++G(d,p), providing an assignment of the AC as (,)-(+)-.

Capture and Reactivity of an Elusive Carbon-Sulfur Centered Biradical.

The initial oxidation product of dimethyl sulfide in the marine boundary layer, the methyl thiomethyl radical, has remained elusive. A structurally analogous biradical with one radical center in the α-position to a sulfur atom could now be obtained by UV irradiation of -nitrobenzaldehyde dithiane isolated in solid dinitrogen (N) or Ar at cryogenic temperatures. A spin-forbidden reaction with triplet dioxygen (O) does not occur.

Making Glycine Methyl Ester Chiral.

We demonstrate that the simple achiral amino acid glycine as its methyl ester inherits the chiral imprint of methyl lactate upon complexation, resulting in induced vibrational optical activity of the methylene C-H bonds. To mimic conditions of ice on comets that are considered long-term reaction as well as storage entities for (organic) molecules, we employ the matrix isolation technique in conjunction with vibrational circular dichroism spectroscopy and DFT computations. The observed chirality transfer is likely a key element for the realization of concepts rationalizing chirogenesis, that is, the generation of a chiral imbalance.

Heavy Atom Secondary Kinetic Isotope Effect on H-Tunneling.

Although frequently employed, heavy atom kinetic isotope effects (KIE) have not been reported for quantum mechanical tunneling reactions. Here we examine the secondary KIE through C-substitution of the carbene atom in methylhydroxycarbene (HC-C̈-OH) in its [1,2]H-tunneling shift reaction to acetaldehyde (HC-CHO). Our study employs matrix-isolation IR spectroscopy in various inert gases and quantum chemical computations.

Isotope-Controlled Selectivity by Quantum Tunneling: Hydrogen Migration versus Ring Expansion in Cyclopropylmethylcarbenes.

Using the tunneling-controlled reactivity of cyclopropylmethylcarbene, we demonstrate the viability of isotope-controlled selectivity (ICS), a novel control element of chemical reactivity where a molecular system with two conceivable products of tunneling exclusively produces one or the other, depending only on isotopic composition. Our multidimensional small-curvature tunneling (SCT) computations indicate that, under cryogenic conditions, 1-methoxycyclopropylmethylcarbene shows rapid H-migration to 1-methoxy-1-vinylcyclopropane, whereas deuterium-substituted 1-methoxycyclopropyl-d-methylcarbene undergoes ring expansion to 1-d-methylcyclobutene. This predicted change in reactivity constitutes the first example of a kinetic isotope effect that discriminates between the formation of two products.

Formation of a Tunneling Product in the Photorearrangement of o-Nitrobenzaldehyde.

The photochemical rearrangement of o-nitrobenzaldehyde to o-nitrosobenzoic acid, first reported in 1901, has been shown to proceed via a distinct ketene intermediate. In the course of matrix isolation experiments in various host materials at temperatures as low as 3 K, the ketene was re-investigated in its electronic and vibrational ground states. It was shown that hitherto unreported H-tunneling dominates its reactivity, with half-lives of a few minutes.

Synthesis and Stereochemical Assignment of Crypto-Optically Active (2) H6 -Neopentane.

The determination of the absolute configuration of chiral molecules is at the heart of asymmetric synthesis. Here we probe the spectroscopic limits for chiral discrimination with NMR spectroscopy in chiral aligned media and with vibrational circular dichroism spectroscopy of the sixfold-deuterated chiral neopentane. The study of this compound presents formidable challenges since its stereogenicity is only due to small mass differences.

Preparation of a silanone through oxygen atom transfer to a stable cyclic silylene.

We report the evaporation of a stable cyclic silylene and its oxidation (with ozone or N2 O) through oxygen atom transfer to form the corresponding silanone under matrix isolation conditions. As uncomplexed silanones are rare owing to their very high reactivity, this method provides an alternative route to these sought-after molecules. The silanone, as well as a novel bicyclic silane with a bridgehead silicon atom derived from an intramolecular silylene CH bond insertion, were characterized by comparison of high-resolution infrared spectra with density functional theory (DFT) computations at the M06-2X/cc-pVDZ level of theory.

NMR studies of dilithiostyrenes: aggregation, NMR parameters, and DFT calculations for (E)-1-Lithio-2-(o-lithiophenyl)-1-trimethylsilylethene.

The dilithio compound (E)-1-lithio-2-(o-lithiophenyl)-1-trimethylsilylethene (5) was synthesized from 2-trimethylsilylbenzo-[b]tellurophene (6) with lithium-6 and a detailed analysis of its H, Li, C, and Si NMR spectra showed 5 to form a dimer 5 in tetrahydrofuran and diethylether, while addition of tetramethylethylenediamine stabilizes a monomer 5 . A monomer-dimer equilibrium exists with K at 230 K = 1.25 and ΔG230o = -0.

Domino Tunneling.

Matrix-isolation experiments near 3 K and state-of-the-art quantum chemical computations demonstrate that oxalic acid [1, (COOH)2] exhibits a sequential quantum mechanical tunneling phenomenon not previously observed. Intensities of numerous infrared (IR) bands were used to monitor the temporal evolution of the lowest-energy O-H rotamers (1cTc, 1cTt, 1tTt) of oxalic acid for up to 19 days following near-infrared irradiation of the matrix. The relative energies of these rotamers are 0.

Hydrogen-tunneling in biologically relevant small molecules: the rotamerizations of α-ketocarboxylic acids.

Quantum mechanical tunneling governs the C-O bond rotamerization of simple alkyl and aryl carboxylic acid conformers at cryogenic temperatures. In this study, we report tunneling investigations on a series of electronically different α-ketocarboxylic acids including glyoxylic, pyruvic, cyclopropylglyoxylic, and phenylglyoxylic acid in solid Ar and Ne as host materials at temperatures ranging from 3 to 20 K. The higher-lying rotamers generated through photoirradiation with wavelengths of λ = 313 nm or λ > 850 nm convert to their low-energy conformers through hydrogen-tunneling, as evident from the time evolution of their infrared spectra, and the complete suppression of this process by deuteration.

Two-dimensional infrared spectroscopy reveals the structure of an Evans auxiliary derivative and its SnCl4 Lewis acid complex.

Determining the structure of reactive intermediates is the key to understanding reaction mechanisms. To access these structures, a method combining structural sensitivity and high time resolution is required. Here ultrafast polarization-dependent two-dimensional infrared (P2D-IR) spectroscopy is shown to be an excellent complement to commonly used methods such as one-dimensional IR and multidimensional NMR spectroscopy for investigating intermediates.

Tunnelling control of chemical reactions--the organic chemist's perspective.

Even though quantum mechanical tunnelling has been appearing recurrently mostly in theoretical studies that emphasize its decisive role for many chemical reactions, it still appears suspicious to most organic chemists. Recent experiments in combination with powerful computational approaches, however, have demonstrated that tunnelling must be included to fully understand chemical reactivity. Here we provide an overview of the importance of tunnelling in organic chemical reactions.

σ/σ- And π/π-interactions are equally important: multilayered graphanes.

The properties of single-sheet [n]graphanes, their double-layered forms (diamondoids), and their van der Waals (vdW) complexes (multilayered [n]graphanes) were studied for n = 10-97 at the dispersion-corrected density functional theory (DFT) level utilizing B97D with a 6-31G(d,p) basis set; for comparison, we also computed a series of structures at M06-2X/6-31G(d,p) as well as B3LYP-D3/6-31G(d,p) and evaluated SCS-MP2/cc-pVDZ single-point energies. The association energies for the vdW complexes reach 120 kcal mol(-1) already at 2 nm particle size ([97]graphane dimer), and graphanes adopt layered structures similar to that of graphenes. The association energies of multilayered graphanes per carbon atom are rather similar and independent of the number of layers (ca.

Cyclopropylhydroxycarbene.

Cyclopropylhydroxycarbene was generated by high-vacuum flash pyrolysis of cyclopropylglyoxylic acid at 960 °C. The pyrolysis products were matrix-isolated in solid Ar at 11 K and characterized by means of IR spectroscopy. Upon photolysis, the carbene undergoes ring expansion, thereby paralleling the reactivity of other known cyclopropylcarbenes.

Methylhydroxycarbene: tunneling control of a chemical reaction.

Chemical reactivity is conventionally understood in broad terms of kinetic versus thermodynamic control, wherein the decisive factor is the lowest activation barrier among the various reaction paths or the lowest free energy of the final products, respectively. We demonstrate that quantum-mechanical tunneling can supersede traditional kinetic control and direct a reaction exclusively to a product whose reaction path has a higher barrier. Specifically, we prepared methylhydroxycarbene (H(3)C-C-OH) via vacuum pyrolysis of pyruvic acid at about 1200 kelvin (K), followed by argon matrix trapping at 11 K.

Light- and heavy-atom tunneling in rearrangement reactions of cyclopropylcarbenes.

We investigated both light- and heavy-atom tunneling in the rearrangements of a series of cyclopropylcarbenes using canonical variational transition state theory with multidimensional tunneling corrections (CVT/MT) and the Wentzel-Kramers-Brillouin (WKB) formalism. Halogeno- and hydroxy-substituted cyclopropylcarbenes were found not to undergo carbon tunneling owing to wide reaction barriers. However, while carbon tunneling plays a major role in the ring expansion of parent cyclopropylcarbene yielding cyclobutene, cyclopropylmethylcarbene is prone to undergo hydrogen tunneling to give cyclopropylmethylene.

Intramolecular hydroxycarbene C-H-insertion: The curious case of (o-methoxyphenyl)hydroxycarbene.

The first C-H insertion of a hydroxycarbene species in the gas phase has been observed experimentally by means of high vacuum flash pyrolysis (HVFP) and subsequent matrix isolation: (o-Methoxyphenyl)glyoxylic acid gives non-isolable (o-methoxyphenyl)hydroxycarbene upon pyrolysis at 600 °C, which rapidly inserts into the methyl C-H bond. The insertion product, 2,3-dihydrobenzofuran-3-ol, was trapped in an excess of Ar at 11 K and characterized by infrared spectroscopy. The insertion process kinetically outruns the alternative [1,2]H-tunneling reaction to o-anisaldehyde, a type of reaction observed for other hydroxycarbenes.