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 ΔΔG‡ 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). This translates into a >50% improvement in relative ΔG‡ from 0.9 to 1.4 kcal mol-1. We underscore the transformative potential of machine learning in accelerating catalyst design because we rely on a manageable small data set and a key-intermediate graph representing a combination of catalyst and substrate graphs in lieu of a transition-state model. Our results highlight the synergy of synthetic chemistry and data-centric approaches and provide a blueprint for future catalyst optimization.

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.e., atrazine, was suppressed in MSI investigations of earthworm tissue sections. Herbicide accumulation in earthworms was investigated by time-of-flight secondary ion mass spectrometry and matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). Additionally, earthworm tissue sections without accumulation of atrazine but with a homogeneous spray deposition of the herbicide were analyzed to highlight region-specific ion suppression. Furthermore, the relationship of signal intensity and GB in binary mixtures of lipids, amino acids, and atrazine was investigated in both MSI techniques. The GB of atrazine was determined experimentally through a linear plot of the obtained intensity ratios of the binary amino acid mixtures, as well as theoretically. The GBs values for atrazine of 896 and 906 kJ/mol in ToF-SIMS and 933 and 987 kJ/mol in MALDI-MSI were determined experimentally and that of 913 kJ/mol by quantum mechanical calculations. Compared with the GB of a major lipid component, phosphatidylcholine (GBPC = 1044.7 kJ/mol), atrazine's experimentally and computationally determined GBs in this work are significantly lower, making it prone to ion suppression in biological samples containing polar lipids.

Preparation and Spectroscopic Identification of the Cyclic CO2 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. We further assert our spectroscopic assignments by 18O isotopic labeling and high-level N-electron valence state perturbation theory and coupled-cluster computations. The successful isolation of 1,2-dioxetanedione supports its viability as the postulated high-energy intermediate in the well-known and ubiquitously exploited "peroxyoxalate" chemiluminescent system.

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. To address the need for fast and accurate electronic energies of larger systems, we created a database of around 8000 small organic monomers (2000 dimers) optimized at the B3LYP-D3(BJ)/cc-pVTZ level of theory. This database also includes single-point energies computed at various levels of theory, including PBE1PBE, ωΒ97Χ, M06-2X, revTPSS, B3LYP, and BP86, for density functional theory as well as DLPNO-CCSD(T) and CCSD(T) for coupled cluster theory, all in conjunction with a cc-pVTZ basis. We used this database to train machine learning models based on graph neural networks using two different graph representations. Our models are able to make energy predictions from B3LYP-D3(BJ)/cc-pVTZ inputs to CCSD(T)/cc-pVTZ outputs with a mean absolute error of 0.78 and to DLPNO-CCSD(T)/cc-pVTZ with an mean absolute error of 0.50 and 0.18 kcal mol-1 for monomers and dimers, respectively. The model for dimers was further validated on the S22 database, and the monomer model was tested on challenging systems, including those with highly conjugated or functionally complex molecules.

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. However, high-level computations, often using coupled cluster theory, are generally resource-intensive. To expedite the process using machine learning techniques, we generated a database of energies for small organic molecules at the CCSD(T)/cc-pVDZ, CCSD(T)/aug-cc-pVDZ, and CCSD(T)/cc-pVTZ levels of theory. Leveraging the power of deep learning by employing graph neural networks, we are able to predict the effect of perturbatively included triples (T), that is, the difference between CCSD and CCSD(T) energies, with a mean absolute error of 0.25, 0.25, and 0.28 kcal mol-1 (R2 of 0.998, 0.997, and 0.998) with the cc-pVDZ, aug-cc-pVDZ, and cc-pVTZ basis sets, respectively. Our models were further validated by application to three validation sets taken from the S22 Database as well as to a selection of known theoretically challenging cases.

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

We report the synthesis and absolute configuration of monodeuterated cis-perhydroazulene (d1-1), 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 cis-fused bicyclic system in d1-1. 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 d1-1.

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, 0.01 M CaCl2 solution, and aqueous soil extracts, using both spectrofluorometric and tensiometric methods. Additionally, eight organic model compounds were employed at concentrations of 15 mg C L-1 as background solutes in order to test the effect of dissolved organic carbon (DOC) on CMCs. Results found CMCs decreased with an increasing length of the alkyl chain from 188 mM for BAC-C8 to 0.1 mM for BAC-C18. Both methods yielded similar results for measurements in water and CaCl2 solution; however, the spectrofluorescence method did not work for soil extracts due to fluorescence quenching phenomena. In soil extracts, CMCs of BAC-C12 were reduced below 3.7 mM, while the CMC reduction in soil extracts was less pronounced for BAC-C16. Besides ionic strength, molecular structures of BACs and dissolved organic compounds also affected the CMC. The number of carboxyl groups and small molecular weights of the DOC model compounds reduced the CMCs of BAC-C12 and BAC-C16 at pH 6. This study highlights that CMCs can be surpassed in soil solution, pore waters of sediments, or other natural waters even at (small) concentrations of QAACs typically found in the environment.

Absolute Configuration of trans-Perhydroazulene.

We present the absolute configuration (AC) determination of an alkane, trans-perhydroazulene (1), that displays the naturally very common trans fused [5,7] ring system. We outline the first synthesis yielding enantiopure 1 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 (R,R)-(+)-1.

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 p-nitrobenzaldehyde dithiane isolated in solid dinitrogen (N2) or Ar at cryogenic temperatures. A spin-forbidden reaction with triplet dioxygen (3O2) does not occur. The dithiane of o-nitrobenzaldehyde rather undergoes a series of rearrangements under the same conditions, resulting in overall photodeprotection.

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 13C-substitution of the carbene atom in methylhydroxycarbene (H3C-C̈-OH) in its [1,2]H-tunneling shift reaction to acetaldehyde (H3C-CHO). Our study employs matrix-isolation IR spectroscopy in various inert gases and quantum chemical computations. Depending on the choice of the matrix host gas, the KIE varies within a range of 1.0 in xenon to 1.4 in neon. A KIE of 1.1 was computed using the Wentzel-Kramers-Brillouin (WKB) CVT/SCT, and instanton approaches for the gas phase at the B3LYP/cc-pVTZ level of theory. Computations with explicit consideration of the noble gas environment indicate that the surrounding atoms influence the tunneling reaction barrier height and width. The tunneling half-lives computed with the WKB approach are in good agreement with the experimental results in the different noble gases.

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. Unexpectedly, the tunneling product is different from o-nitrosobenzoic acid formed in the photoprocess: Once prepared by irradiation, the ketene spontaneously rearranges to an isoxazolone via an intriguing mechanism initiated by H-tunneling. CCSD(T)/cc-pVTZ computations reveal that this isoxazolone is neither thermodynamically nor kinetically favored under the experimental conditions, and that formation of this unique tunneling product constitutes a remarkable and new example of tunneling control.

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-d3-methylcarbene undergoes ring expansion to 1-d3-methylcyclobutene. This predicted change in reactivity constitutes the first example of a kinetic isotope effect that discriminates between the formation of two products.

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 1 H, 6 Li, 13 C, and 29 Si NMR spectra showed 5 to form a dimer 52 in tetrahydrofuran and diethylether, while addition of tetramethylethylenediamine stabilizes a monomer 51 . A monomer-dimer equilibrium exists with K at 230 K = 1.25 and ΔG230o = -0.43 kJ mol-1 . Homonuclear 6 Li,6 Li coupling of 0.25 ± 0.07 Hz in the dimer was detected by a 1D-6 Li,6 Li INADEQUATE experiment, and scalar 6 Li,13 C coupling constants were obtained from 13 C satellites in the 6 Li spectrum, from 13 C multiplet simulation and 6 Li,13 C-HMQC spectra. In addition, structures and coupling constants of 51 and 52 were calculated by density functional theory (DFT) methods. It was found that the magnitude of the 6 Li,13 C spin-spin interactions shows an inverse correlation with the C-Li bond lengths. The intra-aggregate exchange in the dimer, caused by 180° rotation of one monomer unit within the solvent cage, was studied by 6 Li DNMR and line shape analysis and yielded ΔG298≠ = 60 ± 3 kJ mol-1 ; ΔH≠ = 84 ± 3 kJ mol-1 ; ΔS≠ = 80 ± 3 J mol-1 K-1 for this process. Copyright © 2015 John Wiley & Sons, Ltd.

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. For this purpose, we selectively prepared both enantiomers of (2) H6 -1 through a concise synthesis utilizing multifunctional intermediates. While NMR spectroscopy in chiral aligned media could be used to characterize the precursors to (2) H6 -1, the final assignment could only be accomplished with VCD spectroscopy, despite the fleetingly small dichroic properties of 1. Both enantiomers were assigned by matching the VCD spectra with those computed with density functional theory.

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.

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 0.0 (1cTc), 2.6 (1cTt), and 4.0 (1tTt) kcal mol(-1). A 1tTt → 1cTt → 1cTc isomerization cascade was observed with half-lives (t1/2) in different matrix sites ranging from 30 to 360 h, even though the sequential barriers of 9.7 and 10.4 kcal mol(-1) are much too high to be surmounted thermally under cryogenic conditions. A general mathematical model was developed for the complex kinetics of a reaction cascade with species in distinct matrix sites. With this model, a precise, global nonlinear least-squares fit was achieved simultaneously on the temporal profiles of nine IR bands of the 1cTc, 1cTt, and 1tTt rotamers. Classes of both fast (t(1/2) = 30-50 h) and slow (t(1/2) > 250 h) matrix sites were revealed, with the decay rate of the former in close agreement with first-principles computations for the conformational tunneling rates of the corresponding isolated molecules. Rigorous kinetic and theoretical analyses thus show that a "domino" tunneling mechanism is at work in these oxalic acid transformations.

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. The conversion rates sensitively depend on the choice of matrix material and the tunneling half-lives range from a few hours to several days and are higher in Ne than in Ar for glyoxylic, pyruvic, and cyclopropylglyoxylic acid. The advent of tunneling in α-ketocarboxylic acids dominates their conformational preferences and conceivably also the reactivity of biologically and pharmacologically relevant acid congeners.

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. P2D-IR spectroscopy allows structure determination by measuring the angles between vibrational transition dipole moments. The high time resolution makes P2D-IR spectroscopy an attractive method for structure determination in the presence of fast exchange and for short-lived intermediates. The ubiquity of vibrations in molecules ensures broad applicability of the method, particularly in cases in which NMR spectroscopy is challenging due to a low density of active nuclei. Here we illustrate the strengths of P2D-IR by determining the conformation of a Diels-Alder dienophile that carries the Evans auxiliary and its conformational change induced by the complexation with the Lewis acid SnCl(4), which is a catalyst for stereoselective Diels-Alder reactions. We show that P2D-IR in combination with DFT computations can discriminate between the various conformers of the free dienophile N-crotonyloxazolidinone that have been debated before, proving antiperiplanar orientation of the carbonyl groups and s-cis conformation of the crotonyl moiety. P2D-IR unequivocally identifies the coordination and conformation in the catalyst-substrate complex with SnCl(4), even in the presence of exchange that is fast on the NMR time scale. It resolves a chelate with the carbonyl orientation flipped to synperiplanar and s-cis crotonyl configuration as the main species. This work sets the stage for future studies of other catalyst-substrate complexes and intermediates using a combination of P2D-IR spectroscopy and DFT computations.

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.