Evaluating and clustering retrosynthesis pathways with learned strategy

With recent advances in the computer-aided synthesis planning (CASP) powered by data science and machine learning, modern CASP programs can rapidly identify thousands of potential pathways for a given target molecule. However, the lack of a holistic pathway evaluation mechanism makes it challenging to systematically prioritize strategic pathways except for using some simple heuristics. Herein, we introduce a data-driven approach to evaluate the relative strategic levels of retrosynthesis pathways using a dynamic tree-structured long short-term memory (tree-LSTM) model. We first curated a retrosynthesis pathway database, containing 238k patent-extracted pathways along with ∼55 M artificial pathways generated from an open-source CASP program, ASKCOS. The tree-LSTM model was trained to differentiate patent-extracted and artificial pathways with the same target molecule in order to learn the strategic relationship among single-step reactions within the patent-extracted pathways. The model achieved a top-1 ranking accuracy of 79.1% to recognize patent-extracted pathways. In addition, the trained tree-LSTM model learned to encode pathway-level information into a representative latent vector, which can facilitate clustering similar pathways to help illustrate strategically diverse pathways generated from CASP programs.

Tree-structured long short-term memory neural model learns to understand the retrosynthesis design strategies from patent-extracted retrosynthetic pathway data.     

‘Sugaring’ carbosilane dendrimers via hydrosilylation

Two new pathways to introduce carbohydrate derivatives into dendritic carbosilane structures were explored. Pathway one utilised alcoholysis of a chlorosilane with a protected hydroxyethyl glycoside resulting in Si-O linkages. Pathway two proceeds via a hydrosilylation reaction of a protected allyl glycoside with a carbosilane containing Si-H end groups in the presence of a platinum catalyst, thus leading to Si-C linked structures.     

EXCITATION ENERGY TRANSFER IN THE CRYPTOPHYTES. FLUORESCENCE EXCITATION SPECTRA AND PICOSECOND TIME-RESOLVED EMISSION SPECTRA OF INTACT ALGAE AT 77 K

Excitation spectra of chlorophyll- a (Chl- a ) fluorescence in intact cells of Cryptomonas ovata, Chroomonas pauciplastida and Chroomonas salina were determined at 77 K. For all species the excitation spectra for emission from Chl- a associated with photosystem II (PSII) showed increased contributions by a carotenoid (493 nm) and phycobiliproteins, and decreased contributions by carotenoid (417 nm, 505 nm) and Chl- a (445 nm) as compared to excitation spectra for emission from Chl- a associated with photosystem I (PSI). Excitation spectra of C. salina and C. ovata showed an increased contribution by Chl- c ² to PSII Chl- a fluorescence emission. In all three species the absorbance band positions of Chl- a , as determined from the excitation spectra, were similar to those previously described in green plants. green algae and phycobilisome-containing organisms. Time-resolved 77 K fluorescence emission spectra of C. ovata and C. salina showed successive emission from both phycoerythrin and Chl- c ², PSII Chl- a , and PSI Chl- a. C. pauciplastida showed successive emission from phycocyanin, PSII Chl- a , and PSI Chl- a. Spectral red-shifts with time were observed for the phycobiliprotein peaks in all three species. The fluorescence decay of phycoerythrin in C. ovata and C. salina was faster than that of phycocyanin in C. pauciplastida. The results are discussed in relation to the organization of the antenna pigments of PSII and PSI in the cryptophyte algae.     

Excited-state characters and dynamics of [W(CO)(5)(4-cyanopyridine)] and [W(CO)(5)(piperidine)] studied by picosecond time-resolved IR and resonance Raman spectroscopy and DFT calculations: roles of W --> L and W --> CO MLCT and LF excited states revised

The characters, dynamics, and relaxation pathways of low-lying excited states of the complexes [W(CO)(5)L] [L = 4-cyanopyridine (pyCN) and piperidine (pip)] were investigated using theoretical and spectroscopic methods. DFT calculations revealed the delocalized character of chemically and spectroscopicaly relevant molecular orbitals and the presence of a low-lying manifold of CO pi-based unoccupied molecular orbitals. Traditional ligand-field arguments are not applicable. The lowest excited states of [W(CO)(5)(pyCN)] are W --> pyCN MLCT in character. They are closely followed in energy by W --> CO MLCT states. Excitation at 400 or 500 nm populates the (3)MLCT(pyCN) excited state, which was characterized by picosecond time-resolved IR and resonance Raman spectroscopy. Excited-state vibrations were assigned using DFT calculations. The (3)MLCT(pyCN) excited state is initially formed highly excited in low-frequency vibrations which cool with time constants between 1 and 20 ps, depending on the excitation wavelength, solvent, and particular high-frequency nu(CO) or nu(CN) mode. The lowest excited states of [W(CO)(5)(pip)] are W --> CO MLCT, as revealed by TD-DFT interpretation of a nanosecond time-resolved IR spectrum that was measured earlier in a low-temperature glass (Johnson, F. P. A.; George, M. W.; Morrison, S. L.; Turner, J. J. J. Chem. Soc., Chem. Commun. 1995, 391-393). MLCT(CO) excitation involves transfer of electron density from the W atom and, to a lesser extent, the trans CO to the pi orbitals of the four cis CO ligands. Optical excitation into MLCT(CO) transition of either complex in fluid solution triggers femtosecond dissociation of a W-N bond, producing [W(CO)(5)(solvent)]. It is initially vibrationally excited both in nu(CO) and anharmonicaly coupled low-frequency modes. Vibrational cooling occurs with time constants of 16-22 ps while the intramolecular vibrational energy redistribution from the v = 1 nu(CO) modes is much slower, 160-220 ps. No LF excited states have been found for the complexes studied in a spectroscopically relevant range up to 6-7 eV. It follows that spectroscopy, photophysics, and photochemistry of [W(CO)(5)L] and related complexes are well described by an interplay of close-lying MLCT(L) and MLCT(CO) excited states. The high-lying LF states play only an indirect photochemical role by modifying potential energy curves of MLCT(CO) states, making them dissociative.     

Bromination of 2,1,3-benzothiadiazoles

The bromination of 2,1,3-benzothiadiazoles in 47% hydrobromic acid at elevated temperature has led to a general preparative method for the synthesis in high yield of otherwise difficulty accessible brominated 2,1,3-benzothiadiazoles. The typical addition reaction is apparently eliminated under these reaction conditions and substitution takes place exclusively. Bromination of 2,1,3-benzothiadiazole occurs successively at positions 4 and 7. 4-Substituted 2,1,3-benzothia-diazoles are selectively brominated at position 7. 5-Bromo- and 5-methyl-2,1,3-benzothiadiazole are brominated consecutively at positions 4 and 7.     

Universal quenching of common fluorescent probes by water and alcohols

Although biological imaging is mostly performed in aqueous media, it is hardly ever considered that water acts as a classic fluorescence quencher for organic fluorophores. By investigating the fluorescence properties of 42 common organic fluorophores recommended for biological labelling, we demonstrate that H₂O reduces their fluorescence quantum yield and lifetime by up to threefold and uncover the underlying fluorescence quenching mechanism. We show that the quenching efficiency is significantly larger for red-emitting probes and follows an energy gap law. The fluorescence quenching finds its origin in high-energy vibrations of the solvent (OH groups), as methanol and other linear alcohols are also found to quench the emission, whereas it is restored in deuterated solvents. Our observations are consistent with a mechanism by which the electronic excitation of the fluorophore is resonantly transferred to overtones and combination transitions of high-frequency vibrational stretching modes of the solvent through space and not through hydrogen bonds. Insight into this solvent-assisted quenching mechanism opens the door to the rational design of brighter fluorescent probes by offering a justification for protecting organic fluorophores from the solvent via encapsulation.

Overtones and combinations of O–H vibrations in the solvent efficiently quench red-emitting fluorophores by resonant energy transfer.     

Evaluation of molecule-microbe interactions with capillary electrophoresis: procedures, utility and restrictions

Understanding the interactions between molecules and living organisms is of paramount importance for the evaluation of pharmaceutical activity, chemical toxicity and all manner of microbiological studies. The capability of capillary electrophoresis (CE) in the evaluation of molecule-microbe interactions is examined in the present paper. The fundamental chemical concept of the binding or association constant for molecular systems measured in free solution is discussed for biological systems where microorganisms uptake or associate with molecules from their environment. The heterogeneity of the living organisms must be understood and accounted for including differences related to semantics such as concentration units and the nature of the associations between two entities and large differences in the size and number of microorganisms as compared to molecules. Finally, the added complexity and even inhomogeneity of a cell compared to most molecular systems must be considered and possibly controlled. The binding of specific molecules to viruses is discussed. CE can be utilized to quickly determine if a molecule binds very strongly or not at all to a cell (i.e., a binary yes/no answer). This could be useful for initial high-throughput screening purposes when using capillary arrays, for example. CE can be useful for determining unusual (large) molecule/microbe stoichiometries. Finally, CE can sometimes be used to determine the size of binding constants (K(RL)) within certain limits provided experimental conditions can be formulated that minimize problems of biological heterogeneity.     

A novel general route for the preparation of enantiopure imidazolines

A novel procedure for the preparation of enantiopure 1,4-disubstituted 2-imidazolines is reported. Enantiopure beta-amino alcohols are converted into N-hydroxyethylamides, which are reacted with excess thionyl chloride, or with thionyl chloride followed by phosphorus pentachloride to yield N-chloroethylimidoyl chlorides. These intermediates are treated with amines and anilines to produce N-chloroethylamidines, which are converted into imidazolines upon workup with aqueous hydroxide. The method is simple and efficient and has been used to prepare a wide variety of enantiopure imidazolines, in a modular fashion, from readily available amino alcohols.