Chemists behind Lego-like automated synthesis of complex organic molecules have unveiled the next generation of this technology, cutting cycle times down by an order of magnitude from 30 hours to just three. To date, this approach has been limited because each carboncarbon bond-forming step takes about a day, wrote the team led by Martin Burke at the University of Illinois at UrbanaChampaign.

Over the last decade, Burkes group has pioneered this snap-and-go approach to synthesis, weaving together complex organic structures using SuzukiMiyaura cross-coupling reactions and N-methyliminodiacetic acid (Mida)-protected boron as the linchpin.

Burkes Mida ligand was a game-changer, stabilising boronic acids traditionally prone to decomposition due to borons Lewis acidity. By altering borons hybridisation, Mida significantly reduced unwanted reactivity, enabling sequential SuzukiMiyaura reactions for the first time under mild conditions.

The concept, says Burke, was born from a desire to level the playing field when it comes to molecular discovery. There are 8 billion imaginations in the world but, at present, those that can meaningfully participate in the search for tomorrows medicines and materials represent just a fraction of a fraction of a fraction of this greatest natural resource, he says. Automated iterative small molecule synthesis has the potential to democratise molecular innovation and thereby revolutionise the search for the undiscovered small tools that could transform our society.

While Mida was revolutionary, a key limitation of the current platform is the long cycle time of more than one day per carboncarbon bond-forming step resulting from the slow and variable kinetics of the Suzuki cross-coupling reaction. This is at least an order of magnitude slower than analogous, state-of-the-art peptide synthesisers widely used in the pharmaceutical industry.

To bring their synthesiser up to speed, they reported a major overhaul to the platform in which each step of the iterative cycle has been reimagined and re-optimised for speed, efficiency and generality.

Alongside engineering optimisations, key to the synthesisers newfound success is tetramethyl-N-methyliminodiacetic acid (Tida) boronates developed by the Burke group in 2022. Tida boronates are more than 1000 times more stable than their Mida boronate counterparts, explains Burke. This stability allows them to withstand reaction condition optimisations to the SuzukiMiyaura coupling previously reported in the literature, which speeds up the reaction but is not tolerated by Mida boronates.

This system leverages [Tidas] hyperstability, Burke adds, enabling the team to perform cross-couplings in just minutes and accelerating the rate by an order of magnitude per automated carboncarbon bond-forming step.

[This is] an impressive change in efficiency in the automated synthesis of small molecules based on iterative cross couplings, comments Varinder Aggarwal at the University of Bristol who was not involved in the study. It is currently limited to [SuzukiMiyaura] couplings but once it can do other iterative CC bond-forming reactions, it will be even more powerful.

Whether this is significant enough for widespread adoption in the pharmaceutical industry remains to be seen. I am convinced that it will be adopted over time, but there is always resistance to new technology, adds Aggarwal.

Burke also emphasises that this is not the last iteration of this technology. Peptide and oligonucleotide synthesisers revolutionised science, medicine and technology, because their continued improvement was relentlessly improved.

We are very inspired by this history and likewise plan to continue seeking relentless optimisation of this platform until the traditional synthesis bottleneck that currently limits access to small molecule innovation are shattered.

The rest is here:
Super-fast automated synthesis promises to make chemistry accessible to many more - Chemistry World

CTX-M-14 microcrystals offer perfect conditions for mix-and-diffuse experiments

The TapeDrive system26,27,37 was applied to collect serial diffraction data at the beamline P11, PETRA III/DESY, to explore the kinetics and structural intermediates of ligand binding to the -lactamase CTX-M-14. As a result, protein structures with delay times of 5010,000ms and a resolution range of 1.402.04 were obtained. For this purpose, CTX-M-14 microcrystals were mixed with boric acid to initiate the binding process, and diffraction data were collected after distinct pre-set delay times. To monitor the formation of a diester, microcrystals were pre-soaked with boric acid and subsequently mixed with glycerol and again diffraction data were collected after distinct delay times. The obtained data can reveal the time evolution of populations and, as for all mix-and-diffuse serial crystallography data collections, can represent multiple states in one structure. The delay times, the corresponding PDB entries, the obtained diffraction quality and model refinement statistics are summarized in Supplementary Tables1 and 2. In our own unpublished experiments, macro-crystals of CTX-M-14 were soaked with boric acid and diffraction data were collected by conventional rotation crystallography at cryo-conditions. Glycerol was used as a cryo-protectant, and thus the cyclic glycerol boric acid diester (GBE) in the active site described here has been observed (PDB code 8r7m). However, a time-resolved analysis of the processes seemed very intriguing due to the two sequential reactions. To observe the reactions via time-resolved crystallography applying the available TapeDrive setup of CFEL at PETRA III, DESY, the reaction rates needed to be decreased. In terms of pilot investigations, we observed that kcat is reduced approximately twofold at pH 4.5 compared to pH 7.4. Therefore, the relatively low pH 4.5 applied for the crystallization conditions supported the optimization of time-resolved diffraction data collection of CTX-M-14, although it does not correspond to the physiological pH value. The asymmetric unit of CTX-M-14 crystals contains one monomer with the active site region solvent accessible. The Matthews coefficient of the crystals is 2.153/Da, corresponding to a solvent content of 43%. The solvent channels in the crystal lattice allow rapid diffusion of low molecular weight ligands to the active site, scoring the CTX-M-14 crystals to be ideal for time-resolved serial crystallographic investigations, applying the TapeDrive mixing approach27. Furthermore, the small but excellent diffracting crystals of CTX-M-14 with dimensions of 1115m have a relatively small ligand distribution period within the crystal lattice and due to short diffusion times exhibit sharper delay time points compared to larger crystals38. As a reference, the TapeDrive was also used to collect serial data of the native CTX-M-14 crystals. The occupancies of boric acid and its glycerol diester in the active site obtained after different mixing time points were refined and compared to discuss the stepwise rearrangements in the active site in detail below. To avoid correlation of occupancies and B-factors during refinement, care was taken that between datasets of adjacent time points the individual B-factors of the respective ligands did not differ more than the Wilson B-factors and the average B-factors (Supplementary Fig.2).

CTX-M-14 has a crucial anion-binding site (Fig.1) close to the active site residues that is occupied by the carboxylate of -lactam substrates39. In the native enzyme, this site is occupied by a tetrahedral anion, such as a phosphate (PDB code 4ua640) or a sulfate (PDB code 7q0z13), as in the structures we refined (Figs.1 and 2). In a structure of CTX-M-14 in complex with ixazomib/bortezomib (PDB code 7q11/7q0y13), the inhibitor does not directly occupy the anion-binding site, but still displaces the bulky tetrahedral anion, which is replaced by a smaller chloride to balance the charge13.

a Cartoon plot of the CTX-M-14 -lactamase from Klebsiella pneumoniae and close-up views of the active site in surface representation of b the native constitution with a sulfate ion (SO4-A magenta; SO4-B yellow) in the anion-binding site, c with bound boric acid (BAB, pink) and a sulfate ion, and d with bound glycerol boric acid diester (GBE, pale green). BAB (c) and GBE (d) complex structures are shown with mixing delay times of 10s, respectively.

Stick and cartoon representation (left) as well as 2D-LigPlot+ representation (right) of the active-site amino acid residues highlighting the hydrogen bond network in the native form (a), with bound boric acid (10s, BAB) to Ser70 (b) and with the bound glycerol boric acid diester (10s, GBE) (c). Each equilibrium state is displayed individually without overlapping with the initial states. BAB and GBE oxygen atoms are labeled in red. Potential hydrogen bond distances () are indicated by dashed lines.

The rotationally disordered sulfate occupies two slightly displaced alternative positions in the native enzyme (SO4-A and SO4-B, S to S distance of 0.4, Fig.1). The alternative sulfates (A/B) are coordinated via hydrogen bonds with the side chains of Ser70 (3.1/3.4), Thr235 (3.1/3.3) and Ser237 (3.4/2.8) as well as the main chain nitrogen of Ser237 (3.1/3.2) (Fig.2a). SO4-B forms additional hydrogen bonds with side chains of Ser130 (2.9) and Lys234 (3.2) (Fig.2a). During boric acid binding, the sulfate is reoriented in such a way that it is more distant to the Ser70 side chain and coordinated by hydrogen bonds with the side chain hydroxyl groups of Ser130 (3.1), Thr235 (3.0) and Ser237 (2.9) (Figs.2b and3). In addition, the boric acid O2 (2.6) can act as a hydrogen bond donor for the sulfate. The esterification with glycerol finally displaces the sulfate ion, since the equivalent O2 of the cyclic diester cannot act as a hydrogen bond donor anymore and due to steric competition (Fig.2c). In the electron density maps substantially reduced density is observed at this site (Fig.4). After complete formation of the cyclic diester with boric acid and glycerol, a water molecule (OW357) occupies the position of the anion-binding site. Unlike the sulfate ion, the OW357 can act as a hydrogen bond donor and forms a hydrogen bond with O2 of GBE (2.7). The water molecule OW357 is further stabilized by a hydrogen bond with the hydroxyl group of Thr235 (2.8), as well as a weak hydrogen bond with the main chain carbonyl of Thr235 (3.5).

Polder electron density (contoured at 5 , green mesh) of the active site Ser70, the sulfate ions and bound boric acid are shown at different delay time points after mixing microcrystals with boric acid. The 1h soak structure was obtained with the TapeDrive after microcrystals have been soaked in boric acid for 1h and shows that almost no further increase in electron density is observed after 10s. BAB and GBE oxygen atoms are labeled in red. Potential hydrogen bond distances () are indicated by dashed lines.

Polder electron densities (contoured at 5 , green mesh) of the active site region of CTX-M-14. Microcrystals pre-soaked with boric acid and mixed with glycerol prior to serial diffraction data collection applying the TapeDrive setup at beamline P11, PETRA III/DESY, observing time-resolved the ester bond
formation between glycerol and the Ser70 borate ester. The sulfate anion present in the native conformation is displaced upon binding of GBE and finally replaced by solvent water OW357. BAB and GBE oxygen atoms are labeled in red. Potential hydrogen bond distances () are indicated by dashed lines.

A direct comparison with recently approved inhibitors such as relebactam (PDB code 6qw841) and avibactam (PDB code 6gth42) also shows that utilization of the anion-binding site supports the complex formation. These complexes are stabilized by hydrogen bonds and consequently, the affinity and overall activity of these inhibitors are increased. Accordingly, the sulfonate groups of these new diazabicyclooctane inhibitors occupy the anion-binding site discussed here (Supplementary Fig.3)13. In addition, vaborbactam (PDB code 6v7h43) and taniborbactam (PDB code 6sp612) are bound and coordinated in the active site in a similar way. The carboxylate appendage of their oxaborine or benzooxaborine moieties also occupies the anion-binding site10,12,43. Thus, for inhibition of SBLs, it is evident that the anion-binding site of the native enzyme is occupied by the inhibitor, supporting enhanced binding if inhibitors feature a suitable moiety that can bind in this region (Supplementary Fig.3). This anion-binding site represents a very important structural feature of -lactamases, to be considered in future drug development investigations. In this context, our data are unique, as we show via time-resolved crystallography the time course of the displacement of a sulfate ion from this particularly important binding site.

In addition, the oxyanion hole is utilized by a number of inhibitors forming hydrogen bonds with Ser70 NH and Ser237 NH (see Supplementary Fig.4). Furthermore, these structural features are also used in the binding modes of -lactam substrates such as ceftazidime (Supplementary Fig.4h), as well as in multiple other -lactamases.

The obtained refined time-resolved crystal structures provided insight into the molecular kinetics of the binding of boric acid (Fig.3 and Supplementary Fig.5). Starting from the native CTX-M-14 structure, the above-mentioned sulfate and some water molecules (notably OW174, OW352, OW353 and the catalytic OW10) are present in the active site well-defined in the electron density maps. At a delay time of 50ms after mixing the microcrystals with boric acid initially, no additional electron density for the boric acid was observed. Meanwhile, the electron density of the sulfate ion has already changed, indicating a slight shift between the two alternative locations. Initially, in the native enzyme, the alternative positioned sulfate ions refined to occupancies of 47% and 44% for SO4-A and SO4-B, respectively. These change in the 50ms structure to occupancies of 54% for the SO4-A and 41% for the SO4-B position also indicate that initially the position closer to the Ser70 is preferred before the boric acid will covalently bind to Ser70 OG. After a delay time of 80ms, a weak electron density for the bound boric acid (BAB) was observed in the calculated polder map, with a corresponding occupancy of 35%. At the same time, the sulfate ion in the SO4-B position was reoriented by slight translation and rotation so that an oxygen atom has a distance of 2.6 to the O2 hydroxyl group of BAB (Fig.3). The evaluation of the electron density maps revealed that the hydroxyl groups of BAB occupy approximately the same positions as previously occupied by an oxygen of SO4-A and the two water molecules OW352 and OW353. The calculated occupancy for BAB (Fig.5a, Supplementary Table3) and the corresponding electron density increased with longer delay times after mixing, resulting in a well-defined electron density for BAB in the calculated polder map after only 250ms delay time. At this delay time, the occupancy of BAB is already 49%, whereas the occupancy of SO4-A has dropped to 33%. In the further time course investigated, the occupancy of BAB increases only slightly. After a delay time of 10s, it reaches the maximum occupancy of 53%. Even soaking the CTX-M-14 microcrystals in boric acid for 1h could only increase the occupancy to 57%. This indicates that under these conditions the equilibrium of the BAB formation has been reached.

Plots of BAB (a) and GBE (b) with the refined occupancy values obtained in the context of the respective delay times (no linear display), after mixing with boric acid (BA) or glycerol (GOL). The occupancy of BAB increases with prolonged delay time after mixing with boric acid. Subsequent mixing with glycerol causes the BAB occupancy to decrease again, as it is esterified to GBE. The total boron content continues to increase along mixing with glycerol.

Boric acid binds to the active site of CTX-M-14 (Fig.1c) forming an ester with the Ser70 OG. The hydrogen bonding interactions that stabilize the tetrahedral transition state analog during initial binding include the oxyanion hole (Ser70 NH and Ser237 NH). Similar to the binding mechanism of substrates, the nucleophilic attack of Ser70 OG can be supported via activation of the OG by the general base Lys7344. The unprotonated Lys73 side chain can assist in the nucleophilic attack by acting as a general base thereby accepting the proton from the Ser70 OG when the tetrahedral intermediate is formed. A corresponding proposed reaction pathway is shown in Fig.6. Similar to the carboxylate of the acylenzyme intermediate, one hydroxyl group of boric acid (O1) forms hydrogen bonds with the main chain nitrogen atoms of Ser70 (2.8) and Ser237 (2.8), constituting the oxyanion hole (Fig.2b). In contrast to bortezomib and ixazomib, the remaining two hydroxyl groups of BAB do not form hydrogen bonds with Asn170 and Glu16613 (Supplementary Fig.4). In fact, the boric acid is shifted rather in the opposite direction in the anion-binding site, forcing a reorientation of the sulfate ion from the position of SO4-A to the position of SO4-B (Fig.2b), to prevent too close atomic contacts. The boric acid is further stabilized in this position via hydrogen bond interactions of the BAB hydroxyl group (O2) with the hydroxyl group of Ser130 (3.0) and the sulfate ion (SO4-B, 2.6). The third BAB hydroxyl group (O3) forms a hydrogen bond with the water molecule OW10 (2.8). In all observed time steps OW10 remains well-defined in the same position. This water molecule is well-known as the catalytic water molecule mandatory for the deacylating step in -lactam hydrolysis45, initiated by nucleophilic attack on the carbonyl carbon atom of the acylenzyme complex to hydrolyze the acyl bond. It forms hydrogen bonds with the side chains of Ser70 (2.6), Glu166 (2.6), Asn170 (2.5) and BAB (O3, 2.8) (Fig.7). All these intermolecular interactions ensure that BAB is very well coordinated, e.g. a rotational disorder around the Ser70 borate ester linkage is not observed.

Hydrogen bonds are displayed as dashed lines.

The active site of the (a) bound boric acid and (b) glycerol boric acid diester is shown at the 10s delay time point. OW10 is hydrogen bond donor and acceptor to the boric ester of Ser70 (2.6/2.8). The tetrahedral hydrogen bonding pattern of OW10 is completed by Glu166 (2.6) and Asn170 (2.5). Hydrogen bonds of OW10 to GBE are longer than to BAB (2.8/3.2) while the hydrogen bonding pattern with Glu166 (2.5) and Asn170 (2.6) remains similar. The boron atom is positioned at a distance of 3.0 (BAB,
10s) or 3.4 (GBE, 10s) from the catalytic water OW10. Thus, the catalytic water could perform a nucleophilic attack on the boron atom, leading to the reversible hydrolysis of the boric acid serine ester linkage in BAB and GBE. Potential hydrogen bond distances () are indicated by dashed lines.

After monitoring time-resolved structure and dynamics of boric acid binding in the active site of CTX-M-14, we have further investigated the esterification process of boric acid with glycerol. For this purpose, the TapeDrive setup was used again to mix glycerol with CTX-M-14 microcrystals complexed with boric acid beforehand. We defined the delay time 0ms as the starting condition where no glycerol was added, corresponding to the last time point (1h soak) of the serial data collection with boric acid, considering that CTX-M-14 microcrystals were saturated with boric acid (Fig.4 and Supplementary Fig.6). At this defined time point, the occupancy of BAB was refined to 57%. The first change in the electron density of the polder map appears already at the 50ms mixing/delay point. In the region of the BAB hydroxyl groups extending electron density was observed indicating the formation of a glycerol diester. The obtained electron densities allowed the insertion and refinement of a glycerol boric acid diester (GBE), resulting in a GBE occupancy of 26%, while the BAB occupancy remained almost the same with 55%. This indicated also that the formation of the GBE increases the total occupancy of bound ligand in the active site to 81%. The electron density of the sulfate decreased for SO4-A to zero, as the newly formed glycerol diester occupies this position. The alternatively positioned SO4-B fits into the active site together with the BAB and is therefore still present with the same occupancy as the BAB. The observed electron densities at the 80 and 100ms delay times showed only a slight increase for GBE occupancy. A sharp increase in the corresponding GBE occupancy to 51% was observed and refined at the 150ms time point, while in parallel the BAB occupancy dropped to 35% (Fig.5b, Supplementary Table3). By this time, all atoms of GBE are covered with the calculated polder electron density. At the 750ms time point, the entire GBE was well-fitted and covered in the calculated electron density map with a resulting occupancy of 65%. Consequently, since the GBE can no longer act as a hydrogen bond donor for SO4-B due to the lack of hydrogen atoms at the position O2. The sulfate ion is finally completely replaced by a water molecule, OW357, which is accompanied by an increasing GBE and a decreasing BAB occupancy. This correlates with reduced electron density in the SO4 site. The O3 of GBE can also no longer interact with OW10 as a hydrogen bond donor, but only as a hydrogen bond acceptor. GBE approached a refined occupancy of 67% after only 10s delay time, while BAB occupancy dropped to 21%. However, it is interesting to note that the overall occupancy of the ligands (BAB, GBE) bound to Ser70 increased with the observed increase in electron density obtained and refined for the cyclic diester. Thus, the total occupancy of the binding site and region increased from 57%, obtained for soaking only with boric acid, up to 88% when further mixing with glycerol up to a delay time of 10s. The stepwise blocking of the active site by boric acid and the subsequent glycerol diester formation is shown in Fig.4.

Boric and boronic acids have a propensity to form esters with polyalcohols, resulting in the formation of five- or six-membered rings46,47,48. The observed five-membered scaffold of GBE is reminiscent of the autoinducer-2. This borate diester was first observed in complex with the sensor protein LuxP of the marine bioluminescent bacterium Vibrio harveyi49. The triol glycerol can alternatively form both ring systems, with the formation of a six-membered ring being energetically preferred over the five-membered ring, as shown in a computational study46. The investigation of peptidomimetic-boronic acid inhibitors for flaviviral proteases revealed both, a five-membered ring formation of the boric acid moiety and glycerol in the active site for the West-Nile virus NS2BNS3 protease and a six-membered ring formation for the Zika virus NS2BNS3 protease47,48. Despite the high similarity of these enzymes, both ring formations were observed, clearly showing the influence of the individual active site, resulting in a preference due to steric constraints47,48. In the CTX-M-14 active site, glycerol forms a five-membered cyclic diester with two of the three hydroxyl groups (O2, O3) of boric acid that is bound to the active site Ser70 (Fig.2c). A corresponding proposed reaction pathway is shown in Fig.8. The remaining hydroxyl group (O1) of the boric acid maintains the stabilizing hydrogen bonds with the main chain nitrogen atoms of Ser70 (2.9) and Ser237 (3.0) in the oxyanion hole (Fig.2c). During the esterification the sulfate ion in the anion-binding site is finally replaced by a water molecule (OW357) that forms alternative hydrogen bonds with the cyclic diester O1 (2.7) and the hydroxyl group of Thr235 (2.8) (Fig.2c). The other oxygen of the cyclic diester O3 forms a hydrogen bond with OW10 (3.2), which itself is strongly coordinated by Ser70 (2.8), Glu166 (2.5) and Asn170 (2.7). The remaining free hydroxyl group of GBE (O4) forms an additional hydrogen bond with the amide side chain of Asn132 (3.0) and weak hydrogen bonds with amide side chains of Asn104 (3.5) and Asn170 (3.5) (Fig.2c). In that conformation all oxygen atoms of the GBE are coordinated via hydrogen bonds either directly with the enzyme or via a water molecule. This is probably also the reason for the preference of the five-membered over the six-membered cyclic diester in the CTX-M-14 active site. In a six-membered ring, the free hydroxyl group could not form hydrogen bonds with Asn132 because it would be located in the center of the molecule. In fact, there would probably be no side chain for possible hydrogen bond interactions with the free hydroxyl group in that orientation as it would point out of the active site. Thus, the formation of a hydrogen bond of the free hydroxyl group of GBE with Asn132 is probably the determining factor, explaining our observation of only five-membered cyclic diester formation in all obtained GBE structures.

Hydrogen bonds are displayed as dashed lines.

The central carbon atom of the glycerol diester with boric acid becomes a stereo center with S-configuration. Also, the boron atom of GBE is a stereo center with S-configuration. Both stereocenters are observed without any racemic disorder. This is probably an indication for the specific active site environment of the -lactamase. For example, proteinase K has weak specific substrate preferences and glycerol forms a simple monoester with the boric acid bound to the active site serine (PDB code 2id850). Obviously, the stepwise formation of a monoester and diester is much too fast to be observed with our experimental setup.

As expected, the covalent binding of boric acid and the boric acid diester to the catalytic Ser70 in the active site of CTX-M-14 -lactamase resulted also in the inhibition of the enzyme17,18. Boric acid remains in the active site of the -lactamase in the crystal lattice with an occupancy of 57% even after prolonged soaking. Consequently, it can be concluded that the boric acid diester does not dissociate over time and therefore inhibits the enzyme (in the crystal lattice) for a certain period if the solvent conditions are unchanged. To quantify the effect of the observed occupation of the active site,
enzymatic activity assays applying a photometric determination of the 50% inhibitory concentration (IC50) values were performed. Moderate IC50 values of 2.90.4mM for boric acid and 3.10.4mM for the combination of boric acid with glycerol were determined (Supplementary Fig.7). Interestingly, the IC50 values are quite similar even though the crystallographic data showed a higher occupancy of the GBE in the crystal lattice, which would imply a higher inhibition. Compounds that are considered as inhibitors usually have substantially lower IC50 values, therefore the boric acid and the glycerol diester at this point cannot be considered as effective -lactamase inhibitors. This is in line with the observed incomplete occupancy of the boric acid and its glycerol diester in the crystal structures and the potentially reversible binding of boric acid. The organization of the active site in the endpoint complexes may also indicate that reversible mechanism for the dissociation of the inhibitor. The boron atom is positioned at a distance of 3.0 (BAB, 10s) or 3.4 (GBE, 10s) from the catalytic water OW10 (Fig.7). Thus, the catalytic water is well positioned to perform a nucleophilic attack on the boron atom, leading to the reversible release of boric acid or the GBE. Reversible inhibitors have the advantage of not being depleted or modified by their target, thereby enabling their capacity to inhibit several enzymes during their lifetime. Our data highlight the potential of boric acid derivatives in medicinal chemistry.

Here is the original post:
Time-resolved crystallography of boric acid binding to the active site serine of the -lactamase CTX-M-14 and ... - Nature.com

Nicole Kidman and Zac Efron in A Family Affair. Aaron Epstein/Netflix

In Hollywood, the industrys very particular rules of math state that two attractive movie stars should result in at least a semblance of onscreen chemistry. Its worked for all kinds of bizarre pairings, and it should have worked for Nicole Kidman and Zac Efron, teaming up in A Family Affair for the second time. Kidman is a skilled actor with incredible range and a willingness to take risks on potentially bad projects, and Efron is chiseled, talented and always game for ridiculous comedic scenes centered on self-ridicule. Although separately magnetic and successful in 2012s The Paperboy, together here the actors fumble for any draw.

A FAMILY AFFAIR 1/2(1.5/4 stars) Directed by: Richard LaGravenese Written by: Carrie Solomon Starring: Nicole Kidman, Zac Efron, Joey King, Kathy Bates, Liza Koshy, Wes Jetton, Sherry Cola Running time: 114 mins.

In the film, Efron parodies himself as Chris Cole, a self-absorbed, muscled movie star best known for starring in an action franchise called Icarus Rush. Hes vain, disconnected and apparently hasnt been in a grocery store in decades. He is constantly breaking up with girlfriends with the help of consolation diamond earrings and his assistant Zara (Joey King), a frazzled young woman who wants to be producing movies despite being in her early 20s and having no experience. Chris is so temperamental and childish that he vacillated between threatening to fire Zara and desperately needing her to get him protein powder from the grocery store he cant visit himself.

Zara finally hits her limit with Chris inane antics and quits, reluctantly telling her highly successful writer of a mom Brooke (Kidman) that shes now out of a job. Brooke has been single since the death of Zaras dad, often confiding her woes in her mother-in-law Leila (Kathy Bates), who appears to be some kind of famous photographer. When Chris shows up at Brooke and Zaras house trying to woo Zara back to work, he ends up bondingand drinking tequilawith Brooke. Its an odd dynamic, especially since screenwriter Carrie Solomon and director Richard Lagravenese have already established Chris as a selfish dipshit. Its hard to understand what Brooke, who quotes Greek mythology and is potentially the hottest MILF on planet Earth, sees in him beyond his biceps. But whatever it is, its enough to get them into bed, where Zara immediately discovers them and knocks herself out on the doorway.

The rest of the film is a requisite story about redeeming oneself and making relationships work. You already know the ending without having seen it, although its a moderately entertaining diversion to get there. Brooke gets her groove back (this makes for a good double feature with Anne Hathaways recent rom-com The Idea of You), Chris gets to make a human connection (and go to a grocery store) and Zara gets to skip years of paying her dues to unrealistically ascend the Hollywood ladder. It aims for emotional sincerity in moments and there are some laughs, thanks mostly to King and Efrons dynamic, but its mostly a surface-level fantasy about two successful, pretty people who find love. The hurdle in their way isnt the massive age gap or Chris unwieldy celebrity, but Zaras disapproval and whining. Its all a bit flimsy on paper, although its easier to overlook the gaping cracks in the narrative when youre actually watching Kidman do her thing.

The challenge here is that Kidman and Efron have no spark, which makes it awkward and uncomfortable to witness their coupling. No wonder Zara feels so much ick at the prospect of Brooke and Chris getting together. Its also difficult to reconcile Chriss terrible behavior with him becoming a leading man love interest for a woman as smart and worldly as Brooke. But this is a fantasy where everyone gets what they want, even if that in no way aligns with reality. It worked in The Idea of You, a better version of this story, but here you just want Brooke to find a guy who doesnt need the Icarus myth explained to him. Its ultimately this lack of chemistry that keeps A Family Affair from transcending an existence as a Lifetime movie aired on Netflix.

Read the rest here:
'A Family Affair' Review: Nicole Kidman and Zac Efron Have Zero Sparks - Observer

And all the true fans know that this wasn't Zac and Nicole's first movie together...or even their first time playing love interests. The duo first starred opposite each other in the 2012 thriller The Paperboy. So, here are 15 more celebrity duos that have such great chemistry they've played love interests more than once: 1. Timothe Chalamet and Saoirse Ronan have been in three movies together and played love interests in two: Lady Bird (2017) and Little Women (2019), both directed by Greta Gerwig. 2. Emma Stone and Ryan Gosling have played love interests in all three movies they starred in together: Crazy, Stupid, Love (2011), Gangster Squad (2013), and La La Land (2016). 3. Amy Adams and Christian Bale played opposite each other as love interests in American Hustle (2013) and Vice (2018). 4. Javier Bardem and Penlope Cruz played opposite each other in four movies: Jamn, Jamn (1992), Vicky Cristina Barcelona (2008), Loving Pablo (2017), and Everybody Knows (2018). 5. Adam Sandler and Drew Barrymore have played love interests in three movies: The Wedding Singer (1998), 50 First Dates (2004), and Blended (2014). 6. Jennifer Aniston has also starred alongside Adam Sandler in several movies, and they've played love interests three times in the movies Just Go With It (2011), Murder Mystery (2019), and Murder Mystery 2 (2023). 7. Sanaa Lathan and Omar Epps played love interests in both movies they starred in together: The Wood (1999) and Love & Basketball (2000). 8. Kristen Stewart and Jesse Eisenberg have starred opposite each other as love interests in three movies: Adventureland (2009), American Ultra (2015), and Caf Society (2016). 9. Tom Hanks and Meg Ryan have played love interests in all four movies they've starred in together: Joe Versus the Volcano (1990), Sleepless in Seattle (1993), You've Got Mail (1998), and Ithaca (2015). 10. Jennifer Lawrence and Bradley Cooper have been in four movies together, but only played love interests in two: Silver Linings Playbook (2013) and Serena (2014). 11. Matthew McConaughey and Kate Hudson played opposite each other as love interests in How to Lose a Guy in 10 Days (2003) and Fool's Gold (2008). 12. Kate Winslet and Leonardo DiCaprio have played opposite each other as love interests in Titanic (1997) and Revolutionary Road (2008). 13. Winona Ryder and Keanu Reeves starred as love interests in three of the four movies they've done together: Bram Stokers Dracula (1992), A Scanner Darkly (2006), and Destination Wedding (2018). 14. Eugene Levy and Catherine O'Hara have played a couple in Best in Show (2000), A Might
y Wind (2003), and Schitt's Creek (20152020). 15. Finally, Jennifer Garner and Mark Ruffalo play opposite each other as love interests in 13 Going on 30 (2004) and The Adam Project (2022).

Read this article:
15 Actor Duos With Unmatched On-Screen Chemistry - BuzzFeed

A four-atom bismuth species is the first all-metal ring with aromatic bonding character to have been isolated in the lab. The structure was synthesised by researchers in Germany, who say that their findings raise important questions about the nature of aromaticity in materials composed of heavier elements.

Despite having been studied for almost 200 years, aromaticity remains one of chemistrys most enigmatic phenomena. At school, almost every student will learn about aromatic carbon rings like benzene, but attempts to make analogous compounds entirely from metal atoms have proven much more difficult. In 2001, the aromatic all-metal species Al42 was detected spectroscopically, while the antiaromatic Al44 was detected in 2003. However, the only aromatic metal rings including gallium, gold and thorium species to have been isolated in the lab have needed to be stabilised by covalently bonded non-metal substituents.

Now, a team led by Florian Weigend at Philipps-University Marburg and Lutz Greb at Heidelberg University has isolated a cationic Bi44+ aromatic ring. The species takes the form of a planar rhomboid and is trapped non-covalently between two shells that each feature an indium bromide core bound within a cyclic ligand containing four pyrrole units.

The researchers note that the Bi44+ ring is isoelectronic with the antiaromatic Al44 species. They argue that this suggests that the charge distribution around an ionic aromatic metal ring can influence whether it will take on aromatic or antiaromatic bonding character. The team note that this finding complicates discussions of the Hckel model of aromaticity a concept that they note is valid for second-row elements but less deterministic for the heavier congeners.

Excerpt from:
All-metal aromatic ring isolated for the first time - Chemistry World

Bron Breakker says he really enjoyed working with Baron Corbin during their tag team run in NXT. Breakker and Corbin teamed up as The Wolf Dogs from late last year until they moved to the main roster, and Breakker talked about working with the veteran in an interview with Cameron Hawkins on The Ringer.

Baron and I had hit it off from the get-go, Breakker said (per Fightful). As soon as he came down to NXT, we hit it off immediately. It was really cool for me to be able to get to work with him because obviously, it brought out a different side of me where I was being a little bit more entertaining, just being funny, just goofing off. We both were just loving it and having a great time.

Breakker will face Sami Zayn for the WWE Intercontinental Championship tomorrow at Money in the Bank in Toronto.

Follow this link:
Bron Breakker On His Chemistry With Baron Corbin In NXT: 'We Hit It Off Immediately' - 411mania.com

With the addition of Illinois big man Coleman Hawkins late last month, Kansas State head coach Jerome Tang and his staff wrapped up their roster for the upcoming season. And unlike the previous two years, the coaches got their work done early this year, leaving the rest of the summer for the 10 newcomers on the roster to begin to mesh.

This is the first time weve had our whole roster done in June, Tang said. Our first year, Keyontae (Johnson) didnt show up until August right when school started, and Desi (Sills) didnt get her until October. And then last year, we didnt get a couple of guys until August or September and Will (McNair Jr.) was right after school started. So, were gonna get to spend the whole four weeks in July of workouts with the whole group here. I believe thats gonna make a huge difference in how we develop as a team.

K-State brings in eight Division I transfers, one junior college transfer and one high school recruit to joing senior David NGuessan and sophomore Taj Manning and Macaleab Rich.

Because the Wildcats dont have a large base of returners, the need to create team chemistry among all of the disparate parts becomes even more crucial during this summer period.

It has to happen organically, but we have to create opportunities for it to happen, Tang said. They all live in the same apartment complex. And its 30 seconds from the gym and we spend a lot of time in the gym. We have family dinners. So, were always together in each others homes. We create opportunities for organic chemistry, just for guys to be able to interact with each other in different situations. Its our job to connect with our players hearts.

And once you connect with their hearts, you can get them to understand or at least youll understand where theyre coming from to help them get to where they want to get to.

The rosters make up features multiple athletic and versitile bigs, led by Hawkins along with Daivd NGuessan, Achor Achor (Samford) and Ugonna Onyenso (Kentucky) and Baye Fall (Arkansas).

When NaeQwan Tomlin was dismissed from the team in the middle of last season, K-State found itself short on reliable big men. That should not be an issue this season.

The way the game is played now, the really talented bigs who want to play in the NBA have to play in the 5-out type offenses and do multiple things, Tang said. They no longer just let guys stand on the block anymore. So, knowing the type of talent we wanted to attract, we had to run an offense that fits that personnel.

We can help them get to where they want to get to and because weve done that (in the past) and its given us this opportunity to be able to recruit guys like Coleman, Achor (Achor) and Ugonna (Onyenso).

See the rest here:
Tang looks to build team chemistry after roster completion - The Mercury - Manhattan, Kansas

Our strategy drew inspiration from our electrochemical hypervalent iodine-mediated syn-difluorination of alkenes14, where two fluorides sequentially invert a proposed iodonium intermediate (Fig. 1d). Electrochemical oxidation of iodotoluene provides a controllable and sustainable method for the generation of the difluoro(tolyl)-3-iodane (IF2) mediator. Switching the electrochemical oxidation off and then adding in the substrate (ex-cell approach) was found to better facilitate tolerance to oxidatively sensitive substrates that contain electron-rich functionality14,22,23,24. This is because there is no residual oxidant in solution to decompose the substrate. Wishing to exploit the same electron-rich chemical space, we adopted the ex-cell electrochemical method for generating IF2 and deliberately chose oxidatively sensitive 1a as the model substrate (Fig. 2a). This substrate deliberately contains an unactivated acyclic internal alkene, which is an underexplored alkene-type in fluoro- or chloro-functionalization reactions25,26,27,28,29,30. Adapting our difluorination conditions by adding an excess of various R4N+ chloride salts to a solution of 1a and IF2 in 5.6HF:amine (1:1 (v/v) mixture of 3HFNEt3 and 9HFpy) in dichloromethane (DCM)hexafluoroisopropanol at room temperature led predominately to alkene dichlorination. Without hexafluoroisopropanol, the use of 1equiv. of chloride provided more selective conditions but, surprisingly, not for the expected syn-addition product, 1d or 1e, rather to the anti-addition product, 1b. Nevertheless, we observed six out of the eight possible products (1g and 1h were not observed) (Fig. 2a), confirming the substantial challenge of controlling chemo-, regio-, and diastereoselectivity in the reaction.

For full details, see Supplementary Tables 15. a, Challenges with NuNu chlorofluorination to control chemo-, regio- and diastereoselectivity. Reaction of model compound 1a to products 1bi (n/o, not observed) using the ex-cell electrochemical approach. b, Chemoselectivity with different chloride sources. c, Temperature dependence on regioselectivity for anti-addition. d, Diastereoselectivity switch with changing nHF:amine ratio. e, A summary of the diastereoselectivity switch. IF2 generation: p-iodotoluene in 5.6HF:amine and DCM (13mA, 2.2F, divided cell, Pt||Pt). Anti conditions: alkene (0.6mmol), IF2 (1 equiv.) solution in 5.6HF:amine, NEt4Cl (1 equiv., 0.2 equiv.h1), DCM, 46C, 16h; syn conditions: alkene (0.6mmol), IF2 (1 equiv.) solution in 5.6HF:amine adjusted to 7HF:amine, NEt4Cl (1 equiv., 0.2 equiv.h1), DCM, 46C, 16h.

A range of different chloride salts were tested (Fig. 2b); chloride with inorganic cations led to more dichlorination, and more soluble organic cations led to greater selectivity for chlorofluorination, with NEt4Cl giving the highest yield (Supplementary Table 1). The regioselectivity of the anti-addition product could be improved by lowering the temperature, with 46C (CO2(s) in MeCN) providing the best balance of selectivity and yield (Fig. 2c). By adding chloride slowly, the competing dichlorination could be attenuated, leading to an optimized 85% yield of the anti-addition product 1b with a regioisomeric ratio (r.r.) of 12:1 (Fig. 2e).

During these efforts, product 1d from syn-chlorofluorination was only observed in trace quantities (<5%). However, when we started to increase the nHF:amine ratio beyond 5.6 (by adding 9HFpy to the 5.6HFamine mixture), the diastereoselectivity started to shift. A range of nHF:amine ratios were tested (Fig. 2d), which revealed the mechanism could be flipped with this highly sensitive trigger; increasing the ratio from just n=5.6 to just 7 was sufficient to completely switch the diastereoselectivity, yielding the syn-addition product 1d in good yield and excellent r.r. (Fig. 2e). Although the selectivity enhancement was maintained at ratios above 7HF:amine, the yield dropped, and therefore, optimized conditions for the syn-chlorofluorination of internal, unactivated alkenes remained with 7HF:amine (Supplementary Table 4).

To explore the generality of the reaction, a wide selection of alkene substrates was probed under the conditions (Table 1). Terminal alkenes transformed efficiently under the anti-addition 5.6HF:amine conditions, giving good to excellent yields and selectivity for the 1-chloro-2-fluoro products (nj). Oxidizable functionalities, such as secondary and tertiary amines, alcohols, anilines and styrenes and more complex molecules, were all well tolerated. Remarkably, the expected 1-chloro-2-fluoro (nj) regioselectivity was not observed for the cinchonine 11a, as the 1-fluoro-2-chloro regioisomer 11k preferentially formed, which is probably due to the internal position being sterically more inaccessible than all other substrates.

The anti-chlorofluorination conditions were then successfully applied to a broad range of internal alkenes, including cis and trans acyclic and cyclic alkenes, as well as substituted and electron-poor alkenes (Table 1). Although oxidants (Selectfluor and meta-chloroperoxybenzoic acid) previously used for IF2 formation were found to be inferior (Supplementary Table 8), we found that commercially available (bis(trifluoroacetoxy)iodo)benzene (PIFA) led to only a small drop in yield (73% versus 85% for 1b), which represents a practical alternative to electrochemically generated IF2. Oxidizable and acid-sensitive (29b, 34b and 35b) functional groups were well tolerated, and the yields were good to excellent in all cases. High regioselectivity was observed with fluoride placed on the site best able to stabilize a positive charge, hence, further away from electron-withdrawing groups. Exquisite regioselectivity was observed even four bonds away from a tertiary amine (27b). When there are competing factors for positive charge stabilization (24b) or the alkene is more remote (23d), then the regioselectivity decreases or disappears. Biologically relevant compounds were also transformed, including glucal derivative 35b and cholesterol 28b. Finally, a multigram scale-up of 39b was successfully demonstrated.

Previously reported chlorofluorination conditions are ENu methods that combine an N-chloro electrophilic chlorine reagent (N-chlorosuccinimide (NCS)31,32,33,34, trichloroisocyanuric acid (TCCA)35, N-chlorosaccharin36) with a source of HF37, and all lead to exclusive anti-addition. With few exceptions32, these conditions are demonstrated on limited compound classes, for example, styrenes, and without complex functionality, especially that which is easily oxidized. Hence, we were intrigued to test the complementarity to our NuNu system on substrates containing more varied functionality and alkene-types (Table 1). In all cases, isolated yields from our NuNu conditions proved superior to the nuclear magnetic resonance (NMR) yields from reported procedures, including both cis and trans internal alkenes, electron-poor alkenes and terminal alkenes. The regioselectivity either matched or was superior to the reported conditions.

The scope of the alkene syn-chlorofluorination reaction was then probed (Table 2). Various hetero-cyclic and aliphatic homo-allylic amines afforded the desired products in moderate to very good yields, with excellent tolerance for oxidatively sensitive functional groups. Cis alkenes underwent the syn-addition with generally higher efficiency than trans alkenes
(40d versus 40b). When the yields are moderate, oxidative decomposition probably competes. The anti-addition pathway was strongly attenuated under these conditions, which ensured the diastereoselectivity was excellent throughout. The regioselectivity was also excellent, with an overwhelming preference for the chloride to be placed nearest to nitrogen. Finally, ester 38a also underwent the syn-chlorofluorination.

To rationalize the synthetic results and, in particular, the origin for the regioselectivity and the intriguing switch in diastereoselectivity, we conducted a series of mechanistic experiments. Using 40a as a model substrate, alkene activation with iodane was calculated to occur most favourably by forming an iodine(III) complex, as opposed to the commonly invoked iodonium intermediate (Supplementary Fig. 42)38. To identify the specific iodane species responsible for each mechanism, we calculated energetic barriers for iodine(III) complex formation (Fig. 3a). IFCl was found to have the lowest energy barrier for alkene activation, whereas the transition state with ICl2 is completely inaccessible at 46C. The enhanced reactivity of IFCl over IF2 and ICl2 was also supported by charge and orbital coefficient calculations (Supplementary Fig. 48 and Supplementary Table 18). These findings were consistent with experimental reactivity studies using preformed iodanes (Fig. 3b). When a sample of ICl2 was applied to 1a under the anti conditions (Fig. 3b1), only trace product 1b was formed, confirming that ICl2 cannot be an active iodane and a more reactive species is required. However, when a 50:50 mixture of ICl2 and IF2 was used in the reaction the reactivity switched back on and product 1b formed readily (Fig. 3b2). These stoichiometries support IFCl to be responsible for anti-addition, which is notable considering fluoro-chloro-aryl iodanes have extremely limited presence in literature, with only one report proposing it as a potential intermediate39, in contrast to aryl dichloroiodanes, which are established reagents for alkene dichlorination15,40,41,42. Speciation studies (1H NMR; Supplementary Figs. 26 and 27) of IF2 with added NEt4Cl (01equiv.) and IF2 mixed with ICl2, conducted at 46C, revealed the appearance of a new species that we propose is consistent with the formation of IFCl. Density functional theory (DFT) calculations modelled at 46C also demonstrated IFCl was readily accessible from either IF2 or ICl2 via two possible mechanisms (Supplementary Figs. 51 and 52 and Supplementary Scheme 5).

a, DFT calculations modelled at 46C of iodine(III) complex formation, showing IFCl is the most reactive. Level of theory: M06-2X/6-31+G(d)/LANL2DZ(I)+SMD(CH2Cl2)//M06-2X/def2-TZVP+SMD(CH2Cl2). b, Reactivity studies using preformed samples of IF2 and ICl2 to establish the active iodane under each set of conditions. Anti-addition to 1b is not observed with ICl2 alone but is with 50:50 IF2:ICl2, providing evidence for IFCl to be the active iodane for anti-addition. Syn-addition to 1d does not predominate in the presence of ICl2 and only forms with IF2, providing evidence for IF2 to be the active iodane for syn-addition. c, Natural Bond Orbital (NBO) calculations (DFT) of iodine(III) complex to establish regioselectivity of nucleophile attack. d, Consideration of which halide attacks first. For syn-addition, fluoride attacks first and for anti-addition, chloride attacks first. eg, Anti-addition mechanisms discounted due to unfavourable transition state energies. The energies refer to the following starting materials: 40a in e, cis-but-2-ene in f, 40a in g. h, DFT calculations for the proposed mechanism for anti-addition, which shows a favourable transition state energy for a 1,2-chloride shift.

Under syn-conditions, the active iodane cannot be IFCl, considering anti-addition predominated with a 50:50 mixture of ICl2 and IF2 (Fig. 3b3). Syn-addition occurred only when IF2 was used with slow addition of chloride (Fig. 3b4), indicating IF2 to be the active species. As it is established syn-difluorination occurs through IF212,13,38, we reasoned the levels of difluorination (in the absence of chloride) should mirror those of syn-chlorofluorination (in the presence of chloride) when the nHF:amine ratio is altered. Indeed, a direct match of products 1i and 1d is observed (Supplementary Fig. 40), with 7HF:amine giving the highest yields of both products, suggesting IF2 to be the active iodane for syn-chlorofluorination. An explanation for the current limitation of syn-chlorofluorination to homo-allylic amines was revealed by DFT calculations of iodine(III) complex formation with IF2 (Supplementary Fig. 49); while a barrier of 19.2kcalmol1 was calculated for homo-allylic amine, which is approaching the limit of accessibility at 46C, a barrier of 23.3kcalmol1 was calculated for the corresponding bis-homo allyl amine, which is inaccessible.

To understand the regioselectivity, we undertook natural population analysis calculations (Fig. 3c). A clear difference in charge distribution between the alkenyl carbons is indicated, with the carbon distal to nitrogen more electropositive and, therefore, more reactive towards nucleophilic attack. Transition state calculations predict fluoride and chloride attack onto activated alkene 48aIF2 to be rapid and facile (Supplementary Fig. 47). Hence, we propose syn-addition occurs when fluoride attacks first, followed by a subsequent chloride attack (Fig. 3d).

Formation of the anti-addition product is less obvious. Although chloride attack onto the more electropositive distal carbon occurs very readily and with a low barrier to form INT1 (Fig. 3c and Supplementary Fig. 47), this was initially discounted because it is not consistent with the observed major regioisomer, which places chloride on the proximal carbon. Several inferred mechanisms in literature were considered, including direct chloronium formation, that is, alkene attack of a Cl+ equivalent (Fig. 3e)41,43, syn-ligand-coupling with fluoride attacking first (Fig. 3f)44 and syn IX addition followed by fluoride or chloride attack (Fig. 3g)45,46,47,48. In each case, we considered different chlorinated or fluorinated iodanes and coordinated HF environments (Supplementary Figs. 4447). Of these pathways, only the syn IF addition pathway (Fig. 3g) was found to be energetically feasible. However, this pathway was discounted, because the competing chloride attack on the iodine(III) complex to form the chlorinated-iodanated intermediate (INT1) is far more favourable (Supplementary Fig. 47). A kinetically accessible transition state from INT1 was located for a 1,2-chloride shift with Brnsted acid (HF) activation of the fluoride nucleofuge (Fig. 3h and Supplementary Fig. 43). Incipient chloronium formation through displacement of the iodane (from INT1 to INT2) is followed by very rapid and exergonic attack by fluoride (TS2). Although this pathway for chloronium formation has been offered as a potential mechanism for alkene dihalogenation4, to the best of our knowledge, no examples with theoretical or experimental evidence have been reported. Hence, our proposed pathway for anti-addition is consistent with the observed regio-, chemo-, and diastereoselectivity, the barrier height is consistent with the observed reaction rates, and it is the only pathway that can explain the formation of each iso
mer of compound 35b (Supplementary Figs. 3639).

Since the identity of the halide that attacks the iodine(III) complex first is diastereo-determining, we were inspired to understand how the reaction conditions differed to facilitate this. Hence, several fundamental physical characteristics were measured of the 5.6 and 7.0HF:amine solutions, including the concentrations of fluoride (F) and HF (Fig. 4a). Despite distinct reaction outcomes under each set of conditions, only the equivalents of HF substantially differed. However, when the number of equivalents of HF in 5.6HF:amine were matched to that of 7.0HF:amine (that is, to 204), no syn-chlorofluorination was observed (Supplementary Table 13). Therefore, it cannot solely be the identity of the iodane and manipulation of the equilibrium between ICl2, IFCl and IF2 that dictates the diastereoselectivity.

a, Analysis of the physical characteristics of each medium, which do not show a substantial difference between them. b, Assessment of the difference in nucleophilicity of fluoride in 5.6HF:amine and 7.0HF:amine by measuring the kinetics of the fluorination of p-nitrobenzyl bromide in each medium. The lines through plotted data are modelled second order fits. c, Assessment of the difference in nucleophilicity of chloride in 5.6HF:amine and 7.0HF:amine by measuring the kinetics of a chlorination reaction in each medium, which shows a lower nucleophilicity in 7.0HF:amine. The lines through plotted data are modelled second order fits. d, A diastereoselectivity switch can be achieved by controlling the concentration of chloride. e, A summary of the diastereodivergent NuNu alkene chlorofluorination mechanisms. The bifurcation of mechanisms is dependent on the concentration and the relative nucleophilic activity of chloride and fluoride ions, which in turn dictates the structure and reactivity of the iodane, which halide adds first to the alkene, and the mechanism of iodane displacement.

The relative nucleophilicities of chloride and fluoride were next compared under both sets of conditions by measuring bimolecular nucleophilic substitution displacement rates in appropriately chosen transformations. The rate of reaction between p-nitrobenzyl bromide and fluoride proceeded at similar rates in both HF:amine solutions (Fig. 4b), indicating that fluoride has a similar nucleophilicity under each conditions. However, when chloride competes with fluoride in the substitution of n-butyl mesylate under both sets of conditions, the rate of chlorination was found to be 3.6 times faster in 5.6HF:amine compared with 7.0HF:amine, and no fluorinated product was observed (Fig. 4c). Nucleophilicity calculations of chloride and fluoride ion clusters also mirror these experimental observations (Supplementary Figs. 5355). Combined, these data suggest that the dampened nucleophilicity of chloride in 7.0HF:amine promotes syn-chlorofluorination by allowing fluoride to add first, but in 5.6HF:amine, chloride has higher nucleophilicity and promotes anti-chlorofluorination by adding first.

Increasing the chloride concentration in 7.0HF:amine, via a single portion addition at the reaction outset, reversed the product outcome back to anti-addition product 1b (Fig. 4d). This evidence adds further support to the diastereodivergence being controlled by which nucleophile attacks first; if chloride is in sufficiently high concentration or is sufficiently nucleophilic, then the more reactive IFCl is formed, and chloride can attack the alkene first, resulting in anti-chlorofluorination via a 1,2-chloride shift. Otherwise, fluoride adds first to an IF2-activated alkene and syn-chlorofluorination is achieved, following nucleophilic substitution by chloride (Fig. 4e).

In summary, we have developed a NuNu strategy for the chlorofluorination of unactivated alkenes, which selectively gives either anti- or syn-addition. Good to excellent yields of products, including those that are electron-rich and readily oxidizable, are provided with very high regio-, chemo- and diastereoselectivity. A simple switch was discovered for transitioning between anti-and syn-chlorofluorination based on the HF:amine ratio used in the solution. Mechanistic studies revealed that different iodanes promote each pathway but that the identity of the halide adding to the alkene first is diastereo-determining, with fluoride leading to syn-addition and chloride leading to anti-addition. The anti-addition pathway follows an unusual 1,2-chloride shift followed by rapid fluoride addition from iodane. These results represent an important advance in the application of hypervalent iodine for the vital elaboration of fluorinated motifs in an ever-expanding chemical landscape, and show how capitalizing on a subtle and simple variation of reaction solvent composition can influence product selectivity.

More here:
Diastereodivergent nucleophilenucleophile alkene chlorofluorination - Nature.com

Alchivemycin A, a molecule produced by Streptomyces bacteria, has interesting antimicrobial properties that scientists would love to study for cues on how to make better antibiotics. But every previous attempt to assemble it in the lab was stymied by the molecules structural complexity. The trickiest bits include a highly oxidized macrocyclic core and an unusual 2H-tetrahydro-4,6-dioxo-1,2-oxazine (TDO) ring.

Now, Xiaoguang Lei of Peking University and coworkers have overcome the challenge by looking to nature. The researchers used enzymes from the molecules biosynthetic pathway to carry out three selective late-stage oxidations needed to finish the synthesis (Nat. Synth. DOI: 10.1038/s44160-024-00577-7). The team has been trying to make the molecule for a decade, and its exciting to have finally done it, Lei says in an email.

The 25-step synthesis relies on traditional chemical methods such as Suzuki coupling and nucleophilic substitution to assemble the macrocyclic skeleton. Then its the enzymes turn to add the finishing touches. The two epoxide-installing enzymes, AvmO2 and AvmO3, gave excellent yields right away despite the unnatural substrate, which Lei says was a pleasant surprise. The enzyme responsible for the final step, inserting an oxygen into a lactam to turn it into the elusive TDO ring, needed a little bit of extra engineering for efficiency. Switching a tyrosine for an arginine did the trick, getting the yield of the final step up to 85%.

Integrating enzymes into organic synthesis is becoming increasingly popular, so Lei and coworkers use of biocatalysis isnt inherently novel, says Han Renata, who researches chemoenzymatic synthesis at Rice University, in an email. But he says this study is a well-executed illustration of how enzymes can help chemists tackle daunting targets.

View post:
Alchivemycin A synthesized with help from enzymes - Chemical & Engineering News

Daniel E. Atkinson, a professor of chemistry and biochemistry at UCLA for nearly 40 years who was recognized internationally for his seminal contributions to metabolic biochemistry, died Feb. 2 at his home in Medford, Oregon. He was 102.

Atkinson was just the second biochemist appointed to what is now the UCLA Department of Chemistry and Biochemistry, in 1952. He retired in 1991 but remained active in the UCLA community until moving to Oregon in 2011. Over the years, he trained more than 30 doctoral students in his laboratory, as well as over 20 postdoctoral fellows and visiting faculty.

In his research Atkinson authored more than 90 published studies with his students he pioneered the field of metabolic regulation. His work allowed for the development of the concept of energy charge, which today is a main topic in biochemistry textbooks. He was also responsible for our present understanding of the biological role of the urea cycle in pH regulation.

Atkinsons acclaimed 1977 monograph Cellular Energy Metabolism and its Regulation, is still widely read in the field. In a 2005 review, John Duncan wrote that anyone wanting a readable introduction to the classic ideas of metabolic regulation could scarcely find a better place to start. And in a 2013 review, Ralph Osgood wrote that Atkinson was a pioneer in the field of biochemistry and that the book still had a touch of delicious heresy. A great book still, many years later, from a great scientist.

Read the full obituary on the UCLA Department of Chemistry and Biochemistry website.

Read more here:
In memoriam: Daniel Atkinson, 102, UCLA professor and pioneer in field of metabolic biochemistry | UCLA - UCLA Newsroom

Tuesday, Jul 02, 2024 Katherine Egan Bennett : contact

With a $300,000 grant, the Welch Foundation is supporting University of Texas at Arlington research into creating new materials to safely and effectively deliver medications to treat diseases such as cancer.

Since its founding in 1954, the Houston-based Welch Foundation has contributed over $1.1 billion to the advancement of chemistry through research grants, departmental programs, endowed chairs and other special projects in Texas.

As one of the nations largest private funding sources for chemical research, we are committed to supporting the field in a way that advances science while changing lives, said Adam Kuspa, president of the foundation. Medications can only be so effective at treating diseases if we cant get them to the parts of the body that need them most. I look forward to seeing how Dr. Junha Jeons research can help advance and improve drug production so we can improve lives.

Junha Jeon, associate professor of chemistry and biochemistry at UTA, is leading the project to study arynes, a chemical compound formed by removing two hydrogen atoms from benzene. Although scientists have known about arynes for more than 100 years, they only recently discovered that the compounds have a unique ability to deliver antibiotics and anti-tumor medications.

Im honored that the Welch Foundation sees the value in supporting our research, Dr. Jeon said. Worldwide, an estimated 2 million people are diagnosed with cancer each year, and about one in five people will develop cancer at some time during their lifetime. Im proud we can research new ways to improve outcomes for people living with cancer and other diseases.

The transition metal-catalyzed cross-coupling reaction is one of the most widely used and powerful tools in organic synthesisthe art and science of reconstructing substances in the lab. This technique is extensively used to establish crucial chemical bonds and produce biomedical molecules necessary in modern medicine. Currently, most drugs use transition metal catalysts to deliver medications. However, metals often leave impurities that can lead to side effects from otherwise beneficial medications.

Little is known about widely available transition metal-free cross-coupling, especially one that can be used to deliver medicines. The overarching goal of this project is to develop sustainable transition metal-free cross-coupling technologies using arynes. Chemically speaking, arynes are short-lived intermediates holding a functional group with an extremely strained triple bond into a small ring. The strain-driven reactivity of the arynes makes them very useful for the development of cross-coupling reactions.

Uncovering this new sustainable aryne-forming strategy without using a transition metal catalyst will be valuable for various areas of research, including the production of drugs, said Jeon. Im grateful to the support of the Welch Foundation for our research project.

Visit link:
Welch Foundation supports UTA's drug delivery innovations - News Center - The University of Texas at Arlington - uta.edu

From PittconReviewed by Danielle Ellis, B.Sc.Jul 1 2024

In this interview conducted at Pittcon 2024 in San Diego, we spoke to Professor Arian van Asten about advancements in the chemical analysis of drugs and explosives using portable NIR spectroscopy and its significant impact on improving on-scene investigation methods for law enforcement agencies.

My name is Arian van Asten. I am a professor of forensic analytical chemistry at the Van 't Hoff Institute of Molecular Sciences of the University of Amsterdam. Before that, I worked for a long time at the Netherlands Forensic Institute.

I have a PhD in analytical chemistry and a passion for forensic science. I am involved in many different projects focusing on a wide array of evidence materials and analysis methods, but my special interest is in the analysis of drugs and explosives. What makes them special is that these chemicals are directly related to certain types of crimes.

Starting with illicit drugs, the US is in the midst of the opioid crisis. This translates to forensic experts seeing an increasing number of cases. The caseload is very high, and the chemical complexity of the samples requiring analysis has also increased. It is more difficult to analyze them correctly.

With respect to explosives, this is a challenging area because of the chemical diversity that is encountered. You have organic and inorganic materials, so typically, one single analytical technique does not suffice in a given case.

In addition, there are cases in which intact explosives are present, which we call pre-explosion cases, and cases after an explosion. These two settings yield completely different samples to analyze.

Image Credit:PowerUp/Shutterstock.com

The work that I presented at the Pittcon Conference allows people to conduct chemical analysis in the field using portable technologies that do not require high-end laboratory conditions.

This is focused explicitly on rapid chemical identification of drugs and explosives with operators who do not need a chemistry background. I try to advance forensic analytical chemistryin this way.

As a forensic or analytical chemistry expert, I think the challenge is to create a methodology that allows non-experts to do complex chemical analyses themselves in a simple and error-free manner. If measurements fail because controlling the instrument is too complicated, then we have to make it simpler! This would ultimately allow law enforcement professionals to identify drugs and explosives robustly and instantly.

There are several options or routes that you can consider, such as mobile mass spectrometry, electrochemistry, and colorimetric reactions. Then, there are several spectroscopic methods to consider: Raman, infrared, and near-infrared. We chose near spectroscopy, as it lends itself very well to miniaturization. You can have very small, almost pocket-sized, near-infrared spectrometers, and they are extremely rapid. Using the technology we work with, you record a reflectance spectrum in a few seconds.

When people talk about rapid analysis, they sometimes introduce methods that take a few minutes. If you talk to professionals who operate within law enforcement or customs, a few minutes on the scene doing a measurement can feel like a lifetime. That makes near spectroscopy very attractive. Within 10 to 20 seconds, I can do multiple measurements on the same sample.

For illicit drugs, for example, the first step in the field is often a colorimetric reaction. This is challenging because people in the field have to add liquids to a sample to observe color, and they are not necessarily trained to do so.

We use reflectance sensors, where people simply place a glass vialwith a small amount of powder directly on the sensor, and then press scan. There is no sample preparation, no complex instructions. This is a very convenient process both in the field and in a laboratory situation where you are carrying out high-volume screening.

Pittcon Thought Leader: Arian Van AstenPlay

Credit is due here to Dr. Henk-Jan Ramaker from TIPb. He did and does a lot of the model development and the chemometrics (advanced data analysis).

This is also where one of the technique's challenges comes in. Imagine you are in a forensic setting, and you have a sample with an unknown composition. You have an idea that it could contain explosives or illicit drugs, depending on the context of the case, but you are not sure. The sample is also not pure.

A typical street sample of a drug can contain several other substances in addition to the psychoactive substance of interest. This includes adulterants, diluents, or tableting agents. When taking a measurement, you will get a composite signal with spectral features of all these components. So here, we need data science to help us decipher the complex signal and tell us what compounds are present and at what level.

You can take a machine learning approach, but that typically requires huge amounts of data. We can measure thousands of street samples, for which we have used other techniques like GC-MS to determine the composition. We use that knowledge to look for similar signals if we have an unknown and suggest its composition.

What Dr. Ramaker has developed is much more elegant. He takes pure compound spectra of all the known possible constituents in a sample for a given type of drug. With this limited set of spectral reference data, he subsequently 'explains' the observed signal.This is much faster and requires less reference data for a functional model. You, for instance, only need the NIR spectra for 10-15 pure compounds to fit all cocaine street formulations.

I think both are true. We have more analytical capability to look at very low levels of substances within samples and chemically understand what is going on.

Chemical profiling is a different field that I am involved in. Here, we look at how materials are degrading and what kind of raw materials are used. We are interested in impurities and what they tell us about how the material was made or transported. You cannot typically do that with portable spectroscopy. The technique is not sensitive enough. Compounds need to be present at 5-10 wt% to be 'noticed'.

It is also true that the chemical complexity of illicit drug case samples has increased considerably. There are two reasons for that.

First of all, because many countries work with lists of banned substances in their illicit drug legal framework, we have seen 'creative' criminals producing so-called new psychoactive substances (NPS). These designer drugs look and function very similar to their banned analogs but are not listed and, therefore, do not fall under the illicit drug law. Selling such a product is consequently not an illicit drug crime.

Governments tend to react when they see such new materials entering the illicit drug market. They take legal action to place the new compound on the list of banned substances. But that fuels a rat race in which the criminal makes another variant when the ban is successful. We have seen a rise in what we call designer drugs in many European markets. Meanwhile, there is an additionalchallenge here in the US where the ongoing opioid crisis is leading to drug street samples that contain multiple fentanyl analogs at relatively low levels in the presence of cocaine or heroin.

I think there is. The forensic science domain is open, but it is also a somewhat complex situation. We are scientists, so we wou
ld like to explore new methods, develop them, and share them to contribute to a safe and just society. But at the same time, there is always the risk that this information falls into the wrong hands. This is especially important when you investigate how to make explosives or how to characterize drugs of abuse.

Additionally, forensic science is typically a very international, open environment where people are eager to share, whereas criminal justice is typically more closed, domestic, and local. This makes it for instance difficult and rare to bring in foreign forensic experts to report and testify in a case. This is also understandable, crime is a sensitive and typically a national affair with local victims and perpetrators.

There are a couple of problems here. First of all, when you transition from science and innovation to something used in forensic practice and being presented as forensic evidence in court, you need to be very strict with respect to quality. You need validation studies and accredited methods. You have accreditation bodies that come and check to make sure that 'you say what you do and do what you say.'

So you need to make that new method fit for purpose. You would have to show, quite vigorously, that you know the error rates, you know when things go wrong, you know how to spot an error and how to improve. This is very important because once that evidence is in court, it can have a lot of impact, especially when drugs or explosives are involved. You need it to be free of error.

Of course, where work is done, errors are made; this is inevitable. But in a forensic setting, you need to show that you have minimized and mitigated potential errors and that you have a system in place to spot errors, correct them, and prevent them from happening in the future. Forensic evidence can make a lot of difference to the people involved, including suspects, victims, and family members, and therefore, must be of superior quality.

However, there is also the interesting question of when a forensic investigation is good enough. When is there enough selectivity to say that, with a portable technique, you can do a measurement in seconds and also present the findings with confidence in court? Here, as a forensic scientist from academia, you can run into some conservatism and resistance. People tend to rely on what they trust and have been using successfully in the past. However, these trusted methods were once also highly innovative and groundbreaking!

There is a clash here. If you are in court, then the judge, the people involved, the public prosecutor, and the legal defense all have a very simple question. Did that person fire the gun? Did the suspect produce these cocaine samples? However, forensic scientists and experts need to take scientific uncertainty into account. When the expert involved tries to explain this uncertainty, everybody starts to think, "You are the expert. Why are you telling this difficult story? The question was very straightforward; just say yes or no based on your expertise and experience".This is why forensic scientists and experts must also be great communicators, being able and willing to explain difficult scientific aspects in a simple yet convincing manner.

Collaboration is essential to developing such a methodology and successfully introducing it in forensic practice. For a lot of the research I do, I arrange a 'triangular collaboration' involving academia, commercial companies, and users. I need forensic practice because they need to tell me how an investigation is conducted and the problems and challenges they face. They can also supply me with samples from actual cases rather than artificially created samples. These are really valuable samples on which to test and develop the methodology.

At the same time, we need companies and technology to realize our ideas and develop viable and robust instrumentation. A very powerful method may exist, but the research group involved is often not capable of taking the next step and developing a product that could really make a difference. Many innovations fail because of this. Involving a company that is able to develop, introduce, and maintain a product is the magic ingredient that you need to be successful.

Basic instruction would suffice. It is very simple. You have the platform. You take the PowderPuck, a small portable benchtop, and put it on the table. You take a glass vial, put in 0.5 to 1 gram of a powder sample, put it on the instrument, and press scan. That is it. I think a 5-year-old child could get it right.

I have attended several of the National Institute of Justice (NIJ) sessions here. You hear a lot about forensic science and the advancements in several areas, but there is clearly a lot of interest in portable technology and bringing that analytical technology out of the lab and into the field.

When you go out here on the exhibition floor, there is an interesting transition ongoing in terms of not just technology being presented but also computing possibilities. This allows you to create products that transfer data wirelessly, get results on your mobile phone, and connect to central servers where powerful computers carry out complex data analyses and send results back to the user. I think that we will see many more of these types of developments opening up a whole range of possibilities.

Years ago, you would go into the field with a Raman instrument, and everything would have to take place on that single instrument. But this limitation does not exist anymore. Now, you can take the measurements, send the data to a central location, and share it with other users.

Experts can also examine the data from a distance and perform a quality check on the data in seconds. To the user, this seems almost instantaneous as results appear on the smartphone or tablet. But in the mean time a lot is actually happening 'under the hood'. I think that these data science developments will revolutionize analytical chemistry.

The presentations and meetings with scientists are nice, but I think what makes Pittcon very special is the exhibition. It is massive! There is no equivalent to that in Europe or the Netherlands, and I find that very inspiring.

There is all this energy and activity, particularly when it comes to analytical chemistry. It is never only the science, right? There must be instrumental and technological developments to back it up and really make a difference, and that is what you see on the expo floor.

The first time I attended Pittcon was in 2014 in Chicago, and again in 2017. When you go out on the expo floor for the first time, it is mind-blowing. I had never seen anything like that before, even having been an analytical chemist for many years. You get this feeling of really getting into it, talking to people, touching instrumentation, and hearing about great ideas.

It is inspirational to see other types of applications that can trigger questions like, "Oh, what would the forensic angle be here? Could it be useful? Could I use this to solve a crime?" Then you start talking to people. Some of the projects that I am involved with have actually emerged from these types of discussions.

Arian van Asten is a full-time professor in forensic analytical chemistry and on-scene chemical analysis at the van t Hoff Institute for Molecular Sciences, Faculty of Science, University of Amsterdam. His research interests include the chemical profiling of explosives and drugs, the analysis of (bio)markers of CWA (Chemical Warfare Agent) exposure, rapid chemical identification at the crime scene with portable instruments
, the forensic use of comprehensive 2D chromatography, chemical imaging of forensic traces, and the use of data science and A.I. to generate forensic chemical intelligence from large volume forensic case data. In addition, he is the director of the Master Forensic Science at the Institute for Interdisciplinary Studies of the University of Amsterdam, the only 2-year full-time MSc program in forensic science in the Netherlands. Together with prof dr Maurice Aalders he leads the Co van Ledden Hulsebosch Center (CLHC), a national forensic network organization named after the first Dutch forensic science pioneer. Prior to his transfer to the University of Amsterdam in 2018, he worked for over 12 years at the Netherlands Forensic Institute as a member of the management team, department head, manager of R&D programs and forensic coordinator of complex, international cases, including bomb attacks and airplane crashes. He has (co)authored over 80 peer-reviewed scientific publications on (forensic) analytical chemistry and is the author of the academic course book Chemical Analysis for Forensic Evidence that was published at the end of 2022.

This information has been sourced, reviewed and adapted from materials provided by Pittcon.

For more information on this source, please visit Pittcon.

Disclaimer: The views expressed here are those of the interviewee and do not necessarily represent the views of AZoM.com Limited (T/A) AZoNetwork, the owner and operator of this website. This disclaimer forms part of the Terms and Conditions of use of this website.

See the original post:
Chemical Clues: Real-time Forensic Analysis of Drugs and Explosives - AZoM

The preserving agent polyethylene glycol (PEG) has been removed from a sample of the 4th-century BCE Greek Kyrenia ship, allowing radiocarbon dating to provide a better estimate of when it sank. This is the first time a real proper effort at scientific dating has been made, says lead author Sturt Manning of Cornell University, US.

The Kyrenia was found off the north coast of Cyprus in 1965 and is believed to be a 4th-century BCE ancient Greek merchant ship. Radiocarbon dating was attempted to date the ship, along with evidence including coins in its cargo, but doubts remain about the accuracy of estimates for its construction and last voyage.

Modern radiocarbon dating uses accelerator mass spectrometry (AMS) to detect the levels of radiocarbon in objects. The level of radiocarbon in the atmosphere has changed over time due to changes in solar activity, the geodynamo and the carbon cycle, explains Tim Heaton, an environmental statistician at the University of Leeds. By radiocarbon dating the wood of trees, the ages of which are known from their rings, scientists have constructed a calibration curve for the northern hemisphere called IntCal. We now have trees extending back to 14,300 years ago, says Heaton, who is part of the IntCal working group. IntCal provides an estimate of radiocarbon levels over the last 55,000 years.

Radiocarbon dating of wooden artefacts recovered from water is complicated by the agent commonly used to preserve them polyethylene glycol (PEG). Impregnation of PEG is a standard treatment in wet wood conservation in many institutions worldwide, explains Malin Sahlstedt, a conservator at the Vasa Museum. This is because it helps to prevent warping and shrinking of the wood. The Mary Rose, the flagship of Henry VIIIs navy, for example,spent years soaking in PEG. However, because PEG is derived from fossil fuels, it introduces dead carbon-14 into the wood rendering accurate radiocarbon dating impossible.

To test a method for removing PEG from wood that had been developed at the University of Groningen, the team acquired a PEG-preserved piece of wood from Colchester, UK. Because dendrochronology had been done on this wood, we knew it dated from exactly when Boudicca had her revolt in Britain, says Manning. After soaking samples at 80C in ultrapure water for 36 hours, radiocarbon analysis was accurate enough to show that the majority of the PEG had been removed.

The researchers repeated the process with a tiny sample from the Kyrenia and also took radiocarbon measurements for some almonds, and a small piece of the boat that had been stored in water rather than PEG-treated. However, the results gave dates that made no sense. It was like, What on Earths going on here? Because this doesnt seem to match up with anybodys archaeological estimate and doesnt seem possible, says Manning. And we then realised that not a single recent AMS date was part of the period between 350 and 250 BC.

Prior to AMS becoming the standard, radiocarbon dating was done using a beta-counting method that required a lot of material and was far less accurate. Youre literally using an iPhones worth of some unique historic something to get one not very accurate measurement, Manning notes. Tree ring samples were also typically measured over five or 10-year periods, rather than annually. Until recently, people didnt think atmospheric radiocarbon levels could vary that much from one year to the next, explains Tim Heaton.

To fix the calibration curve, the team sourced sequoia from the US and oak from the Netherlands and performed AMS measurements on annual rings at two different laboratories. Using their data to revise the calibration curve, they now believe the Kyrenia was constructed between 426400 BCE, with its last voyage taking place in 383355 BCE.

With their changes to a century of the calibration curve, Manning believes that there will be new interest in trying to relook at some of the debated cases of artefacts. Their successful removal of PEG from wood may also inspire some new discoveries regarding other archaeologic specimens.

For Manning, the slow process of refining the history of the Kyrenia is the scientific process in action. It just shows that often science involves repeatedly improving things, rather than you just get the right answer immediately.

More:
Pioneering preservative removal from ancient Greek ship allows accurate dating - Chemistry World

Juris, A. et al. Ru(II) polypyridine complexes: photophysics, photochemistry, eletrochemistry, and chemiluminescence. Coord. Chem. Rev. 84, 85277 (1988).

Article CAS Google Scholar

Dixon, I. M. et al. A family of luminescent coordination compounds: iridium(III) polyimine complexes. Chem. Soc. Rev. 29, 385391 (2000).

Article CAS Google Scholar

Lytle, F. E. & Hercules, D. M. Luminescence of tris (2,2-bipyridine) ruthenium(II) dichloride. J. Am. Chem. Soc. 646, 253257 (1968).

Google Scholar

Arias-Rotondo, D. M. & McCusker, J. K. The photophysics of photoredox catalysis: a roadmap for catalyst design. Chem. Soc. Rev. 45, 58035820 (2016).

Article CAS PubMed Google Scholar

de Groot, L. H. M., Ilic, A., Schwarz, J. & Wrnmark, K. Iron photoredox catalysispast, present, and future. J. Am. Chem. Soc. 145, 93699388 (2023).

Article PubMed PubMed Central Google Scholar

Twilton, J. et al. The merger of transition metal and photocatalysis. Nat. Rev. Chem. 1, 0052 (2017).

Article CAS Google Scholar

McCusker, J. K. Electronic structure in the transition metal block and its implications for light harvesting. Science 363, 484488 (2019).

Article CAS PubMed Google Scholar

Wegeberg, C. & Wenger, O. S. Luminescent first-row transition metal complexes. JACS Au 1, 18601876 (2021).

Article CAS PubMed PubMed Central Google Scholar

Beaudelot, J. et al. Photoactive copper complexes: properties and applications. Chem. Rev. 122, 1636516609 (2022).

Article CAS PubMed Google Scholar

Sinha, N., Wegeberg, C., Hussinger, D., Prescimone, A. & Wenger, O. S. Photoredox-active Cr(0) luminophores featuring photophysical properties competitive with Ru(II) and Os(II) complexes. Nat. Chem. 15, 17301736 (2023).

Article CAS PubMed PubMed Central Google Scholar

Herr, P., Kerzig, C., Larsen, C. B., Hussinger, D. & Wenger, O. S. Manganese(I) complexes with metal-to-ligand charge transfer luminescence and photoreactivity. Nat. Chem. 13, 956962 (2021).

Article CAS PubMed Google Scholar

Smeigh, A. L., Creelman, M., Mathies, R. A. & McCusker, J. K. Femtosecond time-resolved optical and Raman spectroscopy of photoinduced spin crossover: temporal resolution of low-to-high spin optical switching. J. Am. Chem. Soc. 130, 1410514107 (2008).

Article CAS PubMed Google Scholar

McCusker, J. K. et al. Subpicosecond 1MLCT5T2 intersystem crossing of low-spin polypyridyl ferrous complexes. J. Am. Chem. Soc. 115, 298307 (1993).

Article CAS Google Scholar

McCusker, J. K., Rheingold, A. L. & Hendrickson, D. N. Variable-temperature studies of laser-initiated 5T21A1 intersystem crossing in spin-crossover complexes: empirical correlations between activation parameters and ligand structure in a series of polypyridyl ferrous complexes. Inorg. Chem. 35, 21002112 (1996).

Article CAS Google Scholar

Monat, J. E. & McCusker, J. K. Femtosecond excited-state dynamics of an iron(II) polypyridyl solar cell sensitizer model. J. Am. Chem. Soc. 122, 40924097 (2000).

Article CAS Google Scholar

Bressler, C. et al. Femtosecond XANES study of the light-induced spin crossover dynamics in an iron(II) complex. Science 323, 489492 (2009).

Article CAS PubMed Google Scholar

Zhang, K., Ash, R., Girolami, G. S. & Vura-Weis, J. Tracking the metal-centered triplet in photoinduced spin crossover of [Fe(phen)3]2+ with tabletop femtosecond M-edge X-ray absorption near-edge structure spectroscopy. J. Am. Chem. Soc. 141, 1718017188 (2019).

Article CAS PubMed Google Scholar

Kitzmann, W. R. & Heinze, K. Charge-transfer and spin-flip states: Thriving as complements. Angew. Chem. Int. Ed. 62, 117 (2023).

Article Google Scholar

Dorn, M. et al. in Comprehensive Inorganic Chemistry III 3rd edn, 707788 (Elsevier, 2023).

Zhang, W. et al. Tracking excited-state charge and spin dynamics in iron coordination complexes. Nature 509, 345348 (2014).

Article CAS PubMed PubMed Central Google Scholar

Woodhouse, M. D. & McCusker, J. K. Mechanistic origin of photoredox catalysis involving iron(II) polypyridyl chromophores. J. Am. Chem. Soc. 142, 1622916233 (2020).

Article CAS PubMed Google Scholar

Liu, Y. et al. Towards longer-lived metal-to-ligand charge transfer states of iron(II) complexes: an N-heterocyclic carbene approach. Chem. Commun. 49, 64126414 (2013).

Article CAS Google Scholar

Fredin, L. A. et al. Exceptional excited-state lifetime of an iron(II)N-heterocyclic carbene complex explained. J. Phys. Chem. Lett. 5, 20662071 (2014).

Article CAS PubMed Google Scholar

Chbera, P. et al. FeII hexa N-heterocyclic carbene complex with a 528 ps metal-to-ligand charge-transfer excited-state lifetime. J. Phys. Chem. Lett. 9, 459463 (2018).

Article PubMed Google Scholar

Paulus, B. C., Nielsen, K. C., Tichnell, C. R., Carey, M. C. & McCusker, J. K. A modular approach to light capture and synthetic tuning of the excited-state properties of Fe(II)-based chromophores. J. Am. Chem. Soc. 143, 80868098 (2021).

Article CAS PubMed Google Scholar

Mukherjee, S., Bowman, D. N. & Jakubikova, E. Cyclometalated Fe(II) complexes as sensitizers in dye-sensitized solar cells. Inorg. Chem. 54, 560569 (2015).

Article CAS PubMed Google Scholar

Braun, J. D. et al. Iron(II) coordination complexes with panchromatic absorption and nanosecond charge-transfer excited state lifetimes. Nat. Chem. 11, 11441150 (2019).

Article CAS PubMed Google Scholar

Steube, J. et al. Excited-state kinetics of an air-stable cyclometalated iron(II) complex. Chem. Eur. J. 25, 1182611830 (2019).

Article CAS PubMed Google Scholar

Yarranton, J. T. & McCusker, J. K. Ligand-field spectroscopy of Co(III) complexes and the development of a spectrochemical series for low-spin d6 charge-transfer chromophores. J. Am. Chem. Soc. 144, 1248812500 (2022).

Article CAS PubMed Google Scholar

Alowakennu, M. M., Ghosh, A. & McCusker, J. K. Direct evidence for excited ligand field state-based oxidative photoredox chemistry of a cobalt(III) polypyridyl photosensitizer. J. Am. Chem. Soc. 145, 2078620791 (2023).

Article CAS PubMed
Google Scholar

Kalsi, D., Dutta, S., Barsu, N., Rueping, M. & Sundararaju, B. Room-temperature CH bond functionalization by merging cobalt and photoredox catalysis. ACS Catal. 8, 81158120 (2018).

Article CAS Google Scholar

Pal, A. K., Li, C., Hanan, G. S. & ZysmanColman, E. Blueemissive cobalt(III) complexes and their use in the photocatalytic trifluoromethylation of polycyclic aromatic hydrocarbons. Angew. Chem. Int. Ed. 57, 80278031 (2018).

Zhang, P. et al. Mass production of a single-atom cobalt photocatalyst for high-performance visible-light photocatalytic CO2 reduction. J. Mater. Chem. A 9, 2628626297 (2021).

Article CAS Google Scholar

Zhang, G. et al. External oxidant-free oxidative cross-coupling: a photoredox cobalt-catalyzed aromatic CH thiolation for constructing CS bonds. J. Am. Chem. Soc. 137, 92739280 (2015).

Article CAS PubMed Google Scholar

Chan, A. Y. et al. Exploiting the Marcus inverted region for first-row transition metal-based photoredox catalysis. Science 382, 191197 (2023).

Article CAS PubMed PubMed Central Google Scholar

Langford, C. H., Group, H. E., Malkhasian, A. Y. S. & Sharma, D. K. Subnanosecond transients in the spectra of cobalt(III) amine complexes. J. Am. Chem. Soc. 106, 27272728 (1984).

Article CAS Google Scholar

Ferrari, L. et al. A fast transient absorption study of Co(AcAc)3. Front. Chem. 7, https://doi.org/10.3389/fchem.2019.00348 (2019).

Kaufhold, S. et al. Microsecond photoluminescence and photoreactivity of a metal-centered excited state in a hexacarbeneCo(III) complex. J. Am. Chem. Soc. 143, 13071312 (2021).

Article CAS PubMed PubMed Central Google Scholar

Gray, B. & Beach, N. A. The electronic structures of octahedral metal complexes. I. Metal hexacarbonyls and hexacyanides. J. Am. Chem. Soc. 85, 29222927 (1963).

Article CAS Google Scholar

Miskowski, V. M., Gray, H. B., Wilson, R. B. & Solomon, E. I. Position of the 3T1g 1A1g transition in hexacyanocobaltate(III). Analysis of absorption and emission results. Inorg. Chem. 18, 14101412 (1978).

Article Google Scholar

McCusker, J. K., Walda, K. N., Magde, D. & Hendrickson, D. N. Picosecond excited-state dynamics in octahedral cobalt(III) complexes: intersystem crossing versus internal conversion. Inorg. Chem. 32, 394399 (1993).

Article CAS Google Scholar

Viaene, L., DOlieslager, J., Ceulemans, A. & Vanquickenborne, L. G. Excited-state spectroscopy of hexacyanocobaltate(III). J. Am. Chem. Soc. 101, 14051409 (1979).

Article CAS Google Scholar

Sinha, N., Wegeberg, C., Prescimone, A. & Wenger, O. S. Cobalt(III) carbene complex with an electronic excited-state structure similar to cyclometalated iridium(III) compounds. J. Am. Chem. Soc. 144, 98599873 (2022).

Article CAS PubMed PubMed Central Google Scholar

Caspar, J. V., Kober, E. M., Sullivan, B. P. & Meyer, T. J. Application of the energy gap law to the decay of charge-transfer excited states. J. Am. Chem. Soc. 104, 9195 (1982).

Article Google Scholar

Englman, R. & Jortner, J. The energy gap law for radiationless transitions in large molecules. Mol. Phys. 18, 285287 (1970).

Article Google Scholar

Bressler, C. & Chergui, M. Ultrafast X-ray absorption spectroscopy. Chem. Rev. 104, 17811812 (2004).

Article CAS PubMed Google Scholar

Damrauer, N. H., Boussie, T. R., Devenney, M. & McCusker, J. K. Effects of intraligand electron delocalization, steric tuning, and excited-state vibronic coupling on the photophysics of aryl-substituted bipyridyl complexes of Ru(II). J. Am. Chem. Soc. 119, 82538268 (1997).

Article CAS Google Scholar

Strouse, G. F. et al. Influence of electronic delocalization in metal-to-ligand charge transfer excited states. Inorg. Chem. 34, 473487 (1995).

Article CAS Google Scholar

Bozzi, A. S. & Rocha, W. R. Calculation of excited state internal conversion rate constant using the one-effective mode Marcus-Jortner-Levich theory. J. Chem. Theory Comput. 19, 23162326 (2023).

Article CAS PubMed Google Scholar

Al-Obaidi, A. H. R. et al. Structural and kinetic studies of spin crossover in an iron(II) complex with a novel tripodal ligand. Inorg. Chem. 35, 50555060 (1996).

Article CAS PubMed Google Scholar

McGarvey, J. J., Lawthers, I., Heremans, K. & Toftlund, H. Spin-state relaxation dynamics in iron(II) complexes: solvent on the activation and reaction and volumes for the 1A 5T interconversion. J. Chem. Soc. Chem. Commun. 29, 15751576 (1990).

Google Scholar

ShariAti, Y. & Vura-Weis, J. Ballistic S = 2 intersystem crossing in a cobalt cubane following ligand-field excitation probed by extreme ultraviolet spectroscopy. Phys. Chem. Chem. Phys. 23, 2699026996 (2021).

View original post here:
Establishing the origin of Marcus-inverted-region behaviour in the excited-state dynamics of cobalt(III) polypyridyl ... - Nature.com

A new compound that binds to a part of the -opioid receptor (OR) could be a useful tool in preventing deaths from opioid overdose. The molecule works in conjunction with naloxone, boosting its effectiveness seven-fold.

Naloxone is an effective treatment for opioid overdose. However, larger and repeated doses are needed in response to overdoses from more potent synthetic opioids such as fentanyl.

In a search for a potent alternative to naloxone, researchers screened a large DNA-encoded chemical library and identified a potential candidate that was highly selective for the -opioid receptor. This new compound codename 368 is a negative allosteric modulator that binds to the OR but at a different site to opioids. The researchers explained that, until now, selective potent negative allosteric modulators for the OR had remained elusive.

The researchers found that when 368 was bound to the OR, it enhanced the binding affinity of naloxone, boosting its potency by over seven-fold. Observations made using cryo-electron microscopy showed that 368 worked cooperatively with naloxone to potently block opioid agonist signalling.

In vivo mouse models revealed that the addition of 368 meant that lower doses of naloxone could be used to effectively inhibit the effects of morphine and fentanyl, while minimising withdrawal symptoms.

Further screening of other negative allosteric modulators could help uncover their mechanism of action and improve the effectiveness of these compounds, the researchers write.

Continue reading here:
Companion compound for naloxone could boost opioid reversal effects, save lives - Chemistry World

By Antonis Stroggylakis/info@eurohoops.net

There were a lot of things that Greece guard Thomas Walkup loved about the win of his team over the Dominican Republic for the Olympic Qualifiers. What particularly pleased him was the level of basketball that he and his teammates delivered in a sold-out Peace and Friendship arena.

Its not just about the winning, Walkup said. Its about the quality of basketball for us. Not just tonight but in general. From the very first day it was about the quality of basketball. And tonight I think we had a pretty good quality of basketball.

Thats an understatement. Greece produced 109 points on 27 assists for just eight turnovers a number that gets even more impressive considering how fast-paced the game was at times. Vassilis Spanoulis players executed with the precision of 36 out of 57 from the field and their offensive prowess and fluidity generated plenty of beautiful plays and highlights.

Everybody is unselfish, everybody is willing to pass, everybodys passing the ball when they should pass the ball, Walkup commented. Its really just fun basketball to be a part of because you see how the ball is moving and how everybodys playing in rhythm.

Follow all the action of the Olympics qualifiers with Courtside 1891 on DAZN

Walkup himself successfully played a perhaps unlikely part of a scorer rather than his usual role of facilitator. He finished with 17 points on 6 out of 9 shots, including 3-6 triples and a couple of key buckets when the Dominican Republic was trying to come back in the game during the third period.

Strangely enough, he didnt register any assists. There was no need to.

Im comfortable wherever I need to be used, Walkup stated. Whats great about this team is that everybody is playing for the guy next to him. Thats what makes it flawless.

Considering that training camp began just two weeks ago, Greece is displaying some enviable chemistry. The kind of which you find in groups that have been together for a long time.

The players communicate with each other on the floor very quickly and quite smoothly, finding each other easily, distributing the ball around with speed and being at the right spot at the right moment for their teammates to find them.

Walkup doesnt believe that this is about any tactic or strategy and attributes this to the mentality that he and the rest of the guys carry on the court.

I think its the character of the team, Walkup mentioned. Everybody is unselfish. Everybody wants the guy beside him to do just as well as themselves. It makes it easy to play for someone else. To play for the next pass, the extra pass. It also helps when you have Giannis who can create everything.

Speaking of Giannis Antetokounmpo, the Milwaukee Bucks superstar had a literally unstoppable performance of 32 points on 11 out of 11 shots. The only way that the Dominican Republic could hope to put any brakes on him was by fouling often rather hard and sending him to the line.

It was great, Walkup said on sharing the floor with Giannis for the first time in an official game. He was flying up and down the court. Hes creating something out of nothing a lot of the times. Nick [Calathes] also did a pretty good job of getting him involved too, giving him a lot of easy buckets. I dont have to tell you guys you can watch the game and see how incredible he is.

The one who has infused Greece with this kind of team ethos is none other than Spanoulis. Walkup went into detail on how the legendary player and now coach set the tone from the get go on what should the dominant mindset around the squad.

From the very first day he said that there are no clubs, no egos, none of that on this team, Walkup explained. From the start, that its about the national team. Its about Greece, representing Greece. This is so much bigger than our clubs, for ourselves, than our families our friends and everything that you typically play for as an individual. Youre playing for something much-much bigger. I think thats where this comes in.

While often the main ball handler with Olympiacos Piraeus, Walkup finds himself adjusting to a different situation on the Greek national team, especially when he shares the floor with star playmaker Nick Calathes.

How does he feel about being the off-the-ball guy for a change?

I love it, Walkup said, rather enthusiastically. Of course there are still times when I do play on the ball. But I think that Nick and guy can help each other and take pressure off each other. Its tiring to play defense, bringing the ball up, create offense. I think we play off each other pretty well.

Continued here:
Greece's Thomas Walkup reveals key to chemistry, praises team unselfishness and Giannis - Eurohoops

That trust definitely showed up on screen and off resulting in viral chemistry. So who would Nyongo want to work with next? When we asked her our signature Unbothered question about what the actress needs right now (in our opinion Black womens needs arent prioritized enough. Period), she had a quick response: What do I need? I need to work on a project that is funny. I need to work on a light and funny project. You can say a lot about Nyong'o's filmography but "light" probably isn't the first word that comes to mind. After winning an Oscar for 12 Years A Slave, Nyong'o's biggest films have been Us, the Black Panther and Star Wars franchises, and spy thriller The 355. None of those are going to leave you in stiches, but as Nyong'o proved in our interview and throughout the Quiet Place press tour, she's got comedy chops. She even has some dream co-stars in mind: "Yahya Abdul-Mateen II or Donald Glover," she says after some thought.

Read more from the original source:
Lupita Nyong'o On Cats & Chemistry With Joseph Quinn - Refinery29

Chemists at the University of Konstanz describe how they have made a very unusual reaction possible.

An old dream of mankind is to combine the best of two worlds: to bring together the advantages of two opposing things without having to accept their disadvantages. This old dream is also being pursued in chemistry: how good would it be to combine the properties of organic and inorganic substances?

Organic substances stand for high functional diversity, while inorganic substances are very stable. The fact that chemists want to bring them together in the form of hybrid materials is nothing new. The only problem is that organic and inorganic substances require very different reaction conditions. You can't just throw them into a pot and stir them twice. Or can you? Prof. Dr. Miriam Unterlass' research group at the University of Konstanz has developed a process that can do just that: a "one-pot synthesis", as the chemists call the process, or rather a "one-pot synthesis".

"One-pot synthesis" means exactly what the name suggests: The very different reagents are not treated separately, but are all brought together in a common vessel. It is very important that the reactions of the different substance classes take place at the same time and synergistically. However, for this to work at all, the right balance must be found between the very different reaction conditions. This is very tricky and requires a lot of laboratory work, but as the chemists in Constance show, it can be very easy with the "right recipe".

"The beauty of our approach lies in its simplicity," emphasizes Frank Sailer, who was instrumental in developing the one-pot synthesis in his doctoral thesis. "Just like a stew, you have to find the right cooking point so that the lentils have not yet disintegrated, but the potatoes are already cooked through." Applied to chemical reactions, this means You need the right ratio of pressure, temperature and time. And, of course, the right ingredients.

"We don't need any toxic catalysts or solvents," says Sailer, citing the advantages of the process - it is therefore sustainable and environmentally friendly. The only solvent used is pure isopropanol (the main component of disinfectants), which is harmless and available in large quantities. The main ingredients of the new material class are special dye molecules, so-called pigments, and layered titanium dioxide.

If it is so simple, why wasn't this reaction process discovered long ago? "Because the idea is very unusual. The organic components are not normally synthesized under such conditions," explains Sailer. Finding such reaction pathways is a declared goal of Miriam Unterlass' working group: she is investigating how chemical synthesis processes can be optimized by choosing the right framework conditions and lead to better, more sustainable results. "We produce better materials in a faster and more environmentally friendly way," explains Miriam Unterlass.

So is it the best of both worlds that has come out of one-pot synthesis? Strictly speaking, it is much more than that. "We don't just want a sum of the properties, but a synergetic interaction," explains Frank Sailer, "new properties that the two starting materials don't have." The new class of material that Sailer and his colleagues have created is virtually predestined for batteries due to its layered structure. The name of the new material class: Pigments@TiO2.

Read the original post:
Chemistry by type of stew - Can it be so easy to combine very different substances in a "one-pot synthesis" to create a ... - Chemie.de

Researchers can ask Generative Chemistry for molecules with desired characteristics, as well as provide information about their targeted application and let the system help determine relevant molecular properties, according to Microsoft. The feature not only will provide them with candidates matching their parameters, but also suggest molecules that have not been seen before with useful properties tuned for a specific application, and whose synthesis is feasible in a reasonable number of steps.

Density Functional Theory (DFT) is a method used across a variety of molecular simulations that helps researchers to simulate and study the electronic structure of atoms, molecules and nanoparticles, as well as surfaces and interfaces. Such DFT simulations can be complex and compute-intensive to optimize and run, often requiring the use of supercomputers.

Microsoft has now added Accelerated DFT as a managed service to Azure Quantum Elements to run these simulations at what the company said is an unprecedented speed; that is, an order of magnitude faster compared to PySCF, a widely used open-source DFT code, according to the post.

The rest is here:
Microsoft bolsters quantum platform with gen AI, molecular simulation capabilities - CIO

At Microsoft, our vision is to empower scientists with the latest breakthroughs in AI to unlock their full creative potential and tackle some of our most pressing challenges. This vision will require bringing the full power of generative AI together with quantum-classical hybrid computing to augment every stage of the scientific method. Whether expanding knowledge research, creating better hypotheses, or accelerating experimentation and analyses, doing so demands a purpose-built cloud platform for science. This is why we built Azure Quantum Elements for chemistry and materials science.

Today, were announcing Generative Chemistry and Accelerated DFT, which will expand the ways researchers can harness the full power of this platform. These breakthrough capabilities will empower scientists to compress the next 250 years of chemistry into the next 25.

With Generative Chemistry, we want to broaden the horizons of scientific exploration. Researchers can generate and explore novel molecules suited for specific industry applications using the latest AI models trained on hundreds of millions of compounds, and then evaluate the steps suggested by the workflow for synthesizing the most promising candidates in a lab more efficiently all in a matter of days rather than years.

With Accelerated DFT, researchers can expedite and scale their chemical discovery pipelines by simulating the quantum-mechanical properties of molecules at an unprecedented speed an order of magnitude faster compared to other Density Functional Theory (DFT) codes.

This brings us closer to a new paradigm for scientific discovery, where advanced AI and digital tools are more accessible than ever to scientists, students, and labs across industries. Below is our vision for how researchers will be able to leverage these breakthrough capabilities to design new molecules and enable the transformation of entire sectors from consumer goods and medicine, to manufacturing and energy, in turn addressing some of our most pressing societal challenges.

YouTube Video

Click here to load media

Were working towards this vision today. As part of the private preview of Azure Quantum Elements, scientists and developers have the opportunity to explore Accelerated DFT today, with the potential to access Generative Chemistry in the coming weeks.

Were already putting our vision into practice by collaborating with Unilever, a global leader in consumer goods, which serves over 3.4 billion people every single day. Unilever is harnessing the power of Microsoft supercomputing and AI services to support their digital R&D transformation and product innovation.

From global ambitions like reversing climate change and pioneering renewable energy sources to personal ones like living more sustainably and using healthier and safer products, we all want to do our part to create a better world. Time is of the essence for many of these goals, with more than 8 million scientists1around the globe working to pioneer innovative solutions and unlock progress. At Microsoft, we aim to empower them with state-of-the-art digital tools to harness the full collective ingenuity of every researcher and lab around the world.

Just as generative AI has unleashed new waves of creativity and improved productivity with collaborative tools like Copilot, we are now bringing AI and natural language processing capabilities to science. Our goal is to integrate AI reasoning into every stage of the scientific method: this requires the power of next-generation AI models to speed up the scientific process from hypothesis to results. It starts with knowledge research and hypothesis generation, connecting the dots by generating millions of potential molecular candidate solutions, then narrowing down candidates with digital experiments and analyzing the outcomes all in a matter of days. We demonstrated how this approach can land real-world results in our collaboration with PNNL, where we screened over 32 million candidates to discover and synthesize a new material that holds the potential for better batteries a tangible example of the possibilities in this new era of scientific discovery.

When powered by natural language tools, this new paradigm will help create an autonomous reasoning loop with AI at every stage as a scientific assistant. It will redefine how we approach innovation by democratizing these capabilities for breakthrough discoveries.

Generative Chemistry will unleash a new wave of creativity for scientists tasked with discovering and designing new molecules. This will enable breakthrough growth across many industries, whether helping an oil and gas company discover a stronger fuel additive for enhancing the longevity of engine life, or an adhesive firm creating a new chemical for strengthening adhesion while removing unwanted residue.

We could compare this discovery process to searching for a small box in a large, crowded and dark warehouse with one small flashlight. We can only focus the light on a small area at a time while the rest of the warehouse remains completely dark and unknown. Generative AI gives us a much smarter light that can point in new directions, providing visibility where we may not have considered or have been able to look before.

Researchers can ask Generative Chemistry for molecules with desired characteristics, such as the ability to degrade rapidly or be recycled more easily. They can also provide information about their targeted application and let the system help determine relevant molecular properties. After a few more steps, they receive a set of candidates matching those parameters for further study.

However, simply generating candidates is not sufficient for transforming the discovery process with AI. The essential criteria for computational tools in chemistry are that they help scientists discover molecules that are novel, synthesizable and useful in the real world. This is why Im excited to see our approach to Generative Chemistry come to life, suggesting molecules that have not been seen before, with useful properties tuned for a specific application, and whose synthesis is feasible in a reasonable number of steps.

For this reason, Generative Chemistry will offer researchers potential steps to consider as they develop their recipe for synthesizing these molecular candidates in a laboratory. Support for this critical component has been developed from the capabilities of our AutoRXN software, exploring chemical reactions in reverse order, which can help to evaluate synthesis pathways for creating a target molecule.

This capability is truly groundbreaking for scientific discovery. Businesses and research groups can look for efficient, cost-effective and innovative methods to develop new molecules in a matter of days, compressing the iterative process of extensive database searches and trial-and-error laboratory experiments. This end-to-end workflow will provide scientists with entirely new compounds that could lead to the next breakthrough in manufacturing, medicine and more.

Were also announcing Accelerated DFT to offer a simplified and more powerful quantum chemistry solution for scientists. For the past few decades, DFT has been an extremely popular method used across a variety of molecular simulations, helping researchers to simulate and study the electronic structure of atoms, molecules and nanoparticles, as well as surfaces and interfaces.

We can liken molecular systems to traffic systems, where cars moving in various directions at different speeds represent electrons.
From a traffic helicopter, we can observe the overall flow of traffic even if we dont know each cars speed and destination. DFT provides this helicopter view of molecular systems, simplifying the complex task of tracking individual electrons by instead mapping out the density of them at a higher altitude.

Such DFT simulations can be complex to optimize and run, and often require supercomputer-scale resources. This is why our managed DFT service, based on innovation developed by Microsoft Research, enables researchers to perform substantially faster calculations than other DFT codes and offers a 20-fold average increase in speed compared to PySCF, a widely used open-source DFT code.

Accelerated DFT is already used by many organizations such as AspenTech, DTU Energy University of Denmark and Unilever. It seamlessly integrates into broader chemistry and materials science workflows, and paves the way for expediting innovations in therapeutics, environmental sustainability and beyond.

You can learn more about this announcement in the technical blog, Introducing two powerful new capabilities in Azure Quantum Elements: Generative Chemistry and Accelerated DFT.

Unilever stands at the forefront of the consumer goods industry, with a strong portfolio of household brands that are used by 3.4 billion people every day, including Dove, TRESemm, Omo, Degree, Hellmanns and Ben & Jerrys. Whether cleaning, beauty or care products, each requires the latest scientific breakthroughs to ensure the best possible consumer experience and enhance daily life.

Over the past two and a half years, Unilever has worked with Microsoft to identify new digital capabilities to drive product innovation forward. Unilever is bringing its digital vision to life through the transformational DataLab its digital counterpart to the companys physical laboratories with the help of Microsoft Azure. From unlocking the secrets of our skins microbiome to reducing the carbon footprint of a multi-billion-dollar business, Unilever is redefining what it means to be a consumer goods company in the modern world with leading science.

YouTube Video

Click here to load media

With Copilot and the advanced simulation capabilities of Azure Quantum Elements, Unilever can query scientific information using natural language, performing thousands of computational simulations in the time it would take to run tens of laboratory experiments. Unilever scientists can use the data gathered from these simulations to fine-tune models that screen tens of thousands of materials at substantial speed or enable the exploration of intricate chemical reactions.

For example, R&D teams can expand their search space for novel molecules that restore natural bonds in hair fibers across more hair types, in turn redefining the standards of personalized hair care for brands like Dove and TRESemm. Furthermore, by placing scaled simulations at the forefront of the discovery funnel, Unilever will be further empowered to expedite the delivery of solutions within their key sustainability focus areas.

Digital tools are unlocking an unprecedented age of scientific discovery. Using advanced computing power and AI, we are able to compress decades of lab work into days, accessing a level of insight we could not previously have imagined. This technological leap, coupled with our vast repository of proprietary data and a century of expertise in personal and household care, means our scientists are able to lead the industry in developing the next generation of consumer goods. Alberto Prado, Global Head of R&D Digital and Partnerships at Unilever

We stand on the cusp of unprecedented innovation, and at Microsoft, we continue to pioneer state-of-the-art solutions to usher in a new era of scientific discovery. We remain focused on achieving scaled quantum computing and more breakthroughs on our path to engineering our topological qubits with inherent hardware-level stability.

Earlier this year, we demonstrated with Quantinuum the most reliable logical qubits on record, further advancing the state-of-the-art for quantum computing. And recently, we simulated a chemical catalyst combining classical supercomputers, AI and logical qubits created with Microsofts qubit-virtualization system and Quantinuums H1 hardware. This combination holds the key to unlocking scientific breakthroughs enabled by a new generation of hybrid-computing applications.

In the coming months, we will bring advanced logical qubit capabilities using our software and Quantinuums hardware in private preview in Azure Quantum Elements. As logical qubit capabilities scale to deliver increasingly reliable results, we will unlock simulation accuracy, moving us from scientific advantage to commercial advantage, and ultimately to solving some of the worlds most pressing problems.

Were committed to advancing these technologies responsibly, always focusing on innovation, empowerment and trust. Thats why we are committed to responsible computing practices and the Microsoft AI principles, to help ensure that safety measures adequately account for the increasing power of AI and quantum.

For more information about todays announcements:

Top image: Leaders from Unilever and Microsoft discuss the Azure Quantum Elements program.

Sources

1. Statistics and resources | 2021 Science Report. This translates into 8.854 million full-time equivalent (FTE) researchers by 2018.

Tags: Accelerated DFT, AI, Azure Quantum Elements, Generative Chemistry, quantum computing

See more here:
Empowering every scientist with AI-augmented scientific discovery - The Official Microsoft Blog - Microsoft