Homogeneous Gold Catalysis: understanding ligand and counterion effects, first steps in green chemistry

Since the last 20 years, homogeneous gold catalysis is receiving considerable attention and great efforts have been made to disclose the mechanism of the catalytic cycle and the role of many variables: nature of the ligand, structure of the catalyst, effect of the additives, etc. Although a wealth of empirical information on ligand effects is now available on homogeneous gold catalysis, the development of new L-Au-X catalysts and reactions continues to rely upon trial and error, and the outcome of the reaction is often unpredictable. The mechanistic understanding of the gold(I)-catalysed nucleophilic addition to a carbon-carbon unsaturated bond has been pursued and appreciably extended in this thesis by experimental and theoretical investigations. We focused our study on weak interactions and counterion effects with the aim to better understand these often not considered variables. We explained that the anion is influencing each single step of the catalysis and that it is modulating its role depending on its nature (coordination power and basicity) and position. Of course, its effect is also depending on the type of reaction and on which is the rate determining step of the latter. This deep study on the ligands and counterions role in gold homogeneous catalysis, matching both experimental and theoretical studies, allow us to setup a green, room temperature, acid-free, solvent-free and sustainable methodology for the hydration of alkynes. This reaction is generally working only with acidic additives and at high temperature, thereby here is reported for the first time an innovative way to perform it. These preliminary studies open new avenues to consider and rationalize the homogeneous gold catalysis, spreading light into the weak interactions that were underestimated in this field for a long time. This study clearly demonstrates that the interplay between ligand nature and anion effect is crucial in different steps of the catalytic cycle. The multiple roles played by counterions and L-Au+ fragments in chemical transformations require more comprehensive computational and experimental studies of the ligand/anion correlatio

Selectively measuring π back-donation in gold(I) complexes by NMR spectroscopy

Even though the Dewar-Chatt-Duncanson model has been successfully used by chemists since the 1950s, no experimental methodology is yet known to unambiguously estimate the constituents (donation and back-donation) of a metal-ligand interaction. It is demonstrated here that one of these components, the metal-to-ligand π back-donation, can be effectively probed by NMR measurements aimed at determining the rotational barrier of a C-N bond (ΔHr (≠) ) of a nitrogen acyclic carbene ligand. A large series of gold(I) complexes have been synthesized and analyzed, and it was found that the above experimental observables show an accurate correlation with back-donation, as defined theoretically by the appropriate charge displacement originated upon bond formation. The proposed method is potentially of wide applicability for analyzing the ligand effect in metal catalysts and guiding their design

Experimental validation of specificity of the squamous cell carcinoma antigen-immunoglobulin M (SCCA-IgM) assay in patients with cirrhosis

Background: Squamous cell carcinoma antigen-immunoglobulin M (SCCA-IgM) is a useful biomarker for the risk of development of hepatocellular carcinoma (HCC) in patients with cirrhosis due to its progressive increase associated to HCC evolution. In patients with cirrhosis, other assays have been affected by interfering reactivities of IgM. In this study, the analytical specificity of the SCCA-IgM assay was assessed by evaluating SCCA-IgM measurement dependence on different capture phases, and by measuring the recovery of SCCA-IgM reactivity following serum fractionation. Methods: Serum samples from 82 patients with cirrhosis were analyzed. SCCA-IgM was measured using the reference test (Hepa-IC, Xeptagen, Italy) that is based on rabbit oligoclonal anti-squamous cell carcinoma antigen (SCCA) and a dedicated ELISA with a mouse monoclonal anti-SCCA as the capture antibody. Results: SCCA-IgM concentrations measured with the reference assay (median value=87 AU/mL) were higher than those measured with the mouse monoclonal test (median value=78 AU/mL). However, the differences in the SCCA-IgM distribution were not statistically significant (p>0.05). When SCCA-IgM concentrations measured with both tests were compared, a linear correlation was found (r=0.77, p<0.05). Fractionation of the most reactive sera by gel-filtration chromatography showed that total recovery of SCCA-IgM reactivity was seen only in the fractions corresponding to components with a molecular weight higher than IgM and SCCA (>2000 kDa) with both tests. Conclusions: The equivalence of both SCCA-IgM assays and the absence of reactivity not related to immune complexes support the analytical specificity of SCCA-IgM measurements. The results validate the assessment of SCCA-IgM for prognostic purposes in patients with cirrhosis. Clin Chem Lab Med 2010;48:217–23.Peer Reviewe

Disclosing the multi-faceted world of weakly interacting inorganic systems by means of NMR spectroscopy

The potential of NMR spectroscopy to investigate inorganic systems assembled by, or whose reactivity is affected by, non-covalent interactions is described. Subjects that have received particular attention in recent years (halogen bonding and Frustrated Lewis Pairs) and more classical subjects that remain under-explored (self-aggregation of ion pairs in low polar solvents, behavior of MAO containing metallocenium ion pairs, and hydrogen bonding/ion pairing effects in Au(I) catalysis) are considered, using an innovative approach, always focusing on the crucial information that can be provided by NMR

Impact of Host Genes and Strand Selection on miRNA and miRNA* Expression

Dysregulation of miRNAs expression plays a critical role in the pathogenesis of genetic, multifactorial disorders and in human cancers. We exploited sequence, genomic and expression information to investigate two main aspects of post-transcriptional regulation in miRNA biogenesis, namely strand selection regulation and expression relationships between intragenic miRNAs and host genes. We considered miRNAs expression profiles, measured in five sizeable microarray datasets, including samples from different normal cell types and tissues, as well as different tumours and disease states. First, the study of expression profiles of “sister” miRNA pairs (miRNA/miRNA*, 5′ and 3′ strands of the same hairpin precursor) showed that the strand selection is highly regulated since it shows tissue-/cell-/condition-specific modulation. We used information about the direction and the strength of the strand selection bias to perform an unsupervised cluster analysis for the sample classification evidencing that is able to distinguish among different tissues, and sometimes between normal and malignant cells. Then, considering a minimum expression threshold, in few miRNA pairs only one mature miRNA is always present in all considered cell types, whereas the majority of pairs were concurrently expressed in some cell types and alternatively in others. In a significant fraction of concurrently expressed pairs, the major and the minor forms found at comparable levels may contribute to post-transcriptional gene silencing, possibly in a coordinate way. In the second part of the study, the behaved tendency to co-expression of intragenic miRNAs and their “host” mRNA genes was confuted by expression profiles examination, suggesting that the expression profile of a given host gene can hardly be a good estimator of co-transcribed miRNA(s) for post-transcriptional regulatory networks inference. Our results point out the regulatory importance of post-transcriptional phases of miRNAs biogenesis, reinforcing the role of such layer of miRNA biogenesis in miRNA-based regulation of cell activities

A conjecture on Fermi-Pasta-Ulam and Toda models

In this thesis we will solve a conjecture on Fermi-Pasta-Ulam and Toda chains written in the continuum limit N to infinity: this says that every first integral of the Toda chain admits an extension to the 4th order in the perturbative parameter h that is an approximated first integral of FPU

APPLICATORE ED APPARECCHIATURA PER ELETTROPORAZIONE

Electroporation apparatus and applicator, wherein the applicator comprises a flexible support (2) which defines a plurality of housing seats (7), and a plurality of electrodes (3) each comprising a conductive needle (4) and mountable in the housing seats (7); the support (2) comprises at least a first layer (13) which comprises a sheet (15) of flexible plastic material and, at each housing seat (7), a rigid guiding element (16), made of plastic material and in which the needle (4) of one of the electrodes (3) can be slidably inserted, a first end (10) of an electric conductor (9) being aligned with each housing seat (7) to be in electrical contact with a needle (4) inserted into said housing seat (7), the electrical conductors (9) extending themselves into a second layer (14) of the support (2). Pubblicazione PCT 21 marzo 2019 numero WO2019/05360

Toward Optimizing the Performance of Homogeneous L‑Au‑X Catalysts through Appropriate Matching of the Ligand (L) and Counterion (X^–)

The effects of the ligand (L) and counterion (X^–) are considered the two most important factors in homogeneous gold catalysis, but a rational understanding of their synergy/antagonism is still lacking. In this work, we synthesized a set of 16 gold complexes of the type L-Au-X that differ as follows: (i) L = PPh₃ (<b>L1</b>), P­(^<i>t</i>Bu)₃ (<b>L2</b>), tris­(3,5-bis­(trifluoromethyl)­phenyl)­phosphine (PArF, <b>L3</b>), and 1,3-bis­(2,6-diisopropylphenyl)­imidazol-2-ylidene (NHC, <b>L4</b>), with the deliberate purpose of varying the electron withdrawing ability of the ligand, and (ii) X^– = BF₄^–, OTf^–, OTs^–, and TFA^–, which have various coordinating abilities, basicities, and hydrogen bond acceptor powers. All these catalysts were tested in two different model reactions: the cycloisomerization of <i>N</i>-(prop-2-ynyl)­benzamide to 2-phenyl-5-vinylidene-2-oxazoline and the methoxylation of 3-hexyne. The main results are that the choice of the most efficient L-Au-X catalyst for a given process should not be made by evaluating the properties of L and X^– alone, but rather based on their best combination. For NHC-Au-X, the noncoordinating and weakly basic anions (such as BF₄^– and OTf^–) have been recognized as the best choice for the cycloisomerization of <i>N</i>-(prop-2-ynyl)­benzamide. On the other side, the intermediate coordinating ability and basicity of OTs^– provide the best compromise for achieving an efficient methoxylation of 3-hexyne. A completely different trend is found in the case of complexes bearing phosphanes: OTs^– and TFA^– have been found to accelerate the cycloisomerization of <i>N</i>-(prop-2-ynyl)­benzamide, and BF₄^– and OTf^– are suitable for the methoxylation of 3-hexyne. A possible explanation of the observed differences between phosphane and NHC ancillary ligands might be found in the higher affinity of the counterion (especially OTs^–) for the gold fragment for phosphane instead of NHC

Ion pairing in cationic NHC and NAC gold(I) \u3b72-alkyne complexes

Gold(I) cationic complexes of general formula [LAu+ X-] [L = NAC (Nitrogen-Acyclic-Carbene) or NHCs (N-Heterocyclic Carbenes), X- = weakly coordinating anion] are successfully employed as catalysts in a large variety of organic reactions involving the activation of unsaturated carbon-carbon bonds. A key role in such reactions is played by the counterion. We have studied the ion pair structure in solution of [NHC-Au(\u3b72-3-hexyne)]BF4 and [NAC-Au(\u3b72-3-hexyne)]BF4 by NOE NMR spectroscopy and relativistic DFT calculation. In our previous work, two main orientations were observed for unsaturated NHC ligands: one with the anion close to the carbene backbone (A, most populated) and another with the anion close to the 3-hexyne (B). Here we focus on the effect of different carbenes on the ion pair structure, comparing the aromatic NHC (1BF4) with 5 different ligands: a non aromatic NHC (2BF4), a polycyclic ligand with an extended aromatic system (3BF4) and three different NAC (4BF4, 5BF4 and 6BF4). For 2BF4, the A:B ratio (observed with NOE NMR spectroscopy) remains almost the same as for 1BF4, whilst the ion pair structure of the 3BF4 becomes mainly non-specific, with a slight preference for the orientation B. Both cases can be explained analyzing the DFT Coulomb potential map, that shows an attractive region on the backbone of 2BF4 and a flat weak potential around the whole 3BF4. An interesting result was obtained for 4BF4 that shows a strong attractive region close to the two N-H that makes the IP 100% specific for the orientation A (figure beside). 5BF4 shows a less specific ion pair due to the presence of only one N-H on the back. For the 6BF4 the -OH group on the arm of the carbene introduce a third ion pair configuration, strongly stabilized by the hydrogen bond between the hydroxyl and the anion

Cyclization of 2-Alkynyldimethylaniline on Gold(I) Cationic and Neutral Complexes

The cyclization reaction of 2-(1-hexynyl)dimethylaniline (S) on gold(I) has been studied by NMR spectroscopy, in order to characterize the ion pair structure of the product, [LAuSc]BF4. The latter is a good model for the catalytic intermediate between the nucleophilic attack and the protodeauration step of a typical gold catalytic cycle. 19F, 1H HOESY NMR results demonstrate that in [LAuSc]BF4, with L being three different ligands, the anion mainly interacts with the ammonium moiety of the substrate, thanks to its formal positive charge, even if the ligand can tune the exact position of the anion. Furthermore, also gold chloride is able to promote the cyclization of S, forming [ClAuSc], which is the first example of a new class of precatalysts with potentially interesting catalytic properties. Preliminary data on its catalytic performances and a detailed DFT characterization of its electronic properties are presented, both of which indicate that Sc behaves as a carbene. \ua9 2016 American Chemical Society