Dissipative Systems Driven by the Decarboxylation of Activated Carboxylic Acids.

ConspectusThe achievement of artificial systems capable of being maintained in out-of-equilibrium states featuring functional properties is a main goal of current chemical research. Absorption of electromagnetic radiation or consumption of a chemical species (a "chemical fuel") are the two strategies typically employed to reach such out-of-equilibrium states, which have to persist as long as one of the above stimuli is present. For this reason such systems are often referred to as "dissipative systems". In the simplest scheme, the dissipative system is initially found in a resting, equilibrium state. The addition of a chemical fuel causes the system to shift to an out-of-equilibrium state. When the fuel is exhausted, the system reverts to the initial, equilibrium state. Thus, from a mechanistic standpoint, the dissipative system turns out to be a catalyst for the fuel consumption. It has to be noted that, although very simple, this scheme implies the chance to temporally control the dissipative system. In principle, modulating the nature and/or the amount of the chemical fuel added, one can have full control of the time spent by the system in the out-of-equilibrium state.In 2016, we found that 2-cyano-2-phenylpropanoic acid (1a), whose decarboxylation proceeds smoothly under mild basic conditions, could be used as a chemical fuel to drive the back and forth motion of a catenane-based molecular switch. The acid donates a proton to the catenane that passes from the neutral state A to the transient protonated state B. Decarboxylation of the resulting carboxylate (1acb), generates a carbanion, which, being a strong base, retakes the proton from the protonated catenane that, consequently, returns to the initial state A. The larger the amount of the added fuel, the longer the time spent by the catenane in the transient, out-of-equilibrium state. Since then, acid 1a and other activated carboxylic acids (ACAs) have been used to drive the operation of a large number of dissipative systems based on the acid-base reaction, from molecular machines to host-guest systems, from catalysts to smart materials, and so on. This Account illustrates such systems with the purpose to show the wide applicability of ACAs as chemical fuels. This generality is due to the simplicity of the idea underlying the operation principle of ACAs, which always translates into simple experimental requirements.

Kinetic Trapping of an Out-of-Equilibrium Dynamic Library of Imines by Changing Solvent.

A well-behaved dynamic library composed of two imines and corresponding amines was subjected to the action of an activated carboxylic acid (ACA), whose decarboxylation is known to be base promoted, in different solvents, namely CD2Cl2, CD3CN, and mixtures of them. Two non-equilibrium systems are consequently obtained: i) a dissipative (CD2Cl2) and ii) an out-of-equilibrium (CD3CN) dynamic library whose composition goes back to equilibrium after a given time. In the former case, the library is fully coupled with the decarboxylation of the ACA, while in the latter, an energy ratchet operates. In the mixed solvents, the library exhibits a mediated behavior. Interestingly, in the presence of an excess of added ACA, the different behavior of the imine library in the two solvents is expected to manifest only when the excess acid is consumed.

Signal Transduction Allows Temporal Control of the Potential of a Concentration Cell Driven by the Decarboxylation of an Activated Carboxylic Acid.

The use of Activated Carboxylic Acids (ACAs) allows the time-controlled operation of dissipative chemical systems based on the acid-base reaction by providing both the stimulus that temporarily drives a physicochemical change and, subsequently, the counter-stimulus with a single reagent addition. However, their application is inherently limited to acid-sensitive systems. To overcome this limitation, we herein develop a straightforward device for the transduction of the acid-base stimuli delivered by an ACA into a voltage signal that, in turn, is used to control voltage-sensitive circuits that are not pH-responsive by themselves. The signal transductor can be easily assembled from common laboratory equipment and employs aqueous solutions of readily available chemicals. Furthermore, the operator can simply and intuitively tune the amplitude of the voltage signal, as well as its duration and offset by varying the concentration of the chemical species involved in the transduction process.

Proximity Effects on the Reactivity of a Nonheme Iron (IV) Oxo Complex in C-H Oxidation.

Precise control of substrate positioning and orientation (its proximity to the reactive unit) is often invoked to rationalize the superior enzymatic reaction rates and selectivities when compared to synthetic models. Artificial nonheme iron (IV) oxo (Fe(IV)=O) complexes react with C(sp3)-H bonds via a biomimetic Hydrogen Atom Transfer/Hydroxyl Rebound mechanism, but rates, site-selectivity and even hydroxyl rebound efficiency (ligand rebound versus substrate radical diffusion) are smaller than in oxygenases. Herein, we quantitatively analyze how substrate binding modulates nonheme Fe(IV)=O reactivity by comparing rates and outcomes of C-H oxidation by a pair of Fe(IV)=O complexes that share the same first coordination sphere but only one contains a crown ether receptor that recognizes the substrate. Substrate binding makes the reaction intramolecular, exhibiting Michaelis-Menten kinetics and increased reaction rates. In addition, C-H oxidation occurs with high site selectivity for remote sites. Analysis of Effective Molarity reveals that the system operates at its maximal theoretical capability for the oxidation of these remote sites. Remarkably, substrate positioning also affects Hydroxyl Rebound, whose efficiency only increases on the sites placed in proximity by recognition. Overall, these observations provide evidence that supramolecular control of substrate positioning can effectively modulate the reactivity of oxygenases and its models.

A Doubly Dissipative System Driven by Chemical and Radiative Stimuli.

The operation of a dissipative network composed of two or three different crown-ether receptors and an alkali metal cation can be temporally driven by the use (combined or not) of two orthogonal stimuli of a different nature. More specifically, irradiation with light at a proper wavelength and/or addition of an activated carboxylic acid, are used to modulate the binding capability of the above crown-ethers towards the metal ion, allowing to control over time the occupancy of the metal cation in the crown-ether moiety of a given ligand. Thus, application of either or both of the stimuli to an initially equilibrated system, where the metal cation is distributed among the crown-ether receptors depending on the different affinities, causes a programmable change in the receptor occupancies. Consequently, the system is induced to evolve to one or more out-of-equilibrium states with different distributions of the metal cation among the different receptors. When the fuel is exhausted or/and the irradiation interrupted, the system reversibly and autonomously goes back to the initial equilibrium state. Such results may contribute to the achievement of new dissipative systems that, taking advantage of multiple and orthogonal stimuli, are featured with more sophisticated operating mechanisms and time programmability.

Site-selective methylene C-H oxidation of an alkyl diamine enabled by supramolecular recognition using a bioinspired manganese catalyst.

Site-selective oxidation of aliphatic C-H bonds is a powerful synthetic tool because it enables rapid build-up of product complexity and diversity from simple precursors. Besides the poor reactivity of alkyl C-H bonds, the main challenge in this reaction consists in differentiating between the multiple similar sites present in most organic molecules. Herein, a manganese oxidation catalyst equipped with two 18-benzo-6-crown ether receptors has been employed in the oxidation of the long chain tetradecane-1,14-diamine. 1H-NMR studies evidence simultaneous binding of the two protonated amine moieties to the crown ether receptors. This recognition has been used to pursue site-selective oxidation of a methylenic site, using hydrogen peroxide as oxidant in the presence of carboxylic acids as co-ligands. Excellent site-selectivity towards the central methylenic sites (C6 and C7) is observed, overcoming selectivity parameters derived from polar deactivation by simple amine protonation and selectivity observed in the oxidation of related monoprotonated amines.

Controlling the Conformation of 2-Dimethylaminobiphenyls by Transient Intramolecular Hydrogen Bonding.

Temporal control of molecular motions is receiving increasing attention because it is central to the development of molecular switches and motors and nanoscopic materials with life-like properties. Inspired by previous studies, here, we report that acid 12 can be used to temporally control the conformational freedom around the C-C bond connecting the two aromatic rings of the ditopic bases 4 and 5. Consistent with NMR measurements and DFT calculations, before fuel addition, the conformational motion of the two aromatic rings of both 4 and 5 mainly consists of a large amplitude torsional oscillation spanning about 260° and passing for the anti conformation (the two nitrogen atoms at opposite sides). Immediately after the addition of 12, due to the protonation of one nitrogen and consequent formation of an N-H···N intramolecular hydrogen bond, the torsional oscillation in both 4H+ and 5H+ is not only restricted to a smaller range (about 100°) but explores the previously forbidden conformational space around the syn conformation (the two nitrogen atoms at the same side). However, the new state is an out-of-equilibrium state since decarboxylation of the conjugate base of 12 takes place and, at the end of the process, the system reverts to the more conformationally mobile state.

Dissipative Dynamic Covalent Chemistry (DDCvC) Based on the Transimination Reaction.

This work reports that the composition of a dynamic library (DL) of interconverting imines can be controlled over time in a dissipative fashion by the addition of an activated carboxylic acid used as a chemical fuel. When the fuel is added to the DL, which is initially under thermodynamic equilibrium, the composition of the mixture dramatically changes and a new, dissipative (out of equilibrium) state is reached that persists until fuel exhaustion. Thus, a transient dissipative dynamic library (DDL) is generated that, eventually, reverts back to the initial DL when the fuel is consumed, closing a DL→DDL→DL cycle. The larger the amount of added fuel, the longer the time spent by the system in the DDL state. The transimination reaction is shown to be an optimal candidate for the realization of a dissipative dynamic covalent chemistry (DDCvC).

Two Faces of the Same Coin: Coupling X-Ray Absorption and NMR Spectroscopies to Investigate the Exchange Reaction Between Prototypical Cu Coordination Complexes.

The satisfactory rationalization of complex reactive pathways in solution chemistry may greatly benefit from the combined use of advanced experimental and theoretical complementary methods of analysis. In this work, we combine X-Ray Absorption and 1 H NMR spectroscopies with state-of-the-art Multivariate Curve Resolution and theoretical analyses to gain a comprehensive view on a prototypical reaction involving the variation of the oxidation state and local structure environment of a selected metal ion coordinated by organic ligands. Specifically, we investigate the 2-cyano-2-phenylpropanoic acid reduction of the octahedral complex established by the Cu2+ ion with terpyridine to the tetrahedral complex formed by Cu+ and neocuproine. Through our interdisciplinary approach we gain insights into the nature, concentration time evolution and structures of the key metal (XAS measurements) and organic (1 H NMR measurements) species under reaction. We believe our method may prove to be useful in the toolbox necessary to understand the mechanisms of reactive processes of interest in solution.

Temporal Control of the Host-Guest Properties of a Calix[6]arene Receptor by the Use of a Chemical Fuel.

The host-guest interaction of a 1,3,5-trisaminocalix[6]arene receptor with N-methylisoquinolinium trifluoromethanesulfonate (Kass of 500 ± 30 M-1 in CD2Cl2) can be dissipatively driven by means of 2-cyano-2-(4'-chloro)phenylpropanoic acid used as a convenient chemical fuel. When the fuel is added to a dichloromethane solution containing the above complex, the host is induced to immediately release the guest in the bulk solution. Consumption of the fuel allows the guest to be re-uptaken by the host. The operation can be satisfactorily reiterated with four subsequent additions of fuel, producing four successive release-reuptake cycles. The percentage of the guest temporarily released in the bulk solution by the host and the time required for the reuptake process can be finely regulated by varying the quantities of added fuel.

New horizons for catalysis disclosed by supramolecular chemistry.

The adoption of a supramolecular approach in catalysis promises to address a number of unmet challenges, ranging from activity (unlocking of novel reaction pathways) to selectivity (alteration of the innate selectivity of a reaction, e.g. selective functionalization of C-H bonds) and regulation (switch ON/OFF, sequential catalysis, etc.). Supramolecular tools such as reversible association and recognition, pre-organization of reactants and stabilization of transition states upon binding offer a unique chance to achieve the above goals disclosing new horizons whose potential is being increasingly recognized and used, sometimes reaching the degree of ripeness for practical use. This review summarizes the main developments that have opened such new frontiers, with the aim of providing a guide to researchers approaching the field. We focus on artificial supramolecular catalysts of defined stoichiometry which, under homogeneous conditions, unlock outcomes that are highly difficult if not impossible to attain otherwise, namely unnatural reactivity or selectivity and catalysis regulation. The different strategies recently explored in supramolecular catalysis are concisely presented, and, for each one, a single or very few examples is/are described (mainly last 10 years, with only milestone older works discussed). The subject is divided into four sections in light of the key design principle: (i) nanoconfinement of reactants, (ii) recognition-driven catalysis, (iii) catalysis regulation by molecular machines and (iv) processive catalysis.

Dissipative control of the fluorescence of a 1,3-dipyrenyl calix[4]arene in the cone conformation.

The temporal control (ON/OFF/ON) of the fluorescence of a dichloromethane/acetonitrile 1 : 1 solution of calixarene 3 decorated with two pyrenyl moieties at the upper rim is attained by the addition of CCl3CO2H used as a convenient chemical fuel.

Activation of C-H bonds by a nonheme iron(IV)-oxo complex: mechanistic evidence through a coupled EDXAS/UV-Vis multivariate analysis.

The understanding of reactive processes involving organic substrates is crucial to chemical knowledge and requires multidisciplinary efforts for its advancement. Herein, we apply a combined multivariate, statistical and theoretical analysis of coupled time-resolved X-ray absorption (XAS)/UV-Vis data to obtain detailed mechanistic information for on the C-H bond activation of 9,10-dihydroanthracene (DHA) and diphenylmethane (Ph2CH2) by the nonheme FeIV-oxo complex [N4Py·FeIV(O)]2+ (N4Py = N,N-bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine) in CH3CN at room temperature. Within this approach, we determine the number of key chemical species present in the reaction mixtures and derive spectral and concentration profiles for the reaction intermediates. From the quantitative analysis of the XAS spectra the transient intermediate species are structurally determined. As a result, it is suggested that, while DHA is oxidized by [N4Py·FeIV(O)]2+ with a hydrogen atom transfer-electron transfer (HAT-ET) mechanism, Ph2CH2 is oxidized by the nonheme iron-oxo complex through a HAT-radical dissociation pathway. In the latter process, we prove that the intermediate FeIII complex [N4Py·FeIII(OH)]2+ is not able to oxidize the diphenylmethyl radical and we provide its structural characterization in solution. The employed combined experimental and theoretical strategy is promising for the spectroscopic characterization of transient intermediates as well as for the mechanistic investigation of redox chemical transformations on the second to millisecond time scales.

Time Programmable Locking/Unlocking of the Calix[4]arene Scaffold by Means of Chemical Fuels.

In this work, we report that 2-cyano-2-phenylpropanoic acid and its p-Cl, p-CH3 and p-OCH3 derivatives can be used as chemical fuels to control the geometry of the calix[4]arene scaffold in its cone conformation. It is shown that, under the action of the fuel, the cone calix[4]arene platform assumes a "locked" shape with two opposite aromatic rings strongly convergent and the other two strongly divergent ("pinched cone" conformation). Only when the fuel is exhausted, the cone calix[4]arene scaffold returns to its resting, "unlocked" shape. Remarkably, the duration of the "locked" state can be controlled at will by varying the fuel structure or amount. A kinetic study of the process shows that the consume of the fuel is catalyzed by the "unlocked" calixarene that behaves as an autocatalyst for its own production. A mechanism is proposed for the reaction of fuel consumption.

Direct Mechanistic Evidence for a Nonheme Complex Reaction through a Multivariate XAS Analysis.

In this work, we propose a method to directly determine the mechanism of the reaction between the nonheme complex FeII(tris(2-pyridylmethyl)amine) ([FeII(TPA)(CH3CN)2]2+) and peracetic acid (AcOOH) in CH3CN, working at room temperature. A multivariate analysis is applied to the time-resolved coupled energy-dispersive X-ray absorption spectroscopy (EDXAS) reaction data, from which a set of spectral and concentration profiles for the reaction key species is derived. These "pure" extracted EDXAS spectra are then quantitatively characterized by full multiple scattering (MS) calculations. As a result, structural information for the elusive reaction intermediates [FeIII(TPA)(κ2-OOAc)]2+ and [FeIV(TPA)(O)(X)]+/2+ is obtained, and it is suggested that X = AcO- in opposition to X = CH3CN. The employed strategy is promising both for the spectroscopic characterization of reaction intermediates that are labile or silent to the conventional spectroscopic techniques, as well as for the mechanistic understanding of complex redox reactions involving organic substrates.

Controlling the liberation rate of the in situ release of a chemical fuel for the operationally autonomous motions of molecular machines.

Second-order rate constants of the aminolysis of 2-cyano-2-phenylpropanoic anhydride 3 by a series of N-methylanilines differently substituted in the aromatic moiety (4a-d) were measured in dichloromethane. The common reaction product of aminolysis is 2-cyano-2-phenylpropanoic acid 1, which is known to be an effective fuel for acid-base driven molecular machines, but cannot be used in molar excess with respect to the machine. The motivation behind the kinetic study has been the prospect of using the aminolysis of 3 to supply the machine with fuel at a rate that is never so high as to overfeed the system, thus avoiding the malfunction of the machine with concomitant waste of fuel. Knowledge of the kinetic parameters dictated the choice of 4c as the best nucleophile in the lot for feeding acid 1 into a catenane-based molecular machine at a rate that ensured a correct operation.

Abiotic Chemical Fuels for the Operation of Molecular Machines.

Natural molecular machines require a continuous fuel supply to perform motions and/or remain in a functional state. Consequently, the aim of developing artificial devices and materials with life-type properties has motivated a growing interest in abiotic chemical fuels and in their supply modalities. Many artificial molecular machines have been developed in which the sequential addition of several chemical reagents allows the machine to perform complete cycles of motion. Only recently, examples of molecular machines whose cycles of motion are triggered by a single pulse of fuel have been reported. The latter systems are the object of this Minireview where the abiotic chemical fuels used so far to trigger the complete cycles of motion of molecular machines are described, with particular emphasis on the operation mechanism of the machine/fuel systems.

Predictable Selectivity in Remote C-H Oxidation of Steroids: Analysis of Substrate Binding Mode.

Predictability is a key requirement to encompass late-stage C-H functionalization in synthetic routes. However, prediction (and control) of reaction selectivity is usually challenging, especially for complex substrate structures and elusive transformations such as remote C(sp3 )-H oxidation, as it requires distinguishing a specific C-H bond from many others with similar reactivity. Developed here is a strategy for predictable, remote C-H oxidation that entails substrate binding to a supramolecular Mn or Fe catalyst followed by elucidation of the conformation of the host-guest adduct by NMR analysis. These analyses indicate which remote C-H bonds are suitably oriented for the oxidation before carrying out the reaction, enabling prediction of site selectivity. This strategy was applied to late-stage C(sp3 )-H oxidation of amino-steroids at C15 (or C16) positions, with a selectivity tunable by modification of catalyst chirality and metal.

Coupled X-ray Absorption/UV-vis Monitoring of Fast Oxidation Reactions Involving a Nonheme Iron-Oxo Complex.

Time-resolved X-ray absorption (XAS) and UV-vis spectroscopies with millisecond resolution are used simultaneously to investigate oxidation reactions of organic substrates by nonheme iron activated species. In particular, the oxidation processes of arylsulfides and benzyl alcohols by a nonheme iron-oxo complex have been studied. We show for the first time that the pseudo-first-order rate constants of fast bimolecular processes in solution (milliseconds and above) can be determined by time-resolved XAS technique. By following the Fe K-edge energy shift, it is possible to detect the rate of iron oxidation state evolution that matches that of the bimolecular reaction in solution. The kinetic constant values obtained by XAS are in perfect agreement with those obtained by means of the concomitant UV-vis detection. This combined approach has the potential to provide unique insights into reaction mechanisms in the liquid phase that involve changes of the oxidation state of a metal center, and it is particularly useful in complex chemical systems where possible interferences from species present in solution could make it impossible to use other detection techniques.

The Hydrolysis of the Anhydride of 2-Cyano-2-phenylpropanoic Acid Triggers the Repeated Back and Forth Motions of an Acid-Base Operated Molecular Switch.

This work aimed to render phenomenologically autonomous the otherwise stepwise operation of a catenane-based molecular switch, which is chemically triggered by the decarboxylation of 2-cyano-2-phenylpropanoic acid (2). Given that any amount of 2 in stoichiometric excess with respect to the catenane is consumed in a side reaction, the authors resorted to the corresponding anhydride 5, the slow hydrolysis of which, due to adventitious water in dichloromethane, continuously produces in situ the actual fuel 2. As a consequence, the machine does not require a reloading after each cycle, but switches back and forth as long as fuel is present.