\r\n\tBesides the development of cryptographic tools (hardware and software), we are also interested in the applications of cryptography in current and future scenarios like blockchain, internet of things, industry 4.0, privacy enforcement, cybersecurity and special algorithms such as zero-knowledge proofs and identity-based cryptography.
\r\n\r\n\t
\r\n\tFinally, cryptography does not live in a vacuum, but it is intertwined with our society, sometimes rising questions that are beyond the purely technical realm. For example: Is the weakening introduced by key escrow mechanisms worth the gain? How does cryptography interact with privacy rights? What is the economic impact of cryptography? We welcome contribution to those less technical questions as well.
Clathrochelate is a term used in coordination chemistry to denote the ligands that can encapsulate metal ions. The word is specifically used here as a generic term to designate a family of macrocyclic organometallic compounds that contain tris-glyoximate ligands, forming a cage that is strongly bound to a central metal atom (typically Fe [1] or Co [2]; (Figure 1). Interestingly, such clathrochelates form a wide family of compounds since their apical and ribbed substituents may be varied with ease. Electron donor (such as alkyl) or electron-withdrawing substituents (such as halogens) can be used in the structure to adjust the electronic properties of the metallic center. The XRD structure of the cobalt clathrochelates in their resting state (i.e., neutral molecule with the metal ion in a 2+ oxidation state) shows four N atoms of two glyoximate groups closer to Co, typically at a distance between 1.88 to 1.99 Å, and two other N atoms of the third glyoximate group more elongated at a distance of 2.10 to 2.17 Å [2, 3], reflecting a Jahn-Teller distortion. Another structural parameter employed for their description is the dihedral angle (θ) between the atoms B\'N\'NB (where the apostrophe distinguishes the two apical extremes of the complex), which expresses the rotation between the two N′··N′··N′ and N··N··N triangles, as illustrated in Figure 1. Both Co―N distances and θ depend on the oxidation state of the molecule, reflecting structural variations occurring upon electron gain or loss.
General Lewis structure of a Co clathrochelate. These molecules are versatile since they may bear various apical and ribbed substituents.
The relevant property of these clathrochelates that motivates this chapter is their electrocatalytic activity for hydrogen production from protons in the homogeneous phase (i.e., when the compound is dissolved in solution) [2] known as the hydrogen evolution reaction (HER). The versatility of these molecules makes them further suitable for their incorporation in heterogeneous systems for light harvesting [4] or as precursors for the deposition of Co-containing nanoparticles [5], which are also active for the HER.
Herein, we illustrate the use of DFT to study the electrochemical properties of these clathrochelates with regard to the HER. First, we provide a concise overview of the theoretical methods currently employed to address these complexes and the typical procedures employed to aid and stabilize self-consistent field (SCF) and geometry optimization convergence. Subsequently, we provide examples of the computation of common spectroscopies, such as infrared (IR) or ultraviolet-visible (UV-Vis). The core of this chapter is then devoted to the computation of electron transfer processes and to unravel the HER electrocatalytic mechanism with a model Co clathrochelate. Finally, we provide an overall conclusion of the state of the art regarding the application of DFT methods to clathrochelates, along with conceivable perspectives for future work on the topic.
The choice of the theoretical method is the cornerstone requirement for a successful computation leading to results of predictive value. However, there is no established and unique approach to select the appropriate method for solving a particular problem. Despite this, some general guidelines may be set in order to select the suitable tools.
For example, DFT studies of organic molecules have overwhelmingly been performed with the B3LYP exchange-correlation functional [6], which is currently a standard procedure joined to Pople’s basis sets (the family of 6-31G and so on). At the present time, there are no huge problems with the theoretical treatment of relatively small organic molecules. Conversely, organometallic complexes in general, and clathrochelates in particular, are much more challenging, because of the plethora of functionals and basis sets available. Ultimately, it is the comparison with an experimental quantity that tells whether a theoretical method is satisfactory or not. Typically, the initial manner is to skim the literature to find similar systems which have been treated before and to use such methodology. In the case of Co clathrochelates, the literature is dominated by the use of the B3LYP exchange-correlation functional. We have successfully used the B3LYP functional for geometry optimizations, with excellent agreement to experiment [2]; however, all attempts to use other functionals (M06-L, TPSS, BP86, PBE, or PBE0) yielded unreasonable geometries [7]. Regarding the selection of the basis set, the LANL2DZ with effective core potentials for heavy atoms predicts well the geometry of Co clathrochelates; on the other hand, the use of a more complete and more expensive all-electron basis set cc-pVTZ for Co and cc-pVDZ for all other atoms did not improve significantly the results [7].
Regarding geometry optimization convergence, it is reasonable to be generous on the allowed iteration steps; for instance, we have always employed 100 iterations for these kind of problems. Another frequent issue is SCF convergence. We recommend the use of Pulay’s direct inversion in the iterative subspace (DIIS) and the damping of the Fock matrix, with the purpose to accelerate and stabilize convergence; alternatively to DIIS, the second-order SCF orbital optimization (SOSCF) method may be used as well. Finally, the computation of SCF may be performed directly or not. This has an impact mostly on the calculation time, and the choice depends on the hardware available for work. In the case of direct SCF, the integrals are calculated each time whenever necessary; on the other hand, if direct SCF is not chosen, integrals are calculated only once and then stored in memory. For computers that have mechanical-based hard disks, it is advisable to use direct SCF, because the calculation of integrals by the processor is generally faster than their search in memory. The time spent for the calculation of clathrochelates may be high, of course depending on the functional, the basis set, and the substituents of the molecule. As an illustrative example, by running a parallelized version of GAMESS [8] on 29 processors, it took 1 week for a complete optimization and Hessian computation of complex CoBd3(B―nC4H9)2 which possesses n-butyl and phenyl substituents in the apical and ribbed positions, respectively, using the B3LYP functional and the LANL2DZ basis set with effective core potentials for Co.
A major goal of theoretical chemistry is to be able to predict measurable properties and therefore to provide insights into the behavior of molecular systems. Two of the most ubiquitous techniques available are infrared (IR) and ultraviolet-visible (UV-Vis) spectroscopies, which provide information on the normal modes of vibration (IR) and electronic excitations (UV-Vis). At the end of any geometry optimization, a Hessian calculation should be performed, giving access to the normal modes of the molecule; indeed, all calculated frequencies must be positive in order to verify that the identified stationary point is a true minimum. A typical example of Hessian calculation for the Co(Cl2Gm)3(B―PhF5)2 molecule (where Gm and PhF5 stand for the glyoximate and the pentafluorophenyl moieties, respectively) is depicted in Figure 2a, along with a comparison to the experimental IR spectrum. The calculation was performed with the B3LYP exchange-correlation functional and using the LANL2DZ basis set for all atoms, including effective core potentials for Co and Cl. Note the excellent agreement between experiment and calculation, showing that most signals observed in the experimental spectrum are not pure normal modes but a complex convolution of multiple vibrations that are close in frequency. In particular, the absorption band highlighted with a (1) is essentially composed by a single normal mode. However, such mode is not located in a small part of the molecule but comprises the whole molecular structure, with coupled vibrations from the ligand cage, and the pentafluorophenyl rings, as depicted on the right side of Figure 2b.
(a) Comparison of the experimental IR spectrum (blue lines) of the Co(Cl2Gm)3(B―PhF5)2 molecule and the hessian calculation (red sticks); (b) illustration of the normal mode highlighted with number (1) in item (a), functional B3LYP, and basis set LANL2DZ with ECP for Co and Cl; (c) experimental UV-Vis spectrum superimposed to the theoretical spectrum calculated by TDDFT. Functional B3LYP and aug-cc-pVTZ basis set for Co and cc-pVDZ for all other atoms.
Another important property of these molecules that may be described is their optical absorption. In order to calculate the UV-Vis characteristics, time-dependent density functional theory (TDDFT) formalism has to be employed. The use of the B3LYP functional for the calculation of these kind of spectra has been shown to be an adequate choice [3].
However, the basis function should be chosen to be more complete than for geometry optimizations and Hessian calculations. In particular, it is desirable to include diffuse functions in the basis set, because the optical excitations may occur to nonbonding, unfilled orbitals which develop farther away from the molecule. Previous predictions of optical spectroscopy of clathrochelates have employed a mixture of basis sets, such as the triple-ζ with a polarization function (TZVP) for Co and double-ζ split valence for all other atoms [3]. For our calculations (Figure 2c and d), we have employed the augmented version of the correlation-consistent polarized valence triple-ζ (aug-cc-pVTZ) basis set for Co and the correlation-consistent polarized valence double-ζ (cc-pVDZ) for all other atoms, and we have computed the first 40 excited states. It should be noted that, for the calculation of UV-Vis spectra of usual small organic molecules, it is often sufficient to calculate only four excited states [6], in open contrast to organometallic compounds, where a large number has to be computed in order to adequately reproduce the spectrum. As for IR spectra, these complex molecules exhibit complex UV-Vis spectra, and the assignment of the different contributions is not straightforward because each transition is composed of several contributions from different orbitals. In particular, two transitions occurring in the visible region are highlighted with numbers (2) and (3) in Figure 2c. The main orbitals involved in such transition are depicted on the right side of Figure 2d. Certainly, these transitions cannot be classified simply into metal-to-ligand charge transfer (MLCT) or ligand-to-metal charge transfer (LMCT), because all orbitals involved in the transition have important contributions from the d orbitals of cobalt and from the glyoxime moieties of the ligand.
DFT calculations can also be used to analyze the redox properties of molecules. Electron transfer reactions may take place between chemical species dissolved in solution or between a molecule in solution and a solid-state electrode or photoelectrode. In particular, electrochemistry is the science that studies matter transformation upon the passage of electric current. Species that gain electrons decrease their oxidation state (and are said to be reduced), while species providing electrons to others increase their oxidation sate (and are said to be oxidized). These oxidation-reduction reactions, which necessarily involve the exchange of electrons but may involve chemical steps as well, are referred with the shorthand term “redox.” Certain molecules may exist in two (or more) oxidation states, and these pairs are known as redox couples, represented as O|R, where O stands for the oxidized form, and R represents the reduced form. The redox reaction O + e− = R occurs at a certain electrode potential (E°), which is mainly observable in electrochemistry. The redox potential is important because the more positive it is, the more oxidizing is O; likewise, the more negative it is, the more reducing is R. Essentially, the redox potential is a thermodynamic quantity that allows to predict the feasibility of redox reactions. Absolute redox potentials for molecules are not measurable, and therefore a proper reference electrode is employed. Arbitrarily, the standard hydrogen electrode (SHE) has been adopted as zero in the potential scale [9]. This relative scale is quantitatively related to the absolute energy scale used in physics, i.e., the electron in a vacuum [10].
DFT may provide an estimation of the absolute redox potential of molecules, following two main methodologies. The first method consists in the calculation of a Born-Haber process, by optimizing all relevant species both in gas phase and in the solvent. This procedure is relatively lengthy and therefore shall not receive further attention in this chapter, but the interested reader is referred to the specialized literature [11, 12, 13, 14]. Conversely, the full calculation of the Born-Haber process may be bypassed, and the optimization and Hessian calculation of the relevant redox species, i.e., O and R, in the desired solvent may be undertaken directly [7, 15]. The calculation of the absolute redox potential of the species is found according to Eq. (1):
where F and n represent Faraday’s constant and the number of exchanged electrons, respectively, and
This calculated absolute potential may be referred to an estimated value of the absolute potential of the SHE. Unfortunately, the literature is plenty of different values, for example, 4.2 ± 0.4 V [16] to 4.29 ± 0.02 V [17], 4.05 V [18], and 4.44 V [19], which makes it difficult to assess precision in the calculation, given that all authors provide arguments for their absolute values of the SHE. In order to overcome this drawback, the choice of a reference redox reaction is a safer option. The most commonly used reference reaction is that of the Fc1+|Fc (i.e., ferrocenium|ferrocene) redox couple. When this procedure is used, the optimization and Hessian calculation of both Fc1+ and Fc at exactly the same theoretical level than the O|R couple under study are performed (Figure 3a). Then, the absolute potential of Fc1+|Fc is obtained using Eq. (1). Obviously, this is a sort of “redox calibration” of the computational method. The theoretical estimation of the redox potential of the O|R couple vs. the Fc1+|Fc couple is just the difference between the absolute potentials these two redox pairs.
(a) Optimized structures for ferrocene redox chemistry, which is the reference reaction allowing the calculation of redox potentials; (b) optimized geometries of the Co(Cl2Gm)3(B―PhF5)2 in Co(II) and Co(I) oxidation states. Geometries were optimized with the B3LYP functional and the LANL2DZ basis set, with effective core potentials for Co and Cl in dimethylformamide (DMF). The number in the upper left represents the spin multiplicity.
Current DFT methods provide estimates of redox potentials with an error of at most 200 mV [11, 12, 20], which is nowadays tacitly considered as the limit for a reasonable estimation. There are several causes for such discrepancies with experimental observations, such as the fact that (i) the exact functional linking the electron density and the electronic energy is not known, (ii) the use of an incomplete basis set, (iii) the consideration of only one conformation of the molecule for the computation, (iv) the treatment of the solvent as an electrostatic continuum, and (v) the harmonic oscillator approximation to estimate thermodynamic quantities. Despite these sources of errors, DFT is powerful in predicting reactivity trends while giving reasonable estimations for observable properties.
The comparison between theoretical and experimental redox potentials has another subtlety. Indeed, when an aqueous reference electrode, such as the saturated calomel electrode (SCE) or the silver-silver chloride (Ag|AgCl|Cl−), is used in a nonaqueous environment, there is an inherent liquid junction potential (LJP) [21] which depends on electrolyte composition and biases the measurement. Hence, in order to compare theoretical results with experimental values, the first issue to pay attention to is that an aqueous reference had not been used to make the measurement in a nonaqueous environment. If an aqueous reference has been used in a nonaqueous solvent the Co atom moves to one side, it is still possible to make the comparison with theory, by finding a literature value for the Fc1+|Fc couple and converting the potential scale of the aqueous reference (which was used in a nonaqueous solvent) to the Fc1+|Fc scale. Literature values for Fc1+|Fc have been reported as +0.50 V vs. Ag|AgCl|Cl− [22] or + 0.46 V vs. SCE [2], comprising the LJP.
Finally, it is worth to stress that the redox potential and the energy of molecular orbitals are different things and cannot be equated. Certainly, when representing electron transfer reactions, the educational literature often depicts electrons as being transferred from frontier orbitals [23]. However, such representations might induce to think that the energy of orbitals is somehow linked to redox potentials. As a matter of fact, molecular orbitals are mathematical functions that describe the electron motion in a molecule and are certainly not observable [24], in contrast to the redox potential which is an observable thermodynamic quantity. Despite this, the energetic trend in orbital energies may be commonly paralleled to the oxidizing/reducing power of molecules. For example, with all other things being equal, the more electronegative the substituents in the ligand of a complex, the lower the energy of the molecular orbitals. Hence, the complex will be more likely to gain an electron in the lowest unoccupied molecular orbital (LUMO) than to give it from the highest occupied molecular orbital (HOMO); this is equivalent to say that the complex shall be a better oxidant and its redox potential should be more positive. This kind of trends, linking the energy of molecular orbitals and redox potentials, has been presented several times in the literature [25, 26]. Though we have shown that the CoIII|CoII couple in a series of clathrochelates complies with it, the CoII|CoI redox pair does not follow the orbital trends. Further details may be found in Ref. [2].
The origin of the catalytic activity of metal-containing clathrochelates is currently under debate [1]. It is likely that the role of the ligand is essential to electrocatalysis, since it may stabilize low oxidation states in the metal to enable electron transfer or may participate in protonation reactions that may help bring protons together and evolve H2. That is why the term “ligand non-innocence” has been coined to refer to organometallic complexes in which the organic ligand has a major participation in its redox behavior to account for high reactivity involving small species, such as CO2 or H+ [27, 28, 29].
For example, upon the one-electron reduction process depicted in Figure 3b, we have predicted interesting structural modifications within the molecule. The asymmetry inside the Co―N cage is calculated to be reinforced, with four Co―N distances being at around 1.88 Å and the two other N lying farther apart at 2.45 Å; consequently, the Co atom moves to one side of the cage, thus decoordinating from two N atoms and resulting in a square planar geometry for the reduced complex; furthermore, there is a slight shortening of N―C(sp2) bonds from 1.30 to 1.28 Å.
Ligand non-innocence in the case of clathrochelates may be further investigated because their chemical structure invites to think on multiple sites as putative candidates for protonation. Previous theoretical studies have addressed only protonation on the iminic C(sp2) [30], but we have extended such approach by further exploring other protonation sites. Indeed, the basic character of N and the wide evidence of metal hydrides as intermediates in the HER have led us to explore such alternative protonation sites.
Until now, the most complete theoretical study of hydrogen evolution involving clathrochelates is found in Ref. [7]. The work was performed on a clathrochelate having chlorine and methyl moieties as the ribbed and apical substituents, respectively. Henceforward, this epigraph presents those results in a concise manner.
Optimized structures for three protonation possibilities are illustrated in Figure 4; the investigated protonation sites are highlighted with a red square (C), blue circle (N), and an orange triangle (Co). The insets on the right side of Figure 4 show a magnification of the coordination position of H+. Protonation of the iminic C(sp2) brings a hybridization change to (sp3) with the concomitant change in the geometry of such C from planar to tetrahedral. Protonation of N has a similar effect on the local geometry of the ligand, which is modified from planar to tetrahedral as well. Direct protonation of Co might seem unlikely at the first sight because the metal appears buried inside the organic cage. However, the movement of Co inside the ligand cage upon the one-electron reductive activation and the associated decoordination from two N makes the metal accessible for protonation as well. The calculated X-H distances (where X stands for Co, N, or Csp2) for these three species are 1.09 Å for Csp2-H, 1.45 Å for Co―H, and 1.03 Å for N―H. Such bond distances show that proton binding to N or C results in the formation of a strong bond, in contrast to the binding to the metal center, where a much more elongated Co(III)―H bond is created, indicating a weaker binding and therefore a more labile H+.
Magnification of the organic cage surrounding the Co-containing hexachloride clathrochelate Co(Cl2Gm)3(B―CH3)2 and the different protonation sites available. Geometries were optimized with the B3LYP functional and the LANL2DZ basis set, with effective core potentials for Co and Cl in dimethylformamide (DMF).
An energetic analysis of this initial part of the mechanism is illustrated in Figure 5a. Indeed, there is an energetic gain upon the reductive activation of the [2CoL]0 to yield the catalytically active [CoL]1− intermediate. Then, protonation of N or C(sp2) is likely, but the most favored protonation site was predicted to be the Co central ion.
(a) Energetic diagram of the first electron transfer to produce the catalytically active [CoI]1− species and its further protonation at different sites of the ligand, as depicted in figure X; (b) representation of the second part of the mechanism, showing the unfeasibility of hydrogen evolution through a transition state of high energy and the alternative possibility of concerted proton-electron transfer.
We have also addressed the possibility of double protonation in two adjacent N; in a C(sp2) and a N; in two adjacent C(sp2); in Co and N; and in Co, for both high-spin and low-spin species. However, most optimized structures were largely distorted due to heavy structural changes caused by the sp2 to sp3 hybridization changes that should occur after protonation. As a consequence, the calculated energy of doubly protonated intermediates was prohibitively high, and these species are unlikely to be formed. The most stable doubly protonated species was the one with protons coordinated in two adjacent N atoms. However, it seems unlikely that the mechanism of hydrogen evolution involved initially a mono-protonated species that is a cobalt hydride and that the subsequent species in the mechanism is a double-protonated intermediate with protons in adjacent N atoms.
The Co(III)―H intermediate is interesting and deserved closer attention. In particular, such species may undergo a further one-electron reduction to yield Co(II)―H, which may also have a role in the mechanism. Certainly, we have predicted that such reduction brings an important energetic gain, but the search for doubly protonated intermediates and the search for a transition state to explain hydrogen evolution were unsuccessful. We were able to locate a transition state of the η2―Co(III)―(HH) type, but again this was far too energetic to be a plausible candidate to explain hydrogen evolution (Figure 6b).
Main results from potential energy surface scans showing the relation between the Co―(HH) and the H―H bond distance along with the relative energy involved during the separation of H2 from the complex, (a) Co(II) and (b) Co(III). These calculations were performed in the complex Co(Cl2Gm)3(B―CH3)2 at the B3LYP level and the LANL2DZ basis set, with effective core potentials for Co and Cl. The energy was further refined with the more complete all-electron basis set cc-pVTZ for Co and cc-pVDZ for all other atoms in dimethylformamide (DMF). The zero in the energy scale is the [2CoL]0 species.
Considering that the hydrogen production step is of key importance, we have devoted wide efforts to explain how it happens. When the calculations on a mechanism yield high energy intermediates, it is possible that a concerted electron-proton transfer process occurred, in order to avoid energy-demanding paths [15, 20]. Thus, potential energy surface (PES) scans were performed with the Co(II)―(HH) and Co(III)―HH) species at different (fixed) Co―H distances, while the rest of the structure was allowed to optimize freely. These results are summarized in Figure 6a and b. Interestingly, in the case of Co(II)―(HH), the increase in the Co―H bond distance was linked to a decrease in the H―H distance, approaching the equilibrium bond distance for H2, which is 0.74 Å. At the same time, the energy of the system gradually decreased to approach the final energy level of the reaction (observe the blue scale on the right side of Figure 6a), which is depicted in Figure 5b as [2CoL]0 + H2. These calculations show a nice picture of two protons that come together in the nearby of Co(II) and bind to one another to form H2 while going away from the metal, with the concomitant decrease in total energy. Conversely, the same calculations on the Co(III) species gave the same bond-breaking (Co―H) bond-formation (H―H) sequence as just described for Co(II). However, at the same Co―H distance, the H―H separation was consistently higher in the case of Co(III), thus indicating that Co(III) was less effective than Co(II) to promote the reduction and binding of two protons. Moreover, the total energy of the system for the Co(III) ion did not decrease smoothly as in the case of Co(II) (Figure 6b). Instead, it was excessively high, and therefore such intermediate was definitively ruled out as a possibility to explain the catalytic activity of this clathrochelate.
The clathrochelate family has received attention due to its multiple applications. In this chapter, we have illustrated the use of density functional theory to describe several properties of clathrochelates. We began the presentation by providing tips on the choice of the calculation methodology to address these complex molecules. Then, the spectroscopic properties (IR and UV-Vis) have been reproduced. The possibility to accurately predict spectroscopic properties gives an adequate degree of confidence on the theoretical procedures employed. Subsequently, we have illustrated the procedures to predict the redox potentials of molecules, and we have highlighted some structural changes underwent during the electron transfer process. This chapter has introduced the concept of “ligand non-innocence,” which is relevant in complex electrocatalytic reactions involving complexes of transition metals, where the ligand has a major role to play, not only to stabilize unusually low oxidation states but also to act cooperatively to bind small species, such as H+. Finally, a methodology has been presented to address the complex mechanism of hydrogen evolution. Certainly, the hydrogen production step was particularly intriguing for the Co(Cl2Gm)3(B―CH3)2 complex, given that neither doubly protonated intermediates nor plausible transition states could be found. Therefore, a concerted proton-electron transfer step was envisaged, with the Co(II)―(HH) hydride intermediate playing the most relevant role. The calculation of potential energy surface scans fixing the Co(II)―(HH) bond distance showed that the simultaneous elongation of Co―H bond leads to the decrease in H―H distance and the smooth decrease in energy, which nicely explained hydrogen evolution from this complex in the homogeneous phase. Overall, results reported in this chapter could contribute to stimulate theoretical and experimentalist chemists to explore the influence of different substituents in the organic cage on the HER activity, thereby providing new insights to researchers that try to develop and optimize alternative electrocatalysts for the HER. Clearly, the formal theoretical understanding of clathrochelate’s electrochemistry is still in its early stages, and the missing piece in this scientific challenge is to apply the theoretical methodology outlined in this chapter to other clathrochelates in order to justify the distinct reactivity observed experimentally among different complexes. Moreover, the approach proposed here should provide guidelines to synthetic chemists in the search for more active compounds. Thus, we foresee that the future theoretical research shall be performed in such direction. This is a stimulating moment to conduct research aiming to find novel and efficient catalysts for hydrogen production, and transition metal clathrochelates are perhaps the family of complexes that has received the least attention from the chemical community.
Manuel Antuch is thankful to the French ministerial scholarship and the Initiative d’Excellence (IDEX) program for funding.
The authors do not have conflict of interest.
Nature Aided Drug Discovery (NADD) represents the most ancient approach in finding new active compounds for fighting human diseases, and still today it plays a crucial role in drug discovery [1]. New chemical entities (NCE) from natural derivation represent a relevant slice among the drugs approved by Food and Drug Administration (FDA) and the European Medicines Agencies (EMA) for commercialization and administration on humans [2]. More than half the total anti-infective drugs approved in the last forty years resulted from a NADD approach and a similar trend can be observed for anticancer drugs, where 41% of them derived from natural sources and only 16% are classifiable as totally synthetic small molecules [2]. Moreover, the Global Herbal Medicine Market Size is expected to increase to USD 129 billion by 2023, according to Market Research Future [3].
The success of NADD finds its main reason in the wider and heterogeneous chemical space covered by natural products whether compared with synthetic derivatives. The 83% of the chemical scaffolds found in natural compounds are unique and absent in synthetic NCE, due to the lack of commercially available synthons or cumbersome and prohibitive synthetic procedures [4]. Thus, the screening of libraries of compounds derived from natural sources still remains a worthy procedure for the identification of new and unexplored NCE. Besides, marine sources or lichens are still almost uninvestigated and might therefore represent an inestimable treasure of new potential drugs [5, 6, 7].
The natural compounds of interest in NADD are secondary metabolites that are not directly involved in the essential functions of the cell cycle and duplication processes and are characterized by high structural variability. From a structural standpoint, they are classified into alkaloids, terpenoids, saponins, lignans, flavonoids, and tannins [8]. Secondary metabolites are produced in different amounts for vexillary functions or defensive responses to biotic or abiotic stress being involved in the system of plant defense [9]. For this reason, specific secondary metabolites may be considered as markers of the plant health and may be used to evaluate the quality of the selected natural matrix and the effects that the environmental factors have on it. The evaluation of their content in natural sources, as well as their recovery, require the exploitation of ad hoc extractive procedures since secondary metabolites are mainly present in the intracellular domain. Thus, appropriate extraction procedures involve the rupture of the cell wall and cellular membranes, thus favoring the passage of the secondary metabolites into the extraction solvent, from which they can be recovered.
Over the years different protocols and techniques have been developed for the extraction of metabolites from natural matrices, named Solid–Liquid Extraction (SLEs). SLEs are classified in conventional (or traditional) and non-conventional (or innovative) methodologies [10]. In conventional methodologies, SLE is performed by heating the natural source with conventional heating sources (i.e., flame, heating plate, or mantle) in the presence or not of solvent and with or without stirring. Examples of conventional methodologies are maceration (digestion, infusion, and decoction), percolation, and Soxhlet or steam distillation. Solvents, or generally mixtures of solvents, with wide grades of polarity such as methanol, ethanol, acetone, ethyl acetate, trichloromethane, hexane,
In this chapter, the potential of microwave-assisted irradiation for the extraction of secondary metabolites from plants, and natural resources in general, will be discussed, with a special focus on recent applicative examples of the most representative chemical classes.
The physical principles underlying MASE are completely different from those of conventional extraction because microwave irradiation can cause a more effective disruption of the cellular structures (cell walls and cellular membranes) thus favoring the release of the cellular content and speeding up the extraction process. The interaction of microwave irradiation with the solvents, intracellular water, and ions causes an increase of the dipolar rotation and ionic conductivity of molecules with dipolar moments and ions, which results in a rise of the temperature inside the cell. The vaporization of the intracellular water causes the dehydration of the cellular wall and the reduction of its resistance. This, combined with the abrupt increment of the intracellular pressure, leads to the cell wall and membranes disruption, thus facilitating the passage of the secondary metabolites into the extractive solvent [12, 13].
This is the result of a synergistic combination of heat and mass gradient working in the same direction from the inside to the outside of the cell, as confirmed by Scanning Electron Microscopy (SEM) analysis (Figure 1) [14].
Microwave heating effect on cells.
Monomodal and multimodal microwave systems also referred to as single- or multi-mode systems specifically designed for MASE are nowadays available. A single-mode system permits to focus the microwave radiation on a restricted zone where the sample is subjected to a much stronger electric field. Conversely, in a multimode system, the microwave radiation is randomly dispersed within the microwave cavity, where the sample is irradiated [15]. Both mono- and multi-modal microwave devices comprise a magnetron, which generates microwave radiation, a waveguide, which is used to propagate the microwave from the source to the microwave cavity, the applicator, where the sample is placed and a circulator that allows the microwave to move only in the forward direction. The main difference between the two systems relies on the applicator that in the case of a multimodal system is a closed cavity where the microwaves are randomly dispersed, whereas in the monomodal oven the extraction vessel is directly located in-line with the waveguide [15]. Both systems are effective in extracting metabolites from natural sources, and their use is usually related to the amount of natural matrix. Accordingly, the monomodal system is preferred when the amount of natural source to be treated is relatively low (milligram to gram scale), and vice versa. Microwave extraction may be performed using open or closed extraction vessel systems. The open vessel apparatus originated from a modification of domestic MW ovens. The extraction is conducted at ambient pressure and the vessel is directly connected to a condenser to avoid loss of solvent or volatile components. An evolution of the open vessel apparatus is the Focused Microwave-Assisted Soxhlet (FMASE) which combines the classical Soxhlet extraction (SE) technique with MW irradiation. In the closed vessel system the entire extraction vessel is located within the oven, thus allowing better control of the pressure and temperature during the extraction [16].
The closed-vessel system presents several advantages: i) a higher temperature than open vessel systems can be reached because of the increased pressure inside the vessel raises the boiling point of the solvents used, thus decreasing the time needed for the extraction; ii) the loss of volatile substances is completely avoided because they are confined within the vessel; iii) a low amount of solvent is required because no evaporation occurs and there is little or no risk of airborne contamination thus preventing the oxidation of air-sensitive metabolites; iv) the fumes are contained within the vessel, reducing the hazard of the extractive procedure.
In a closed vessel system high pressure can be reached. The high pressure stimulates various phenomena according to LeChatelier’s principle, such as the transition of phase from one form to another, change in reaction dynamics, change in molecular structure,
Nevertheless, the use of closed-vessel systems presents some drawbacks: the amount of samples that can be processed is limited; the addition of reagents or solvents during operation is forbidden and the vessel must be cooled down before it can be opened to avoid loss of volatile constituents [16]. For processing a large amount of material, an open-vessel system is more appropriate. It allows the possibility to add reagents and to refill the solvent during the extraction, and to remove the excess of solvent during the extraction procedure. Moreover, the extraction of thermolabile metabolites is allowed since it usually reaches low temperatures relative to closed-vessel systems. On the other hand, the open-vessel systems ensure less reproducible results compared to the closed-vessel systems and the extraction in open-vessel could require a longer time to obtain results comparable to those achieved in closed-vessel [16].
The microwave energy may be applied also to extraction in solvent-free conditions (Solvent Free Microwave Extraction-SFME) [12]. In this case, the plant material is directly placed into the microwave reactor, without the addition of any solvent. The heating of the water contained by the plant material distends the natural matrices and causes the rupture of the cells releasing their content. This process has been successfully applied for the extraction of the essential oils. After MW heating, the volatile components co-evaporate with the in-situ water contained in the natural matrix; the vapors condense outside the microwave oven into a collector where they separate between essential oils and the aqueous phase. The latter is brought back into the vessel to refresh the amount of water in the sample, whereas the essential oil is collected apart [12].
The performance of the MASE process is strictly related to the operative conditions employed. Several parameters, such as solvent, solvent-drug ratio, temperature, time, pressure, microwave power, water content, and characteristic of the matrix must be optimized in setting up a MASE procedure. Each of these parameters should not be considered alone, but they are all linked together and the comprehension of the effects and influences of these factors is pivotal for MASE efficiency. A brief discussion about the role of these parameters in the design of a MASE protocol is herein reported.
The selection of the solvent plays a crucial role in MASE, as well as in other conventional extraction processes, and several solvent parameters (solubility of the analyte, penetration, interaction with the matrix, dielectric constant, and mass transfer kinetic process) should be considered to perform the right choice.
As stated in the previous paragraph, a Solvent-Free Microwave Extraction (SFME) is also possible. This procedure foresees the direct irradiation with MW of the plant material, fresh or rehydrated. A crucial role is played by the content of water in the sample, because it is the heating of such water to cause the rupture of the cells of the plant material, favoring the release of the content. This process is mainly applied for the extraction of volatile compounds such as essential oil. The oil evaporates by azeotropic distillation with the water contained in the sample. After cooling outside of the microwave reactor the oil separates from the water and can be collected through a modified Clevenger apparatus. Water is refluxed back into the microwave oven to allow the continuous extraction of the oil from the sample [12].
Another important parameter to consider in the set-up of a MASE protocol is the ratio between the amount of sample and the volume of solvent. The latter should be enough to cover the sample during the entire process, especially when the matrix swells during the extraction process. Although in conventional extraction higher is the volume of solvent, higher is the yield of the extract, in MASE larger volume of solvent may result in more energy and time to heat the suspension and in a lower yield due to a non-uniform distribution and exposure to microwave. Usually, an L/S from 10:1 to 20:1 (mL/mg) is found to be the right ratio in many extractive processes reported in the literature [20].
Strictly correlated to the L/S ratio is the stirring rate since it affects the mass transfer process in MASE. However, the significance of this parameter is rarely explored. By stirring, the mass transfer barrier created by the concentrated compounds in a localized region due to insufficient solvent can also be minimized resulting in better extraction yield. In other words, agitation accelerates the extraction speed by accelerating the desorption and dissolution of compounds bound to the sample matrix [17].
Extraction times in MASE lasts from a few minutes up to half an hour, and this represents an advantage for the extraction of thermal or oxygen labile compounds since it avoids the degradation of the compounds of interest [21]. The extraction yield is directly proportional to the extraction time, although it has been observed that this increment is very small for an extremely long time. Moreover, for longer extraction time overheating may occur, especially with high absorbent solvents, thus exposing thermolabile compounds to degradation. Whether longer extraction time is required, consecutive and shorter extraction cycles are preferable. The solvent can be collected after each extraction cycle and a fresh solvent could be added to the residue to guarantee the exhaustion of the matrix. This discontinuous procedure has been applied for the extraction of several secondary metabolites from plant material, allowing an enhanced yield and low decomposition of thermolabile compounds [22].
Temperature and MW power are strictly correlated. Power is the driving force of the process since it provides the energy necessary to excite the dipolar moments and the ionic conduction of the constituent of the sample, resulting in a proportional increase of the temperature and promoting the destruction of the natural matrix. Thus, the power of the microwave irradiation has to be carefully dosed in function of the amount of the sample, the solvent employed, the extraction time required, and the chemical stability of the secondary metabolites of interest [23]. Increasing the power results in an improved extraction yield and shorter extraction time. However, this result is true until the reaching of an optimal temperature beyond which a decrease in yield is observed, mainly due to the thermal stability of the target metabolite [24].
Accordingly, the temperature is a key parameter to enhance the efficacy of MASE and to avoid at the same time the degradation of the sample. Thus, the choice of the extraction temperature is strictly related to the properties of the solvent, the chemical stability of the metabolites of interest, and the microwave system used. In particular, at high temperatures the viscosity and the surface tension of the solvent diminish; moreover, the capability to solubilize the analytes, and to wet and penetrate the matrix increase, thus resulting in improved extractive efficacy. Also, when operating in a close-vessel, there is the advantage of heating the solvent above its boiling point, thus leading to a more performing extraction [25].
To conclude, the development of a proper MASE methodology must consider at least four variables: solvent, liquid/solid ratio, temperature, and time. To speed up the set-up of the procedure, the Design of Experiment (DoE) approach may be applied. This is a systematic statistic-based tool to assess the best experimental conditions both in the academic and industrial fields [26]. Thanks to this approach, all the variables and their interactions can be evaluated while doing the minimum number of runs.
Over the years, microwave-assisted extraction has been successfully applied to extract diverse classes of secondary metabolites (i.e. polyphenols, flavonoids, coumarins, terpenoids, cannabinoids, and alkaloids) from natural sources, for evaluating the plant productivity, for extracting bioactive compounds both for drug discovery or for commercial purposes.
Here below, studies of plant productivity based on MASE methodology and specific cases of extraction of natural compounds of pharmaceutical and nutraceutical interest will be discussed, with a special focus on resveratrol, terpenoids, and cannabinoids.
Numerous applications report about the use of the MW to assist the extraction of organic and organometallic compounds from various matrices (soils, sediments, water samples, botanicals), with special emphasis on environmental applications [27, 28]. Extraction of natural matrices is essential to compare their productivity under different stress conditions [9], harvesting time [29], and places [30]. MASE offers the possibility of performing multiple extractions and therefore, it is suitable for the rapid screening of a numerous set of samples to evaluate the productivity of organisms.
An example is a work performed by Martino et al., regarding the MASE of
Secondary metabolites extracted via MASE approach and considered as markers of the plant productivity.
Another example is the setup of a fast and reproducible extraction methodology of vitexin and its isomer isovitexin from
Within this context, Martino et al. set up a MASE procedure that can be applied for quantitative extraction of both metabolites from
MASE can also be applied to study the effect of micronutrients or pollutants on secondary metabolites production. Amri et al. investigated the impact of soil copper (II) concentrations on nutrient uptake and the antioxidant system of
To sum up, MASE procedures is a versatile technique suitable for the evaluation of the plant productivity, and to assess the quality of vegetal matrices, since it is fast, reproducible, suitable for extraction of a large number of samples and requires a low amount of natural matrix.
Alkaloids are a well-known class of secondary metabolites characterized by basic nitrogen. Over the years, many active alkaloids have been extracted via MW irradiation, e.g. ephedrine alkaloids, cocaine, and ergot alkaloids [35, 36, 37]. Unfortunately, results obtained for many of them have been comparable or worst if compared with the traditional method [38]. Nevertheless, microwaves have also spurred the discovery of new active alkaloids at the early stage of drug discovery. MASE protocols can be exploited to extract different alkaloids (examples are reported in Figure 3) from different botanicals like tuberous roots, leaves, and seeds [37, 39, 40].
Examples of alkaloids extracted via the MASE approaches.
As an example of MASE applied to the extraction of alkaloids, Pan et al. obtained a good recovery of caffeine and polyphenols from the leaves of green tea (
Xiong et al. developed an efficient MASE protocol, within a drug discovery process, for the isolation of bioactive alkaloids (e.g. liensinine, isoliensinine, neferine, dauricine, nuciferine, Figure 3) from
Recently, Belwal et al. reported an optimized MASE protocol, defined by multicomponent analysis, for the extraction of berberine (Figure 3) and polyphenols from diverse species of
Regarding the alkaloids employed as drugs, or of interest for the toxicological use and/or abuse, few extractive procedures by MASE are reported in the literature. As an example, Brachet et al. extracted cocaine and benzoylecgonine from the leaves of
Stilbene-based polyphenolic compounds, i.e. resveratrol, pterostilbene, and piceatannol, are of particular interest from a medicinal chemistry standpoint, having multiple pharmacological activities (Figure 4).
Chemical structure of polyphenolic-stilbene based secondary metabolites.
In particular,
Even though resveratrol is produced naturally in plants, the extraction of resveratrol in commercial quantities is a problem, because of its low concentration, multiple steps of isolation and purification, unfriendly environmental issues, and seasonal occurrence [53]. Moreover, the preparation of resveratrol by synthesis is difficult owing to the formation of many unwanted side products [54, 55]. Only recently, the production of resveratrol in heterologous engineered microorganisms has been proposed [56]. Thus, resveratrol is still being extracted from wild
The extraction of resveratrol by MASE from different plant materials (i.e.
In another study, Dang et al. combined the aqueous two-phase extraction technique (ATPE) with MASE for the extraction of the total polyphenol content, including resveratrol, from grape seeds [60]. Microwave-assisted ATPE (MAATPE) required lower solvent concentration and less time compared with other methods such as refluxing solvent or SE. A higher level of resveratrol was obtained with MAATPE, in contrast to ATPE. The Authors also compared the effectiveness of three solvents (water, water: ethanol (1:1) and ethanol) and three extraction methods, including MASE and ultrasound-assisted extraction (UAE) and the conventional SE. MASE provided a better extraction with water and ethanol (1:1) obtaining extracts very rich in polyphenolic substances, including stilbenes.
Lastly, MASE has successfully applied also for the extraction of other polyphenolic-stilbene based compounds such as pterostilbene, mainly found in blueberries and in
Terpenes and isoprenoids, in general, gained much attention for their physiological functions (i.e., hormones, aliphatic membrane anchors, maintaining membrane structure), ecological roles (i.e., defense compounds, insect/animal attractants), and extensive pharmaceutical applications such as flavors, fragrances, and medicines.
In particular, artemisinin and paclitaxel represented two milestones in the fight against malaria and cancer, respectively. Artemisinin (Figure 5) is a sesquiterpene lactone isolated from
Chemical structures of artemisinin and paclitaxel.
Recently, Misra et al. developed a rapid and reliable MASE and HPTLC protocol for the analysis of artemisinin. The optimized MASE conditions required 100 mg of dried and grinded drug with a size of 14 mesh dispersed into 10 mL of toluene. The irradiation of the sample at 160 W for 120 seconds led to the extraction of 0.816% of the content of artemisinin.
Paclitaxel (Figure 5) is a member of the taxane class, and it is one of the most important anticancer drugs approved for human use against ovarian, breast, and pulmonary cancer.
Although the total synthesis of paclitaxel has been reported, its application for the commercial production of this drug is impracticable. Thus, paclitaxel is still produced by extraction from taxol biomass. The most commonly used methods for the extraction of paclitaxel require the use of methanol at ambient temperature, although other protocols requiring refluxing methanol, 1:1 methanol-chloroform at ambient temperature, and percolation using ethanol or 95% ethanol-water at ambient temperature have been reported. However, these methods require a long time (12–24 h) for a complete extraction. Incorvia-Mattina et al. reported for the first time in 1997 the use of MASE to optimize the efficiency of the extraction of paclitaxel. The effects of the biomass, solvent ratio and water content on taxane recovery were also determined. Under appropriate MASE conditions an extract equivalent to the one obtained by conventional extraction methods was produced [63].
Talebi et al. investigated the use of MASE to extract paclitaxel from the needles of
Recently, another study for the extraction of paclitaxel from biomass through MASE and based on kinetic and thermodynamic analysis has been carried out. The majority of paclitaxel was recovered from the biomass (∼99%) within 6 min in a single cycle of microwave-assisted extraction at microwave powers of 50–150 W and temperatures of 30–45°C [64].
Chemical structures of CBD-like and THC-like major phytocannabinoids present in
CBD-like derivatives are non-psychotropic compounds but with other recognized pharmacological properties such as anti-inflammatory, antioxidant, and anticonvulsant. As an example, Epidiolex, a CBD-based anticonvulsant drug, has been approved in 2018 by Food and Drug Administration for the treatment of seizures associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome, or tuberous sclerosis complex (TSC) in patients 1 year of age and older.
The discovery of a plethora of pharmacological activities ascribed to CBD and other minor phytocannabinoids has increased attention from both scientists and industries for medical, nutraceutical, and cosmetic applications of these cannabinoids.
Several synthetic procedures have been developed and optimized for the industrial preparations of phytocannabinoids and in particular of CBD. However, this process suffers from several drawbacks such as the cost of the starting materials, reagents and solvents, the formation of by-products with consequent cumbersome purification procedures, and the difficulty to control the stereochemistry, the isomerism of the terpenic double bond, and the easy interconversion of CDB into THCs in the synthetic conditions.
Thus, the extraction and purification of phytocannabinoids from
Focusing on MASE, Lewis-Bakekr et al. investigated the potential to directly extract and decarboxylate dried Cannabis material with the microwave reactor [69]. Dried plant material, suspended in ethanol, was subjected to heating with stirring in a microwave reactor at 150° C. Extraction yield for the concentrated resin was in the range of 19.6–24.4% and it resulted directly proportional to the heating time and dependent on the cultivar employed in the process. Interestingly, a complete decarboxylation of the phytocannabinoids was achieved in one step following this process and no acid forms of phytocannabinoids such as Δ9-THCA and CBDA were detected in the resulting extract. Thus, MASE proves to be a worthy method for extraction and decarboxylation of phytocannabinoids due to the possibility to apply controlled temperatures and shorter extraction times. Moreover, this procedure ensures a more consistent and reproducible
The effect of time and temperature was investigated first. Extraction and decarboxylation of phytocannabinoid resulted in time and temperature dependence. To obtain 100% decarboxylation, the temperature must be sustained over a period without the burning of the cannabis material or the boiling/evaporation of the solvent. Because the solvent of choice is ethanol (b.p. 78°C at 1 atm), to reach a higher boiling temperature (i.e. 100–170°C) the extraction process must be carried out in a sealed vessel and under pressure. 170°C was the highest operative temperature achieved since higher temperatures (>180°C) resulted in the microwave run abortion due to the high pressure reached within the vial.
The extraction of cannabis by MASE at 100°C, 130°C, 150°C, and 170°C for 10 minutes resulted in a 23–25% yield of extract.
Interestingly, it appeared that the addition of a second step, such as SFE, after the MASE did not change the cannabinoid profile in the extract. Thus, MASE alone can perform an almost complete extraction of the cannabinoids from the cannabis plant material. Besides, the extraction and conversion of THCA and CBDA into THC and CBD was better at a temperature above 130°C, than at 100°C.
MASE was compared with the effectiveness of the commonly employed extractive procedure, namely maceration in ethanol, SE, and SFE. The conventional extractive procedures resulted in a low concentration of Δ9-THC, THCA, and CBD, whereas the addition of the microwave step resulted in a significant increase in the concentration of CBD and THC. As expected, no THCA was detected.
To sum up, a worth general procedure for the extraction and decarboxylation of CBD and THC from cannabis plant material can be thus resumed: i) the drug is weighed and macerated in a mortar; ii) the grinded drug is charged in a microwave vial along with a stir bar; iii) the drug is submerged with ethanol and the vial is sealed; iv) the vial is irradiated with MW using the following conditions [a) Pre-stirring = 30 sec; b) run time = 10 min; c) temperature = 150°C; d) absorption = Normal]; v) the suspension is filtered, and the filtrate concentrated; iv) residual plant material may be subjected (but not necessarily) to SFE.
Drinic et al. extended these studies over other polyphenols and flavonoids as well as phytocannabinoids [71]. In particular, the effects of different extraction parameters, namely ethanol concentration, extraction time and solid/liquid ratio on extraction yield, total phenol content, total flavonoid content, antioxidant activity, reductive capacity, CBD content, and THC content were investigated. For MASE, a domestic microwave oven and a round-bottom flask connected with a condenser were used. The solid drug was mixed with the solvent (30, 50, or 70% v/v ethanol) in the selected solid/liquid ratio (S/L = 5, 10, or 15). The extraction was performed irradiating at a potency of 580 W without agitation and for a total extraction time of 10, 20, or 30 min. The results of each extraction were analyzed using response surface methodology. The influence of the three process parameters was investigated on total polyphenols yield, total flavonoids yield, antioxidant activity, and reductive capacity as well. The optimal conditions for the highest CBD content and lowest THC content resulted in 47% ethanol concentration, 10 minutes of extraction time, and an S/L ratio of 5. The model was successfully validated by preparing the Cannabis extract under the calculated conditions.
Alongside the pharmaceutical uses of Cannabis extracts, hemp seeds are widely employed to produce hemp oil. However, the content of Δ9-THC in the processed hemp seed oils must be under the limits imposed by the jurisdictions of each State. Indeed, although the hemp seeds produce negligible amounts of THC, their outer surface can be contaminated with the enriched in the phytocannabinoids resin secreted by the seeds’ bracts. The presence of Δ9-THC in the final hemp seed products had led to intoxication symptoms in the final consumers. Thus, nowadays the content of THC in hemp products is tightly regulated. Yang et al. investigated the effectiveness of various chemical procedures for the extraction of Δ9-THC from three brands of hemp seeds and how the extractive methods could influence their commercialization [72]. Four extraction methods were employed, namely, i) microwave extraction, ii) sonication, iii) SE and iv) SFE. As already investigated by Kore et al., the extraction was performed in ethanol at 150°C with stirring, obtaining a complete conversion of CBDA and THCA into the corresponding neutral form. Hemp seeds were macerated in a mortar, transferred into a microwave vessel, and suspended in ethanol. The suspension was irradiated at 150°C with stirring for 20 min in a closed vessel. The yield of the resin (27–38%) achieved was comparable to the other three extraction procedures. In contrast, SE provided higher yields of Δ9-THC and CBD than the other procedures, resulting in a more robust and appropriate extraction methodology for the testing of hemp seed products. Since the same solvent was used in all the compared extractions, the differences in the number of phytocannabinoids can be attributed to the extraction methods themselves. The results suggest that prolonged heating and solvent cycling in extracting phytocannabinoids from lipid-rich materials such as hemp seeds is mandatory.
MASE has rapidly risen during the latest decades as a method for the extraction of secondary metabolites or compounds of pharmaceutical and nutraceutical interest. The use of microwave can generate peculiar, and otherwise impossible to reach extraction mechanisms. As a result, a reduction of the extraction time, improvement of the extraction efficiency, high reproducibility, and robustness of the procedure can be achieved. An increase of the sample throughput is in addition possible, thus it can be considered as the elective technique when a high number of samples have to be processed specially during the first stage of the NADD process, and for evaluating the quality of the natural matrices [9, 29]. For these reasons, MASE has proven to be effective in all aspects, including economical and practical, compared to traditional extraction techniques, especially over SE. Conversely, in MASE the development of the method must be carefully assessed, and all the variables and factors described above must be thoroughly considered to provide some extraction selectivity. Hence, DoE, response surface methodology, and other statistical approaches are of great help to quickly determine the best conditions to achieve the highest yield of the metabolite of interest from the natural source. However, in the past year, the application of MASE in scalable industrial processes has always encountered several limitation due to the presence of some technological barriers, mainly related to the design of safe instrumentation. Thanks to the technological progress witnessed in recent years, the first industrial-scale ovens finally became commercially available [73, 74].
Food, pharmaceutical, and nutraceutical industries would be benefited from this emerging technology of MASE, which is an excellent substitute for traditional methods such as SE, and other environmentally benign technologies. The promise to be the technique that can respond to the necessities in this field will make MASE the extraction method of choice for the next years.
The authors declare no conflict of interest.
IntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
",metaTitle:"Retraction and Correction Policy",metaDescription:"Retraction and Correction Policy",metaKeywords:null,canonicalURL:"/page/retraction-and-correction-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\\n\\n1. RETRACTIONS
\\n\\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\\n\\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\\n\\nPublishing of a Retraction Notice will adhere to the following guidelines:
\\n\\n1.2. REMOVALS AND CANCELLATIONS
\\n\\n2. STATEMENTS OF CONCERN
\\n\\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\\n\\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\\n\\n3. CORRECTIONS
\\n\\nA Correction will be issued by the Academic Editor when:
\\n\\n3.1. ERRATUM
\\n\\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\\n\\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n3.2. CORRIGENDUM
\\n\\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\\n\\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\n\nPolicy last updated: 2017-09-11
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I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. 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After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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