Review—Use of 1,1,1,3,3,3–hexafluoro–2–propanol (HFIP) Co-Solvent Mixtures in Organic Electrosynthesis

Because of the necessity of carry out electrolysis reactions with considerable quantity of organic molecules, the balance between solubility of starting material, solution conductivity and electrochemical stability of medium and intermediates are key factors in organic electrosynthesis. HFIP has several properties that favor its use in this research area as solvent, among them, its high hydrogen-bond donor has opened the possibility of ﬁ ne tuning reactivity, mainly in anodic reactions because of the helpful effect on the stability of positive intermediates. The cost of this solvent has limited its broad application in chemistry, including electrosynthesis, but the possibility of using mixtures with other cosolvents has demonstrated to help to expand its use without losing the bene ﬁ cial effect on the intermediates. In recent years several HFIP mixtures (HFIP/MeOH, HFIP/CH 2 Cl 2 , HFIP/H 2 O, HFIP/ACN, HFIP/MeNO 2 ) have permitted the control the chemical microstructure of the electrolysis media and have let to adjust the solvent properties to ful ﬁ ll the necessity of electrosynthesis. In this review will be discussed the general properties of HFIP and the mixtures reported to carry out electrochemical synthetic transformations of organic molecules, as well as the reactions where has been demonstrated the bene ﬁ cial effect of HFIP solvent mixtures in the control of the electrogenerated

The solvent in organic electrosynthesis is a critical selection because it is not only the media to promote the rection of molecules in an homogeneous phase, but it has to act as solvent for the raw material and to dissolve and dissociate the supporting electrolyte chosen, which allows the circulation of ionic current in the electrochemical cell. Furthermore, due to the heterogeneous nature of electrochemical reactions, these must be carried out in lowviscosity solvents since convection and diffusion are crucial phenomena in the mass transport towards the electrode. These two factors often determine the success of an organic electrochemical reaction. Currently, the use of 1,1,1,3,3,3-hexafluorisopropan-2-ol (HFIP) as solvent in different areas of chemistry has had an increase, since it has both physical and chemical properties that allow obtaining unique modes of reactivity of molecules and reactive intermediaries. 1 This reactivity is caused by the acid-base or electronic properties of the solvent. The use of HFIP has been reported in various reactions in organic chemistry, 2 such as: in the activation of hydrogen peroxide to carry out epoxidation reactions of alkenes, 3 Baeyer-Villiger oxidation of ketones, 4 intramolecular Schmidt reaction, 5 Friedel-Crafts reaction of acyl chlorides, 6 Hosomi-Sakurai allylation of dimethyl acetals 7 and allylic substitution of alcohols. 8 In all of them, the hydrogen bond donating ability of HFIP allows the activation of the functional groups without the need to use catalysts or any additive. 1 The addition of an acid promoter (organic acid) increases the Brønsted acid reactivity favoring these chemical processes. 9 Elegant examples of oxidative approaches, like those reported years later using organic electrochemistry, were obtained initially using hypervalent iodine reagents in combination with HFIP or 2,2,2trifluoroethanol (TFE) as solvent. These pioneering oxidative routes were reviewed by Kita in the late 2000's. 10 Among the similar reactions that will be reviewed here using this reagent and HFIP we can mention aromatic oxidative coupling, 11 oxidative cycloadditions, 12 among many others reviewed previously elsewhere. 13 Since the 90's Swenton described the similarity between the hypervalent iodine 1e oxidations and the anodic reactions using phenol-styrene couplings. 14 The idea of regenerating iodine (III) species from iodine (I) species was introduced by Fuchigami, who achieve the first electrocatalytic cycle with synthetic applications using the fluorinated ionic liquid Et 3 N-3HF. 15 Recently an efficient electrocatalytic approach to obtain hypervalent iodine arenes in HFIP was described by Francke, 16 opening the door to a mediated process and eliminating the Ar-I co-waste produced during the use of iodine (III) derivatives. 10 This electrochemical reaction and many others that have been developed using pure HFIP does not fit into the scope of this review, which is specifically focused into the use of HFIP-solvent mixtures.
Since the 1980 s, Eberson et al., described HFIP as an excellent solvent to stabilize cation and carbocation radical species, generated through the 1e oxidation of organic compounds with hypervalent iodine 17 or Th (III) trifluoroacetate. 18 The persistence of cationic radicals in HFIP generated by Th (III) trifluoroacetate increased by a factor of 100 times, compared to its analogs trifluoroacetic acid and TFE, 19,20,21 HFIP's ability to stabilize and extend the life of cationic radicals is primarily related to its hydrogen bond donor ability, low nucleophilicity, and the ambivalent polarity domains of HFIP which can form polar and nonpolar microheterogeneous phases. As mentioned, electro-synthetic reactions where the reaction route proceeds through cationic intermediates (cation or carbocation radical) have been substantially benefited by this solvent, which has caused a new revision of the reactions that, with other solvents occurred with difficulty and/ or have low yields. As examples we can mention among many others C-C cross couplings between phenols, 22 C-C coupling between phenols and benzofurans, 23 N-N coupling, 24 electrochemical oxidation of inactivated C-H bonds. 25 The polar and nonpolar microheterogeneous phases was described in detail by means of molecular dynamics simulations by Waldvogel & Kirchner et al., 26 who studied catalytically active mixtures of HFIP/H 2 O 2ac in the cyclooctene epoxidation. These studies revealed that HFIP develops a microheterogeneous structure, like the observed in solid state in florinated compounds (Fig. 1). Thus, the crystal structures of TEFDDOL, 27 a highly fluorinated analogue of the tartrate-derivative whose crystal structure was obtained and the crystal structure of HFIP, 28 both reveal that in solid state they arrange in welldefined fluorinated and polar regions. Hydroxyl groups act as a donor and acceptor of hydrogen bonds and form a continuum of a polar region dominated by hydrogen bonds. The fluorine atoms of the hexafluoroisopropyl group do not participate in the hydrogen bonding despite their electronegativity, and produce a region of low polarity, due to interaction of these fluorinated groups. In the case of TEFDDOL, another low polarity zone is generated by the interactions of the acetonide group. Same effect was shown in HFIP where a helix conformation was observed in the solid state. 28 Some studies propose that the size of this helix is not very long (5 HFIP units) and neat HFIP in liquid phase exists as an agglomerate of short helical chains 28,29 This implies that HFIP, as well as TEFDDOL, is a solvent with very well-defined regions of opposite polarity microstructures and can hold molecules or intermediaries in them, according to their polarity.
This linear structure coincides with the experimental and theoretical estimates, where it is shown that the bulk liquid alcohols form linear aggregated systems (Fig. 2), which have a higher polarity than the monomeric molecules of individual alcohols. This generates a higher solvation capacity caused by an increase in the hydrogen bond donation capacity. 30 It is expected that the addition of other solvents affects this structure and changes the proportion of the equilibria that HFIP has and, therefore, properties such as polarity, microstructure, and solvation would be affected.
The hydrogen bond donor ability of fluorinated alcohols, and in particular HFIP, is mainly dependent on two parameters: (i) the conformation of the alcohol monomer along the C−O bond and (ii) cooperative aggregation to H-bonded alcohol dimers and trimers Fig. 3). Regarding point (i), in the thermodynamically preferred gasphase conformation, the HFIP monomer carries the hydroxyl group  antiperiplanar (ap) to the adjacent CH. The two-degenerate synclinal (sc) conformations are approximately 1 kcal mol −1 less stable (Fig. 3). This equilibrium is reversed if the alcohol is placed within a polarizable environment, as its absolute minimum structure now carries the OH sc or almost synperiplanar (sp) to the adjacent CH. 28 Recently, Hunter and Cols. 31 have described the solute-solvent interactions using the solvent competition model for the formation of a hydrogen bonded complex between two solutes obtaining graphical descriptions of the functional group interaction profiles in each solvent (FGIPs, Fig. 4). This information provides a simple visual method for understanding how solvent affects the free energy contribution due to a single point interaction, such as a hydrogen bond, between two solute functional groups. The FGIP of HFIP showed that quadrant 2 is compressed towards the top of the plot, because only very polar hydrogen bond donors can compete with the HFIP hydroxyl group and quadrant 1 is almost absent, because HFIP is a very poor hydrogen bond acceptor but an excellent donor. The potential use of this FGIPs is related to the possibility of construct them not only with pure solvents (like for HFIP, Fig. 4 bottomright), but the possibility of construct these descriptions with solvent mixtures. Thus, theoretical FGIPs were demonstrated by experimentally measuring the equilibrium constant for formation of a hydrogen bonded complex across the full composition of a range of mixtures of chloroform and tetrahydrofuran. 31 This graphical tool could be applied to divers fields were the importance of optimizing the noncovalent interactions between functional groups is crucial, like the selectivity control of the reactions, enhancement of catalysis or supramolecular design. In the field of synthetic organic  electrochemistry, where HFIP has shown in recent years a very attractive use, the FGIPs description of diverse solvents systems could help to rationalize the results obtained by test-error methodology and to propose new solvent HFIP-solvent systems according with the type of substrates used and/or intermediates that are produced during the electrochemical reaction.
The relevant characteristics that have made HFIP a key solvent in electrosynthesis, such as pKa, viscosity, boiling point and dielectric constant are summarized in Table I. Its high dielectric (ε = 16.7) compared to other organic solvents is noteworthy. So, the supporting electrolyte ionization is suitable for carrying out electrosynthesis reactions with relatively high current values and its compatibility with low polar molecules is good to solubilize them in good quantity for electrosynthesis purposes. Electrochemical stability is another especially important factor to justify the expansion of its use. Using this solvent and a doped diamond (BDD) electrode boron, which has a high oxygen and hydrogen discharge potential, 32 an electroactivity window equivalent to that obtained with of aprotic solvents (almost 6 V) can be obtained. This combination solvent-electrode allows to carry out electrolysis at inaccessible potential values in other systems and with the advantage that positively charged intermediate species can be stabilized. In platinum electrode the hydrogen production limits the cathodic barrier due to the catalytic effect of this metal on this reaction 33 (Fig. 5) and the low pKa (pKa = 9.3) of the solvent. However, the fact that the solvent has a more acidic pKa than a normal alcohol, opens the door to protonate electrogenerated anions and anion radicals without adding water or an acid for this, contributing to tune the intermediates reactivity. 34 Thus, the use of HFIP in cathodic reactions requires a good choice of electrode material. This solvent is truly little nucleophilic, which allows positively charged species to be present longer without evolving through unwanted routes, triggering the reactivity associated with their stabilization. Furthermore, it reduces the nucleophilicity of other solvents when it is used as a cosolvent, thus 3% water in HFIP reduces nucleophilicity drastically. 19,35 The hydrogen donor strength of HFIP has been evidenced through the formation of complexes between HFIP and some ethers such as THF and 1, 4-dioxane, 36 allowing highly polar transition states to be stabilized through hydrogen bonding. 28 Viscosity is another great point in favor of HFIP since, electrochemical reactions are heterogeneous, the mass transfer to the electrode is ultimately controlled by the diffusion of the species to the electrode. A low-viscosity solvent facilitates the process and let to carry out rapid and efficient transformations. 37,38 In this way, not only the diffusion-controlled mass transport of the raw material is maintained within a reasonable time interval, but also supporting electrolyte transport does not limit the electrolysis, factor that would affect negatively conductivity and cell voltage, causing an increase in the resistance and temperature and energy consumption of the cell, 37,39 HFIP boiling point (bp = 58°C) is suitable for normal work in organic chemistry laboratories.
Despite these highly relevant properties, HFIP use is seriously limited by the high cost of the solvent, even with the direct supplier (1 kg-$ 135.00 USD Oakwood chemicals USA or 1 kg-£ 99.00 Fluorochem UK, in July 2020). For this reason, this solvent is often recovered by rotary evaporation under vacuum (it is recommended, when working with HFIP, to use a cold finger of liquid air or CO 2s to protect the vacuum pump in this procedure) at the end of a reaction, which contain a enriched mixtures with HFIP; it can be separated by successive fractional distillations (two at least), and if dry HFIP is required, an additional one using molecular sieves 3 Å. 49 The toxicity is moderate and slightly corrosive, so all the reactions carried out with this solvent and its mixtures must be done inside an efficient extraction hood and with the safety equipment normally used in an organic chemistry laboratory.
Therefore, in order to modify physical-chemical properties like solubility of organic compounds, enhance some solvent properties or carry out reactions in a more economical manner, a variety of solvent mixtures have been explored for its use in electrosynthetical applications. The use of co-solvents such as MeOH, H 2 O, CH 2 Cl 2 , CH 3 CN, AcOH and MeNO 2 together with HFIP in electrosynthesis constitutes a more economical and accessible methodology to take advantage of its ability to promote cationic chemical reactivity. 1 Furthermore, the use of a cosolvent has been particularly attractive to control the selectivity of some reactions since the redox potential of the substrates may depend on their interaction with the medium. This has been elegantly exploited in the cross coupling of phenols, where a proportion of MeOH allows to decrease the redox potential of the phenols used by means of hydrogen bonds interactions. 50 Therefore, this review will focus on the impact that solvent mixtures with HFIP have had on organic electrosynthesis in the recent years.

Electrochemical Conversions Using HFIP Mixtures
HFIP/MeOH as solvent.-A strong interaction between MeOH and HFIP that increase MeOH basic behavior was proposed by Waldvogel in order to explain the lowering of phenols oxidation potential in this mixture. 50 This electrochemical study was complemented with DOSY experiments of aromatic compounds, demonstrating that their diffusion coefficient increases with a linear trend, evidencing a lower viscosity of the mixture than the pristine HFIP. The interaction model is depicted in Fig. 6. This model proposes the formation of MeOH/HFIP clusters which contain the aromatic molecules, in the case of phenols, the hydrogen bond interaction with these clusters facilitates the compound oxidation. The interaction was studied by cyclic voltammetry analysis of different phenols and showed to reach a maximum with a MeOH amount of 15%-20% v/v. The following examples show the applicability of this effect in organic electrosynthesis.
Anodic C-C dehydrogenative aromatic cross coupling reaction.-Waldvogel et al., initially reported the use of MeOH as solvent in the C-C coupling reactions between phenols under anodic oxidation; the results showed poor selectivity and series of oligomers derived from the over-oxidation of the starting materials and products. 22 Since fluorinated alcohols provide a reaction medium with exceptional redox stability, 41 a number of fluorinated solvents were studied for this anodic reaction. In particular the use of HFIP instead of MeOH let to obtain ortho-selective C-C coupling products, decreases the amount of over-oxidation of staring compounds and prevents the oxidative degradation of products. 22 Later the same group reported the use of the HFIP/MeOH solvent mixture to carry out cross-C-coupling reactions of phenols and arenes under anodic oxidation conditions, using BDD as anode (Scheme 1). 51 In HFIP, arene 2b has a lower oxidation potential than phenol 1a and is preferably oxidized at the anode, which favors to obtain the homocoupling product 3bb, in a bb: ab ratio of 3: 1. The use of MeOH as HFIP co-solvent decreases the oxidation potential of phenol 1a below the oxidation potential of 2b. Here MeOH acts as a weak base that interacts with the phenol and deprotonates 1a radical cation, giving a its selective oxidation at the anode to form the radical 5. All these intermediates seem to be stabilized by the solvent mixture polar characteristics facilitating the process. Subsequently, the radical 6 undergoes a nucleophilic attack of 2b, which leads to the formation of the cross coupling product 4ab with selectivity of ab: bb 100: 1. 50 This selectivity exemplifies the control of the reaction pathways by means of a fine tuning of the intermediate's intermolecular interactions with the solvent mixture. This finding was expanded, again with the use of the same cosolvent HFIP/MeOH mixture, to carry out C-C cross coupling between different phenols (7a and 8b) obtaining asymmetric biphenols 9ab (Scheme 2). 52 This solvents mixture provokes the selective oxidation of one phenol (7a) to form its phenoxy radical, which is stabilized by the polar phase of the solvent and subsequently reacts with 8b to selectively obtain the targeted biphenols in a ratio of up to ab: bb 100: 1. 53,54 Anilines, due to their electron-rich nature, have low oxidation potentials and, under anodic oxidation conditions, mainly lead to the formation of unwanted over-oxidation compounds such as oligomers or aniline polymers. 55 Considering this limitation, successful anodic C-C coupling of aniline protected derivatives 10a and 11b, which contain different protecting groups by anodic oxidation using HFIP/ MeOH (18%) as solvent (Scheme 3) is an original strategy to prepare bianiline protected compounds 12ab. 55 As the MeOH content in HFIP increases up to 18% v/v, the oxidation potential of the amides decreases, this let to obtain the final products 12ab in higher yield. These can be selectively deprotected in final synthetic steps to render the corresponding amino group 13. In this solvents mixture, anilines protected with protecting groups such as Boc, acetyl, Piv, benzoyl, trifluoroacetyl, have a higher oxidation potential than anilines, making these substrates less susceptible to oxidation.
Amides 10a are solvated in the polar phase of MeOH/HFIP, as was mention previously MeOH acts as a weak base and deprotonate the radical cation intermediate of 10a rapidly, whose radical specie and subsequently react with (11b) to selectively obtain (12ab) in an  ab: bb ratio of up to 100: 1. The HFIP/MEOH system is crucial to obtain the desired selectivity and a cleaner reaction. 56,57 Electrochemical dehydrogenative annulation reaction from biaryl aldehides and NH 3 .-Xu et al., reported the electrochemical annulation of biaryl aldehydes to carry out phenanthridines 17 synthesis (Scheme 4). 58 In this reaction, the condensation of biaryl aldehydes (14) with ammonia first occurs to form the corresponding imine, the oxidation of the aromatic ring A of the biarylylimine forms the cation radical 15, which is stabilized by the mixture of HFIP/MeOH (5:1) and its cyclization leads to the formation of 16; with a second oxidation and loss of proton phenantridines 17 are obtained. The electrolysis is carried out in the HFIP/MeOH solvent system without supporting electrolyte, because it is sufficiently conductive due to the generation of ammonium ions through the acid-base equilibria between ammonia and HFIP. Thereby avoiding use of expensive salts and, therefore, the generation of waste. Modification of the solvent system used leads to obtain (17) in low yields. 58 This reaction capitalizes the slightly acid media which promotes the imine formation and its capacity to stabilize the positively charged intermediates, favoring intramolecular cyclization.
Electrochemical conversion using HFIP/H 2 O as solvent.-This mixture has been studied in detail from different chemical points. Fluorinated units have been shown to form a continuous microphase, while hydroxy groups form small clusters of approximately 5-10 hydroxyl groups 26 (Fig. 1). The addition of H 2 O decreases the number of HFIP-HFIP hydrogen bonds because water is a strong hydrogen bond acceptor. The small-angle neutron scattering studies (SANS) demonstrate the clustering or microheterogeneities of HFIPwater mixtures; large-angle X-ray scattering (LAXS) demonstrated the persistence of this structure even with large quantity of water (up to 85%) in the mixture. 59 The size of these clusters ( HFIP m Water n ) studied by mass spectra revealed that are dependent of the water content, thus in the water-rich region where the fraction mol x HFIP < 0.01 (m = 2-4 and n = 1) and monomeric HFIP water clusters (m = 1 and n = 55-20) are stabilized in the region of x HFIP > 0.09. 59 This transition was observed by FTIR-ATR, the spectra were analyzed by multivariate curve resolution based on alternating least-square procedure (MCR-ALS) and two-dimensional correlation spectroscopy (2D-COS). 60 These studies agree with the presence of different microstructures depending on the HFIP-water mixture proportion, identifying four components in it, as can be observed in Fig. 7. The first component (Blue dots) has structures typical for very diluted system where a shell of tens of water molecules surround a single molecule of HFIP. The second component (Green dots) confirms the well-known fact that for the 30% HFIP and 70% water system, a micelle-like assemblages with fluoroalkyl groups pointing inside the core surrounded by a water continuum. The third component (Red dots) was not described by the authors and propose an intermediate structure between micelles and the structure of the neat HFIP. The fourth component (Black dots) correspond, assuming that the liquid phase partly resembles the solid state pattern it can be postulated that in neat HFIP the molecules aggregate by H-bonds into finite helices (Fig. 1). 28 The third component showed a maximal presence in the region between 10%-30% v/v of water. This is called the water-poor region and here H-bonded aggregates of HFIP plays the most important interaction generating dimers and trimers where the cooperative effect is most efficient. 28 In consequence, this third component region can lead to an enhancement of H-bond donor ability of the solvent system.
When adding a polar compound to an HFIP/H 2 O mixture, it is preferable solvated by the hydrogen bond donor network which is the polar region of these clusters. The addition of a non-polar compound to the HFIP/H 2 O mixture as cyclooctene, forms small clusters which are solvated by the trifluoromethyl groups (Fig. 8). 26 Theoretical simulations showed the generation of a triphasic solvation model (Fig. 9), where the least polar compounds are in the center of a non-polar sphere made up of fluorinated units. On the other hand, the hydroxyl group of HFIP is immersed in a polar region made up of hydrogen bonding with water. Polar molecules added to this medium, such as H 2 O 2 , will be found in this welldefined region.
These results demonstrate the ambivalent characteristic of HFIP to separate polar and nonpolar substrates, and how the H 2 O addition affects the aggregation structures of pristine HFIP. 26 The microheterogeneous structure of the fluoroalcohol-water mixture influences the solvation, availability of the starting molecules and reactants/additives (catalyst, oxidants); therefore their reactivity modifies accordingly. Theoretical simulations also have predicted that the diffusion constants of the HFIP molecules are modified with the water addition. 26 Interestingly, a mixture HFIP/water (1:1)   facilitates the movement of the fluoroalcohol molecules by a factor of ca. 5, situation very attractive because this phenomenon can be related with a lower viscosity of the solvents mixture, favoring the mass transport in electrochemical reactions. This converts the HFIP/H 2 O mixture into a flexible network of hydrogen bonds that is easily malleable and capable of generating microstructures of well-defined polarity domains which can control the reactivity.
Electrochemical sulfonylation of phenols and aniline derivates.-The electrochemical sulfonylation of arenes substituted with electrodonating groups (18) with sodium sulphinates (19), using HFIP/H 2 O (15% v/v) as solvent (Scheme 5) was recently reported. The dual role of 19, both as a coupling reagent and as a supporting electrolyte, avoids the additional use of salts in the reaction, avoiding the generation of residues. The reaction has acceptable yields with only 1.3 equivalents of the salt, which is notable for the dual role of electrolyte and nucleophile. Hydrogen bond donor ability of HFIP stabilizes the cation radicals derived from the oxidation of 18, allowing them to be trapped by sodium sulphinate, which leads to the formation of 20. H 2 O as co-solvent not only improves conductivity and viscosity of the medium, it also prevents the cathodic reduction of the final product 20. Water on BDD has a reduction potential similar to the final compounds but the results obtained indicate that this cathodic reaction is preferred over sulfone reduction. 61,62 Electrochemical synthesis of benzisoxazoles and quinoline N-oxide.-Quinoline N-oxides are important intermediates in organic chemistry due to the 1, 2-dipole N-O bond, and benzisozaxoles have applications in synthetic and medicinal chemistry. The use of BDD and Pt electrodes to carry out the reduction of o-nitro benzaldehydes (21) and o-nitro cinnamaldehydes (23) respectively, under constant current conditions using glassy carbon as anode, is a efficient strategy for synthesis of benzisoxazoles (22) and quinoline N-oxides (24) (Scheme 6) 34 ; previous reports need to use additives or Pb sacrificial electrodes, thus the overall electrochemical reaction is cleaner. In this reaction, the most sensitive parameter is the solvent; protic solvents are necessary to increase the yield. Solvent mixtures such as EtOH/H 2 O, MeOH/H 2 O, MeCN/H 2 O, iPrOH/H 2 O, gave low yields, probably by the lack of enough protons in the medium, since the reduction of nitro-aromatic compounds is favored in an acidic medium, 63,64 Therefore, the use of the HFIP/H 2 O mixture (1: 1) provides a slightly acidic medium, which improves performance. Decreasing the amount of H 2 O as co-solvent (HFIP/H 2 O 3: 1) leads to low yields of 22 and 24. 34 Electrochemical conversions using HFIP/AcOH as solvent.-Acetic acid is not a good donor of hydrogen bonds in non-protic solvent solutions, since it exists as a cyclic dimer in these media. 65 In combination with HFIP, which is a strong hydrogen bond binding donor, this acid becomes a strong hydrogen bonds donor system. The explanation has been attributed to the fact that in this solvent, the acid could adopt linear aggregates (25) or a microheterogeneous structure network (Scheme 7), equivalent to the observed in the alcohol structure described in Fig. 2. Thus, this system has the possibility of making strong interactions with molecules through the hydrogen bond, modifying is reactivity.
Electrochemical bromination of arenes.-The use of the HFIP/ AcOH solvent system (1: 1) turns out to be essential in the electrochemical bromination of arenes (26) developed by Liu et al. (Scheme 8). 66 This solvent system plays several important roles, in the case of bromination, the strong hydrogen bond promotes electrophilic activation of molecular bromine (29) electrochemically generated in situ. This activation is similar to the effect of a Lewis acid (FeBr 3 ) on the bromine during the classical electrophilic bromation of arenes. 67 The system's ability to solvate free radicals prevents the generation of Br 3 -(30), a less reactive species that leads to low yields (Fig. 10). This was experimentally determined by LiBr cyclic voltammetry in ACN and HFIP/ACOH, where a single reversible system for oxidation of bromide to bromine can be observed, which contrasts with the ACN medium, where two systems are observed. Finally, but not less important, it avoids the passivation of the electrode provoked by the arene over-oxidation. 66 The use of protic systems other than HFIP/AcOH in this type of reaction, for example HFIP/MeOH or HFIP/H 2 O, leads to moderate yields of 27 and 28, and in some cases only traces of the desired compounds are obtained.
Unfortunately, although the rection is reported as potentiostatic, the authors report the power source potential (3 V-4 V) instead of the electrode potential, which is not controlled. As a result, the current that is generated will depend on the cell design and the composition of the medium used to reproduce this reaction. In the case of a cell with two electrodes, it will always be more advisable to report the current density used as a control parameter for the electrochemical reaction, and to use the potential of the power source to calculate the energy used and the electricity cost.
Electrochemical oxidation of thioethers.-The HFIP/AcOH system (1: 1) was a key solvent for obtaining sulfoxides (32) and sulfones (33) from the electrochemical oxidation of thioethers (31) (Scheme 9). 68 The anodically generated sulfoxide interacts with the solvent through hydrogen bonds, which prevents the sulfoxide overoxidation. DFT calculations of the ionization potentials of the sulfoxide structures 34-37, reveal an increase of up to 20.2 kJ mol −1 of the ionization potential of compound 37, provoked by the interaction of the sulfoxide with the solvent mixture by means of hydrogen bonds. 68 The ionization potential is directly proportional to the oxidation potential, which implies that the oxidation potential of the sulfoxide 37 increases and consequently the sulfoxide does not oxidizes easily to the sulphone 33 during the preparation of sulfoxides.
The sulfones 33 are obtained with good yields (75%-91%), increasing the potential from 3 V to 4 V and increasing the electrolysis time. The use of different solvents such as AcOH, DMF, MeCN, HFIP, MeOH, HFIP/MeOH, leads to obtaining (32) in low yields or traces, highlighting the importance the AcOH-HFIP interaction (25) to increase the hydrogen donating character of this mixture and the stabilization of the sulfoxide. The same reproducibility detail with the voltage reported described in the previous section was found in the experimental description of this reaction.
Electro-oxidative synthesis of unsymmetrical disulfides.-Liu et al., under the same electrosynthetic conditions, use HFIP/AcOH to carry out the synthesis of asymmetric disulfides (40) (Scheme 10). The mixture of solvents stabilizes the thionyl radicals formed by the oxidation of thiols (38) and thioalkyls (39) in the anode, allowing their radical combination to form the adducts (40) with good yields. 68 Electrochemical conversions using HFIP/MeNO 2 as solvent.-Nitromethane−lithium perchlorate system has been used by Chiba and cols. as a suitable medium for radical cation mediated reactions, 69,70 Recent studies carried out with Raman spectroscopy demonstrated that radical cation species increases their stability in this media in a certain analogy to the observed behavior in HFIP. This fact was attributed to the low donor number of MeNO 2 , and a solvent-anion clustering formation due to the Lewis acidic behavior of the lithium cation, which increased the reactivity of the radical cation by trapping the counteranion species (the perchlorate anion, ClO 4 − ). 71 This solvent-electrolyte system has been expanded with the use of 10% HFIP, showing interesting properties for reactions mediated by positive intermediates triggered by electrochemistry.
C-C aryl-aryl intramolecular coupling.-The pyrrolophenanthridone alkaloids isolated from amaryllidaceae have a heteropolycyclic skeleton containing N-benzoyl and indole units. Due to their simple fused structure, several research groups have carried out the synthesis of these molecules by using Pd to perform intermolecular cross-C-C coupling and the oxidation of indoline with oxidizing reagents such as DDQ. Chiba and his research group report the use of electrochemistry, for the key step of the C-C aryl-aryl coupling in the synthesis of these alkaloids (Scheme 11). 72 N-benzoylindolines 42 and 43 synthesized from indoline 41 are oxidized at the Pt anode, methanesulfonic acid as an additive, LiClO 4 as a support electrolyte and HFIP/MeNO 2 (1:9) as solvent, allow the selective oxidation of indoline. This solvent system induces the of the indoline radical cation stabilization and increases the electrophilic character, favoring intramolecular aryl-aryl C-C coupling to obtain 44 and 45. After these electrosynthetic step, the nitrogen ring is obtained in a reduced state; a subsequent electrochemical oxidation, now in basic Scheme 8. Electrochemical bromination and chlorination of arenes in HFIP/AcOH 1:1.  Electrochemical conversion using HFIP/CH 2 Cl 2 as solvent.-The use of this solvent mixture is very recent, therefore, there are no studies regarding the microstructure of the mixture or other details of this solvent mixture. Neither additional details of the properties of this mixture is given in the consulted articles.
Electrooxidative C-H azolation of phenols and aniline derivates.-Chen and his research group reported electrochemical and ortho-regioselective azolation of phenols and anilines in a mixture of HFIP/CH 2 Cl 2 solvents (7:3) (Scheme 12). 73 In this methodology, phenol or aniline (51) and azole (52) are oxidized at the platinum anode simultaneously to the corresponding cation radical, which after proton lose form the radicals 53 and 54. Both intermediates are strongly stabilized by HFIP of the solvent avoiding its Scheme 10. Electrochemical synthesis of unsymmetrical disulfides in HFIP/AcOH 1:1.
Scheme 12. Electro-oxidative azolation of phenols and aniline derivatives in HFIP/CH 2 /Cl 2 (7:3). over-oxidation to carbocation, permitting its radical coupling to form the C-N bond that leads to the formation of 55, which evolution into the final compound 56 obtaining yields of up to a 93%. The mixture of solvents is crucial to achieve sufficient reactivity, since when only HFIP, dichloromethane or the mixture HFIP/MeOH is used as solvent, low yields of the desired product are obtained. 73 Electrooxidative [3 + 2] annulation between phenols and indole derivates.-Lei et al., carry out the electro-oxidative [3 + 2] annulation between phenols (57) and N-acetyl indoles (58a and 58b, Scheme 13). 74 Employing anodic oxidation, both 57 and 58a are oxidized at the carbon anode due to the proximity of the redox potentials, the generated phenoxy radical and indole cation radical are stabilized by the HFIP/CH 2 Cl 2 mixture (6:4). Their reaction results in the formation of the C-C bond between phenol and indole. Subsequently, the cyclization by the intramolecular nucleophilic attack of the phenol oxygen atom towards the indole allows obtaining benzofuro [3,2-b] indolines (59) and/or benzofuro [2,3-b] indolines (60), depending of the substrate used as a coupling compound. The use of dichloromethane as co-solvent is not essential to carry out this transformation, however, its use provides an increase in the yield of the desired products. 74 and lowers the cost of the reaction using HFIP. This reaction is remarkably similar the one between phenols and benzofurans in pure HFIP, where a first oxidation to two electrons allows the anodic C-C Cross-Coupling of Phenols with Benzofurans, leading to a Furan Metathesis. A second 2e oxidation produces the oxygenated tetracyclic equivalent of compound 60, the 5a,10b-dihydrobenzofuro [2,3-b] benzofurans. 75 Electrochemical [3 + 2] annulation reaction between phenols and alkenes.-2,3-dihydrobenzofurans (65) constitute the core skeletons of several natural products and bioactive molecules. 76 Wang et al., report the electrooxidative [3 + 2] annulation between phenols (61) and deficient alkenes (62) employing anodic oxidation, and a mixture of HFIP/CH 2 Cl 2 (6:4) as solvent under constant current conditions (Scheme 14). 77 The anodic oxidation of 61 generates radical 63, which is stabilized by the clusters of the HFIP/CH 2 Cl 2 mixture, this allows the EWG to carry out the α addition on 62 producing radical 64. A second oxidation causes cationic cyclization [3 + 2] by phenol to obtain 65. The use of HFIP without CH 2 Cl 2 as solvent for this reaction proceeds with a decrease in the yield, so that CH 2 Cl 2 as co-solvent allows to increase the yield of the products obtained. This electro-synthetic strategy is applied to obtain 65b and its reduction allows obtaining a natural product with biological activity such as 3′,4-di-o-methylcedrusin (66). 77 Electrochemical synthesis of hexafluoroisopropoxy indole and anilines derivates.-In order to study the antitumor activity of a series of indole and anilines derivatives, functionalized with fluorinated substituents, Pa and his research group reported the electrochemical synthesis of a series of hexafluoropropoxy indoles (69) and anilines (70) from N-acylindoles (67) or aryl amides (68), under constant current conditions using HFIP/CH 2 Cl 2 (4: 3) as solvent (Scheme 15). 78 The cation radicals derived from the anodic oxidation of 67 and 68 are stabilized by the effect of the HFIP/CH 2 Cl 2 solvent, thanks to this and despite the low nucleophilicity of HFIP, the cationic radicals undergo nucleophilic attacks by  HIFP to obtain the functionalized compounds 69 and 70. The use of CH 2 Cl 2 as co-solvent increases the yield of the product; as in the previous reaction the yield decreases in the absence of CH 2 Cl 2 . 78 In the two reactions described in this section, it was observed that the absence of CH 2 Cl 2 decreases the yield, however, it is not yet clear why this occurs. Studies like those carried out in the HFIP/MeOH 50 and HFIP/H 2 O 26 mixtures are required to clarify the observed reactivity.
Electrochemical conversions using HFIP/ACN as solvent.-The use of this solvent mixture is very recent, therefore, there are no studies regarding the microstructure of the mixture or other details of this solvent mixture. Neither additional details of the properties of this mixture is given in the consulted articles.
Electrooxidative [3 + 2] annulation of 1,3-dicarbonyl compounds with alkenes.-For Lei and his research group, the HFIP/CH 3 CN (6:2) solvent system is key for the electro-oxidative [3 + 2] annulation of 1,3-dicarbonyl compounds (72) with alkenes (71) (Scheme 16). In this reaction, the α-dicarbonyl carbanion 72 generated with sodium acetate is easily oxidized at the carbon anode, producing a carbon-centered radical 73 that is added to 71; the resulting radical 74 is oxidized in the anode and the cationic species should be solvated by the clusters of the polar part of the HFIP/CH 3 CN mixture. An intramolecular nucleophilic attack of the oxygen of the enol tautomer of one of the carbonyl groups closes the 5-member ring to obtain the annulation product 75. 79 The absence of HFIP as solvent decreases the formation of the targeted final compound, while the absence of CH 3 CN as cosolvent leads to a decrease in the yield to less than 10%; thus, acetonitrile as co-solvent promotes the increase in the yields of the annulation products in a clean electrochemical reaction. 79 Electrochemical synthesis of coumarines and quinolinones.-Coumarins and quinolones are important compounds that are part of important skeletons of biologically active molecules such as anticancer, anti-HIV, anti-psoriasis. The synthesis of this type of compound has been reported, however, its preparation requires oxidizing agents and large amounts of catalyst. Guo and his research group reported the electrochemical synthesis of coumarins (82) and quinolones (83) from alkynoates (76) or alquinamides (77) and aryl chalcogenides (78 and 79), using a carbon electrode as anode, a solvents mixture of HFIP/CH 3 CN 1:4 and under constant current conditions (Scheme 17). This environmentally friendly electrochemical strategy avoids the use of catalysts, additives or oxidizing agents. 80 As the first step, the oxidation of 78 or 79 occurs at the anode, the HFIP/CH 3 CN (1:4) solvent system stabilizes the free radical 80 centered on the selenium or sulfur atom, which adds to the alkyne 76 or 77 and the radical 81 undergoes intramolecular cyclization to form 82 or 83. Although in both HFIP as in CH 3 CN the reaction proceeds the yields are moderate, the use of CH 3 CN as co-solvent together with HFIP increases considerably the yields of the desired products. In this reaction, HFIP is the minor solvent of the mixture, which allows to reduce the costs associated with HFIP and, with the evidence that the reaction can be carried out on a gram scale, its large-scale application is possible. In other solvents such as DCE or DMF, the reaction proceeds in very low yields. 80 Electrochemical synthesis of spiro [4.5] trienones..-The electrosynthetic conditions used for the synthesis of coumarins and quinolones are used by the same group for the electrochemical synthesis of spiro [4.5] trienones 87 and 87 (Scheme 18). This class of compounds are obtained from the oxidation of 86 diselenides in the presence of methoxy-alkynoates (84) or methoxy-alquinamides (85). In order to have a better reaction performance, the ratio of CH 3 CN as co-solvent was decreased with respect to the previous reaction and HFIP/CH 3 CN (1:3) was used; the use of pure HFIP, CH 3 CN or another solvent such as DCE leads to low yields. The use of CH 3 CN as co-solvent instead of DCE increases the yield of the products reaching more than 80% of yield. 81

Conclusions
Organic electrochemistry is an interdisciplinary area of electrochemistry were a large variety of chemical disciplines converge.
Because of the necessity of carry out electrochemical reactions with considerable quantity of starting compounds, the correct balance between key factors like solubility of compounds, solution conductivity and electrochemical stability of medium and intermediates is required to succeed in organic electrochemistry. Additionally, a great challenge to increase the chemical and faradic yields is favoring stability of electrogenerated intermediates and the possibility to control their chemical reactivity through the solvent or mixture of solvents used. HFIP has several properties that favor its use in organic electrosynthesis, among them, its high hydrogen-bond donor property has opened the possibility of fine tuning mainly anodic reactions, because of the helpful effect on the stability of positive intermediates; its relative high acidity limits applicability in reductions. The cost mainly has limited its broad application in chemistry, including electrosynthesis, but the possibility of using mixtures with other cosolvents could be a way of expanding its use without losing the beneficial effect on the intermediates. In recent years mixtures of HFIP with other cosolvents have permited the control the chemical microstructure of the media and adjust the properties of the solvent to fulfill the necessity of electrosynthesis.