Copper-catalyzed reactions: Research in the gas phase.

COPPER-CATALYZED REACTIONS: RESEARCH IN THE GAS PHASE ALEXANDRA TSYBIZOVA and JANA ROITHOVA* Department of Organic Chemistry, Charles University in Prague, Faculty of Science, ; Hlavova 2030, 128 40 Prague 2, Czech Republic Received 27 June 2014; accepted 19 December 2014 Published online 14 May 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/mas.21464

Electrospray ionization mass spectrometry (ESI-MS) is becoming an important tool for mechanistic studies in organic and organometallic chemistry. It allows investigation of reaction mixtures including monitoring of reactants, products, and intermediates, studying properties of the intermediates and their reactivity. Studying the reactive species in the gas phase can be advantageously combined with theoretical calculations. This review is focused on ESI-MS studies of copper-catalyzed reactions. Possible effects of the electrospray process on the transfer of the copper complexes to the gas phase are discussed. The plethora of mass spectrometric approaches is demonstrated on copper mediated C-H activations, cross coupling reactions, rearrangements, organocuprate chemistry, and other examples. # 2015 Wiley Periodicals, Inc. Mass Spec Rev 35:85–110, 2016. Keywords: copper catalysis; DFT calculation; electrospray ionization; mass spectrometry; reaction mechanism; reaction monitoring

I. INTRODUCTION Over the last decade, many areas of organic chemistry have benefited from the integration of electrospray ionization mass spectrometry (ESI-MS) as a research technique. It includes, for example, analysis of metal-ligand solution equilibria (Marco Di and Bombi, 2006; Tsierkezos et al., 2009; Tsybizova et al., 2012), determination of absolute ligand binding energies (Zocher et al., 2007a; Zocher, Sigrist, & Chen, 2007b), catalyst screening (Evans et al., 1999; Teichert & Pfaltz, 2008; M€uller et al., 2009), enantioselectivity investigations for asymmetric catalysis (Reetz et al., 1999; Markert & Pfaltz, 2004), and obtaining thermodynamic and kinetic properties for elemental reaction steps (Riveros et al., 1998; Aubry & Holmes, 2000). ESI-MS allows soft transmission of ions from the solution to the gas phase and it is suitable even for complex mixtures (Yamashita & Fenn, 1984; Fenn et al., 1989; Fenn, 2003). It became often used in the investigations of reaction mechanisms (Eberlin, 2007; Santos 2008; Santos, 2009). There is, however, some skepticism, that comes from the side of synthetic chemists about the limited relevance of gas-phase studies to the “real” solution-phase chemistry. For an example of such a debate we

Contract grant sponsor: European Research Council; Contract grant number: StG ISORI; Contract grant sponsor: Grant Agency of the Czech Republic; Contract grant number: 14-20077S. Correspondence to: Jana Roithova, Department of Organic Chemistry, Charles University in Prague, Faculty of Science; Hlavova 2030, 128 40 Prague 2, Czech Republic. E-mail: [email protected]

Mass Spectrometry Reviews, 2016, 35, 85–110 # 2015 by Wiley Periodicals, Inc.

refer to the correspondence published in Organometallics (Gerdes & Chen, 2006; Labinger, Bercaw, & Tilset, 2006), focused on the platinum(II) catalyzed C-H activation of benzene, from both solution and gas phase perspectives. Therefore it is important to overcome the existing “language barrier” by providing extensive explanations, because both of the sides can only benefit from combining of their results (Agrawal & Schro¨der, 2011; Coelho & Eberlin, 2011). ESI-MS is often coupled with tandem mass spectrometry, where collision induced dissociation (or CID) is used most frequently. During CID an ion of interest is fragmented, and analysis of the fragments provides structural information for an investigated ion (Hoffmann de., 1996; Gronert, 2001; O’Hair, 2006). Another possible combination is ion mobility spectroscopy—mass spectrometry that is able to separate the ions in dependence of their shapes, and is often referred to as “chromatography in the gas phase” (Bohrer et al., 2008; Kanu et al., 2008; Lapthorn, Pullen, & Chowdhry, 2013). Finally, infrared multiphoton dissociation ion spectroscopy (IRMPD) can provide structural characteristics of an investigated ion by obtaining its IR spectrum in the gas phase (Polfer, 2011; Roithova, 2012; Brodbelt, 2014). We will not discuss instrumentation and experimental setups for the studies reviewed here; details can be found in the original literature. Many of the gas-phase mechanistic studies have benefited from so-called “on-line monitoring” of the reaction mixture. This strategy is useful for detection of reaction intermediates or kinetic monitoring of a reaction. The monitoring is usually performed either by continuous infusion of a reaction mixture (Fig. 1a) (Vikse et al., 2012), or by repetitive sampling of the reaction mixture at given time intervals. Samples are then diluted in an appropriate solvent suitable for ESI-MS, and introduced into the instrument (Fig. 1b) Reactions that proceed at room temperature, in polar volatile solvents (e.g., acetonitrile, methanol, or water), in air and contain ionic reaction intermediates are ideally suited for ESI-MS studies. This is mostly true for the copper-catalyzed reactions reviewed here. Nevertheless, even reactions proceeding at unsuitable conditions (e.g., in aggressive and/or nonvolatile solvents, requiring higher temperatures, or the absence of O2/H2O) can be monitored by ESI-MS by sampling (Fig. 1b) or by maintaining special conditions (Vikse et al., 2010). Investigation of reaction intermediates, that are not charged and cannot be easily ionized by e.g., protonation, can be achieved by the introduction of a charged tag. A charged tag is a remote group that is permanently charged (e.g., trimethylamonium substituent or sulphonic group) and is supposed not to influence the course of the reaction. It can be placed either on a substrate molecule (Schade et al., 2010), or on a catalyst (Chisholm &

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FIGURE 1. a) Continuous pressurized sample infusion (PSI), set-up with on-line sample dilution via a syringe pump (reprinted from ref. Vikse et al. (2012), Copyright (2012) with permission from Elsevier); b) Repetitive sampling of a reaction mixture.

McIndoe, 2008; Vikse et al., 2010) and it provides easy and efficient ESI-MS detection of the components of a reaction mixture.

II. COPPER IN THE ESI PROCESSES Copper is an inexpensive and readily available metal. A great number of copper catalysts are commercially available and are often used in organometallic synthesis (Beletskaya & Cheprakov, 2004; Allen et al., 2013). Prior to the introduction of ESI-MS investigations of Cu-catalyzed reactions, we will present studies dealing with the behavior of copper complexes during the ESI process. Electrospray ionization can influence the sampling of reaction intermediates and speciation of components of a reaction mixture. Therefore, it is crucial to understand these processes for the correct interpretation of the results.

A. Reduction From Copper(II) to Copper(I) Cu(II)/Cu(I) is a redox couple that is frequently observed both in the gas phase and solution. In aqueous solution, the equilibrium can be illustrated with a simple equation (Equation 1) (Powell et al., 2007): 2Cu þ @Cu2þ þ CuðsÞ

ðEquation1Þ

The equilibrium constant for this reaction is log10 K 6 (Latimer, 1952), indicating that most of the copper is present in the Cu(II) form. Complexes of bare ions with water molecules, although they may seem simple, represent an area of great interest in gasphase chemistry (Beyer, 2007). Thus, the solvation of copper(I) ions by water molecules was extensively studied by a number of groups (Stone & Vukomanovic, 1999; Lamsabhi et al., 2009). It was found that for the copper(I) complex [Cu(H2O)2]þ, the binding energy (BDE) of the second water ligand exceeds the BDE of the first one (Dalleska et al., 1994). This effect was first discovered by Marinelli and Squires for a series of solvated firstrow transition metal ions (Marinelli & Squires, 1989), and then was explained computationally. The metal-water bond is a result of the balance between electrostatic attraction and Paul repulsion. The calculations showed that the metal–water repulsion is 86

decreased by the 4s-3d hybridization in the [Cu(H2O)2]þ complex thus the bonds are strengthened, resulting in an increased binding energy for the second water ligand (Rosi & Bauschlicher, 1989; 1990). Copper(I) ions prefer coordination of just two molecules of water in the first solvation shell. The strong preference of the linear coordination of two ligands is found also in the gas phase. The large binding energy of the second ligand is a reason for common observation of artifacts in mass spectrometers with a higher background pressure such as quadrupole ion traps. Initially singly coordinated copper ions formed from the ESI process or upon collisional experiments have a large tendency to associate with molecules from the background gas of a given mass spectrometer. Therefore, often adducts of [LCu]þ (L ¼ any ligand) with water, methanol, or acetonitrile are observed. In contrast, Cu(II) ions prefer higher coordination numbers not only in the solution (Pasquarello et al., 2001), but also in the gas phase (Roithova & Schr€oder, 2009). Electrospray ionization of Cu(II) solutions are often accompanied by the formation of Cu(I) species. This observation indicates that the redox reaction occurs during the ESI process. There are, basically, three scenarios for such a reduction to take place: i. electrochemical reduction on the walls of the capillary ii. sequential desolvation of the solvated Cu(II) ions associated with electron transfer during ionization and transfer of the ions to the mass spectrometer (Schr€oder, Weiske, & Schwarz, 2002; Tsierkezos et al., 2008; Revesz et al., 2010) iii. reduction in the solution due to the reaction of copper (II) with other molecules present in the solution (e.g., ligands) (Tintaru et al., 2009; Tsybizova et al., 2012) Let us look more closely at the examples described above.

1. Electrochemical Reduction During ESI-MS In 1991 Blades et al. reported that electrochemical reactions might occur during ESI-MS when zinc or stainless steel capillaries were used (Blades, Ikonomou, & Kebarle, 1991). They observed the formation of Zn2þ cations during the course Mass Spectrometry Reviews DOI 10.1002/mas

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FIGURE 2. ESI spectra of an aqueous solution of Cu(NO3)2 and urea at different cone voltages (UC), adapted from ref. Schr€ oder et al. (2002).

of ESI and the abundance of the ions depended on the electrospray current. However, most of the contemporary instruments are equipped with silica capillaries, thus occurrence of electrochemical reduction on the capillary walls is rather unlikely.

2. Reduction During the Electrospray Course In 2002 Schr€oder et al. showed that different ionization conditions can dramatically change the speciation of aqueous

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solutions containing a copper (II) salt and urea (Schr€oder, Weiske, & Schwarz, 2002). Figure 2 shows the source spectra of the investigated solution recorded with different cone voltages. While at low cone voltages representing mild ionization conditions (UC ¼ 10 V) only Cu(II) species were observed, the increase in the cone voltage made the formation of Cu(I) species preferable. An increase of UC destroys the multi-ligated Cu(II) complexes until the [CuNO3(H2O)]þ and [CuNO3(urea)]þ cations start to prevail; upon further increase of UC the monoligated copper(II) complexes prefer to lose a •NO3 radical rather than the closed shell ligands, thus undergoing reduction.

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SCHEME 1. Structures of the investigated acridines A and B.

SCHEME 2. Suggested structures for the different Cu(I) and Cu(II) complexes of acridines A and B.

Similar studies of an aqueous Cu(SO4)2 - DMF solution were later performed by Tsierkezos et al. (Tsierkezos et al., 2008) ESI-MS of the solution led to the formation of the following dications: [Cu(DMF)n]2þ, [Cu2(DMF)nSO4]2þ, and [Cu3(DMF)n(SO4)2]2þ, and the monocations [Cu(OH) (DMF)n]þ, [Cu(DMF)n(HSO4)]þ, and [Cu(DMF)n]þ, where the latter were formed under harder ionization conditions as a result of desolvation-reduction processes. The dissociation of [Cu(DMF)n]2þ was studied with the use of CID experiments. It was shown that for the ions with n > 3 the CID spectra showed the elimination of a DMF molecule according to the equation 2: ½CuðDMFÞn 2þ ! ½CuðDMFÞn1 2þ þ DMF

ðEquation2Þ

However, already for the tris-ligated dication the electron transfer pathway from DMF ligand to Cu (II) started to compete with simple dissociation (Equations 3 and 4):

½CuðDMFÞ3 2þ ! ½CuðDMFÞ2 þ þ DMFþ

ðEquation3Þ

½CuðDMFÞ3 2þ ! ½CuðDMFÞ2 2þ þ DMF

(Equation 4)

The reduction from Cu(II) to Cu(I) upon CID was also found to be occurring in copper-pyridine complexes (Revesz et al., 2010): ½ðpyÞ2 CuClþ ! ½ðpyÞ2 Cuþ þ Cl (Equation 5) In general, the reduction of copper (II) to copper (I) occurs during the ESI process, when the coordination number of the original copper (II) complex drops to two. It is associated with the stabilization of copper (I) by linear coordination of two ligands. A nice demonstration of this effect was published in 2008 by Schr€oder and co-workers. They investigated the behavior of CuCl2 solution in methanol in the presence of acridine ligands (Schemes 1 and 2) (Tintaru et al., 2009). It was observed that ESI of the CuCl2 solution with acridine A led to the formation of Cu(II) complexes [ACu(A-H)]þ, whereas the acridine B almost exclusively formed Cu(I) complexes [B2Cu]þ (the complex [BCu(B-H)]þ was also observed, but was very low abundant). Obviously, the difference between ligands A and B originates in the chelating ability of ligand A. Thus, while the copper atom is coordinated by four atoms in the complex [ACu(A-H)]þ, only the linear coordination of two acridine ligands is possible in [BCu(B-H)]þ. As a result, the successive de-coordination of the copper complex during the ESI process (elimination of solvent molecules or the chlorine counter ion) is associated with the reduction of copper and formation of [B2Cu]þ (Alcamet al., 2004). We note in passing that ionization parameters such as spray voltage or capillary temperature usually do not have a big effect on the oxidation state of copper. Nevertheless, they were found to be influencing the ion cluster formation (see, for example: Jakl et al., 2014) and solvation. For example, a pronounceable effect of the capillary temperature on solvation was found for ions solvated with H2O or methanol (see, for example: Rodriguez-Cruz, Klassen, & Williams, 1999). It implies that high temperatures leading to ultimate desolvation indirectly do influence oxidation state of copper complexes transferred to the gas phase as explained above.

3. Reduction in the Solution

SCHEME 3. Structures of investigated thiacrown ethers (L).

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Although the previous examples showed that Cu (II) is frequently reduced to Cu (I) during the electrospray process, the reduction can also occur in the solution upon interaction with a large organic ligand. Such an example was found during an investigation of the speciation of CuCl2 in methanol/dichloromethane solution in presence of thiomacrocyclic ligands (Scheme 3) by Tsybizova et al. (2012). ESI–MS of the CuCl2-thiacrown solution led to the formation of Cu(I) complexes [Cu(L)]þ and no Cu(II) complexes (e.g., [CuCl(L)n]þ) were observed under any ionization conditions. Electron paramagnetic resonance (EPR) spectroscopy revealed that the reduction of copper occurs already in the solution, followed up by the reaction with another ligand: Cuþ þ L ! [Cu(L)]þ. The findings also suggest that the radical cation Lþ• that is formed during the reduction of copper, most likely undergoes a follow up reaction with a solvent molecule, forming a product with a Mass Spectrometry Reviews DOI 10.1002/mas

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SCHEME 4. Sketch of the mechanism suggested for the oxidation of alcohols in the active center of galactose oxidase reprinted from ref. (Milko et al., 2008a), Copyright # [2008] WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

closed shell electronic configuration (i.e., [L-OCH3]þ or [LCH2OH]þ) that is EPR inactive.

B. Interaction of Copper(II) With Redox-Active Ligands An interesting example of redox chemistry is represented by the interaction of copper(II) with phenoxy ligands (for other studies with redox-active ligands see Cerchiaro et al., 2004; Chiavarino et al., 2012; Brea et al., 2013). A series of gas phase studies were carried out in order to investigate the [Cu(PhO)]þ complex (Ph ¼ phenyl). This complex can be viewed as a simple model for studying the interaction between copper and a tyrosine rest in various biological systems. For example, such a motif is present in galactose oxidase—a member of the oxidoreductase enzymes family—that contains two tyrosine moieties and a single copper ion in the active center.

The suggested mechanism of the oxidation of primary hydroxyl groups at the active center of galactose oxidase in shown in Scheme 4. ESI-MS and computational studies aimed at the investigation of the interaction between copper and redox active phenol-based ligands in more detail (Milko et al., 2008a). The ESI-MS of an aqueous solution of copper nitrate with phenol revealed the formation of [Cu(PhOH)(PhO)]þ, [Cu(PhO)]þ, and [Cu(PhOH)]þ cations, where copper atoms can be bound either to the p-electron system of the phenol rings or to the lone electron pairs of the oxygen atom. The DFT calculations showed that, in the case of [Cu(PhOH)]þ the Cu atom prefers binding to the p-electron system with small energy barriers between structures 1a, 1b, and 1c (Fig. 3a). It thus suggests a dynamic equilibrium between these structures which could be described as a “copper ring-walk”. Similar studies on [Cu(PhO)]þ cation revealed that the structure can be best described as a Cu(I) ion being attached to the oxygen atom of the phenoxy radical (Fig. 3b).

FIGURE 3. a) Possible structures of [Cu(PhOH)]þ obtained by B3LYP/TZVP and their energies (in eV) relative to the most stable species 1a. b) Structures of [Cu(PhO)]þ calculated by B3LYP/TZVP and their energies (in eV) relative to the most stable species 2a; the bottom right graphic exemplarily shows the computed spin density of 2a (a-spin: light gray, b-spin: dark gray, isosurface at 0.005 a.u.) Reprinted from ref. (Milko et al., 2008a), Copyright # [2008] WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


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FIGURE 4. a) Structures of [Cu(PhOH)(PhO)]þ calculated by B3LYP/TZVP and their energies (in eV) relative to the most stable species 3a; b) IRMPD spectra of [Cu(PhOH)(PhO)]þ (black line) compared with the B3LYP/ TZVP calculated spectra (grey area, with Gaussian broadening of all signals by 20 cm-1 of the structural isomers 3a (top), 3b (middle), and 3c (bottom). Reprinted from ref. (Milko et al., 2008a), Copyright # [2008] WILEYVCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 4a shows that the interaction of a [Cu(PhO)]þ cation with a neutral phenol ligand leads to a variety of possible cationic structures.. All of the suggested isomers lie very close in energy and allow large structural flexibility in the Cu/PhOH coordination. In the energetically most favorable structure, the copper atom is coordinated to the carbon atoms of neutral phenol and to the oxygen atom of the phenoxy ligand. This structure was proved by IRMPD spectroscopy (Fig. 4b). The IRMPD spectrum suggests that theoretical spectra of the complexes 3a and 3b provide a good match with the experiment and thus most likely equally contribute to the real structure of [Cu(PhOH)(PhO)]þ, whereas the structure 3c can be excluded based on the expected red-shift of the C-OH stretching mode, which was not observed experimentally.

In 2008 Milko et al. investigated in more detail the influence of different additional ligands L (where L ¼TMEDA, pyridine or H2O) on the cationic [Cu(PhO)]þ core system (Milko et al., 2008b; Rezabal et al., 2010). The combined IRMPD and theoretical studies of [Cu(PhO)(L)n]þ showed that the addition of two or more electron donating ligands (i.e., n > 1) results in a shift of the radical center from the phenyl ring to the oxygen and copper atoms. Hence, the addition of the ligands to the Cu(I)/phenoxy complex changes its electronic structure to the Cu(II)/phenolate complex (Fig. 5). The change of electronic structure can be experimentally observed by monitoring the stretching vibration of the C–O bond of the phenoxy ligands. While it has a double-bond character in the phenoxy radical and can be found at about 1500 cm1 in the IRMPD spectra of the respective copper(I)/phenoxy ions, it changes to a single C-O bond in the copper(II)/phenolate complexes and is red-shifted to about 1300 cm1 (cf. Fig. 5).

C. Copper Acetate: Single Site Versus Cluster Chemistry

FIGURE 5. Mesomeric structures of [Cu(PhO)]þ and the dependence of n(C-O) (in wavenumbers) on the calculated spin density of the phenyl ring. The open symbol corresponds to the calculated value of free phenol. Reprinted with permission from ref. (Milko et al., 2008b). Copyright (2008) American Chemical Society.

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Copper acetate is a cheap and easily available catalyst, frequently used for coupling reactions. Tsybizova et al. (Tsybizova et al., 2014a) have investigated the speciation behavior of Cu(OAc)2 in organic solvents (methanol and acetonitrile) by means of ESI-MS. The spectra revealed a high degree of clustering with a prevailing abundance of clusters containing three to six copper atoms. However, small amounts of water significantly suppressed the clustering and resulted in the dominance of monomeric clusters. Further investigation of the Cu(OAc)2 speciation by studying solubility properties, conductivity, and EPR confirmed the fundamental water effect observed with ESI-MS. Specifically, EPR spectra showed that with an increased amount of water in the Mass Spectrometry Reviews DOI 10.1002/mas

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FIGURE 6. (a) EPR spectra of Cu(OAc)2 solutions (3.75 mm) in methanol with variable water content. (b) Fraction of EPR-active Cu(II) species in Cu(OAc)2 solutions in methanol with variable water content obtained by double integration of the spectra relative to that of an external standard. Reprinted from ref. (Tsybizova et al., 2014a), Copyright # [2008] WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

SCHEME 5. Activation of methane by [CuO]þ. Adapted according to ref. (Dietl et al., 2011).

solution, the EPR signal of copper (II) increased (Fig. 6). Cu(OAc)2 in pure methanol is mostly present as “paddle-wheel” dimer and thus is EPR inactive. The increase in the EPR signal confirms that the addition of water leads to the de-aggregation of the salt in the solution. The redox behavior of different copper clusters was studied in CID experiments. It was shown that copper clusters undergo redox processes (i.e., reduction of copper (II) to copper (I) associated with oxidation of counterions) with different efficiencies depending on their size and solvolysis. This finding indicated that coordinatively unsaturated copper (II) clusters might represent catalytically active species in redox reactions. Hence, presence of traces of water may significantly influence the formation of copper clusters and thus the catalytic activity of copper salts (e.g., of studies using copper acetate as catalyst Lisboa da et al., 2011).

III. CATALYTIC REACTIONS FIGURE 7. Schematic PES for the C-H bond activation of propane by [(phen)CuO]þ. As far as available, energies (in eV) are taken from the B3LYP calculations, all other energy levels are tentative. Assumed TS denotes the transition structures for C-H bond activation and C-O bond formation, and CP stands for the assumed crossing point between the singlet and triplet surface. The picture only refers to the activation of the secondary C-H bond and thus the formation of i-propanol as the neutral product. Adapted from ref.(Schr€ oder et al., 2004).


A. Cu-Catalyzed C-H Activation of Pure Hydrocarbons. Copper(I)/Copper(III) Catalytic Cycle. Selective activation of C-H bonds in pure hydrocarbons, especially methane, is probably the most challenging task for the chemical catalysis (Roithova & Schr€oder, 2010; Schwarz, 91

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SCHEME 6. Suggested scheme for the aromatic C-H bond activation of the phenantroline ligand of the copper oxide cation.

2011). Already in 2000 it was predicted that bare [CuO]þ (among other metal oxide cations) is a suitable and powerful candidate for conversion of methane to methanol (Shiota & Yoshizawa, 2000). However, only in Dietl et al. (2011) reported on the studies of bare [CuO]þ in the gas phase and showed that it is indeed able to activate the C-H bonds of methane (Dietl et al., 2011). The [CuO]þ ions were generated by laser vaporizationionization of pure 63Cu in the presence of a He/N2O plasma and studied by using a FT-ICR mass spectrometer. The experiments revealed that at room temperature [CuO]þ brings about enough energy for both proton abstraction (Scheme 5, Eq (1)) and oxygen atom transfer (Scheme 5 Eq. (2)). Moreover, the product radical cation [CuOH]•þ could cleave the C-H bond of methane molecule yielding a water complex (Eq. (3)). Following theoretical mechanistic studies confirmed the reactivity of the [CuO]þ species towards methane under thermal conditions, and have shown that, in general, metal oxides with even number of electrons are capable of a homolytic bond cleavage (Dietl et al., 2012Dietl, Schlangen, & Schwarz, 2012). Some earlier studies focused on the investigation of [CuO (L)]þ species, where L stands for an organic ligand. In 2004 Schr€oder et al. reported that [(phen)CuO]þ (phen ¼ 1,10phenantroline) can activate a C-H bond of propane and larger alkanes (Schr€oder, Holthausen, & Schwarz, 2004). The [(phen) CuO]þ cations were prepared in the gas phase using electrospray ionization. In brief, an aqueous solution of Cu(NO3)2 with 1,10phenanthroline was sprayed into the mass spectrometer. The resulting mass spectrum showed the formation of the [(phen)Cu (NO3)]þ cations which were then mass-selected and subjected to MSn experiments. The CID of [(phen)Cu(NO3)]þ revealed two fragmentation pathways leading to [(phen)Cu]þ and [(phen) CuO]þ, respectively. The latter product ions contain a ligated copper oxide cation formally in the Cu(III) oxidation state. The reactivity of [(phen)CuO]þ towards various alkanes was further tested in a collision cell, revealing that [(phen)CuO]þ reacted well with alkanes larger than ethane. The combination of experimental data and theoretical DFT calculations suggested the potential energy surface (PES) shown

in Figure 7. The complex [(phen)CuOH(C3H7•)]þ was suggested to serve as the key intermediate of the investigated reaction. In addition to that, harder ionization conditions during the ESI-MS experiments led to the formation of another isomer of [(phen)CuO]þ with the same m/z ratio. This isomer however, showed no activity toward alkanes and lost a CO molecule upon CID. This finding suggested that the oxygen atom was transferred to the molecule of phenanthroline. The structure of the oxidized ligand and the mechanism of aromatic C-H activation was later studied by means of IRMPD spectroscopy and DFT calculations by Jaskova et al. (2012). The comparison of the calculated IR spectra for several structures of [(phen)CuO]þ with the experimental IRMPD spectrum revealed that the aromatic C-H bond activation occurs at the position 2 of the phenanthroline ring. The reaction mechanism starts with abstraction of a hydrogen atom from position 2 by the oxygen atom, which leads to the formation of an intermediate copper (II) complex (Scheme 6). The subsequent migration of the hydroxyl group from the copper to the radical carbon atom finishes the process and yields the copper (I) product. The reaction is associated with a spin isomerization from the triplet state to the singlet state. Recent studies by Rijs et al. (2014) have shown that the isomers a and b (Scheme 6) can be separated using ion mobility mass spectrometry by changing the ESI cone voltage. The experiments were performed on a modified travelling wave ion mobility spectrometry-mass spectrometer (TWIMS–MS), capable of performing ion-molecule reactions. The reactivity of each separated isomer was tested against propane and arylhalides. The isomer a showed C-H activation of propane and an ability to react with arylhalides with a subsequent O-atom transfer or concerted oxidation and halide transfer, whereas in the case of the isomer b no such reactions were observed. In 2012 Shaffer et al. reported on a copper oxide bipyridinium-based system for intramolecular aliphatic C-H bond activation (Shaffer et al., 2012). They synthetized a reagent molecule 2 by attaching a long-chain alkyl group to a bipyridine unit through an ester linkage (Scheme 7). Similarly to the previous experiments, ESI-MS of the methanol/water (1:1) solution of 2 with Cu(NO3)2 led to the formation of [(2)Cu(NO3)]þ cation. CID experiments with [(2) Cu(NO3)]þ showed that the major fragment [(1)Cu(NO3)]þ arises from ester cleavage and subsequent octene elimination. The second fragmentation pathway leads to the loss of NO2 and thus to the formation of the [(2)CuO]þ cation. Subsequent fragmentation of mass-selected [(2)CuO]þ leads either to the elimination of a water molecule or to the formation of [(1)Cu]þ (occurring most likely again due to the ester cleavage). Dehydration of [(2)CuO]þ suggests that the complex had to

SCHEME 7. Synthesis of 2 followed by ESI-MS to generate [(2)Cu(NO3)]þ.

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FIGURE 8. Region of the parent ion and the dehydration product upon CID of deuterium labeled compounds. Adapted from ref. (Shaffer et al., 2012).

undergo a C-H activation reaction at ligand 2 (similarly as shown in Scheme 6). To support this suggestion a series of CID experiments with a deuterium labeled ligand 2 were carried out (Fig. 8). The observed elimination of D2O from the ligand 2 with the perdeuterated octyl group ([(D17-2)CuO]þ) confirmed that the hydrogen atoms were indeed abstracted from the ester moiety and not the bipyridine. CID of the cation labeled at the terminal position of the octyl group ([(8,8,8-D3-2)CuO]þ) revealed the elimination of H2O and HDO in approximately 1:1 ratio, which demonstrates that the oxidation occurs at the terminus of the alkyl chain. Thirdly, the fragmentation of the ion ([(7,7-D2-2) CuO]þ) led to a 1:5 ratio of H2O and HDO loss suggesting that C-H activation of the three most terminal carbon atoms is highly selective. Ion mobility mass spectrometry studies (IM-MS) gave further insight into the structural features of the investigated ions. The IM-MS studies have advantage that they contain

information not only about masses of the investigated ions, but also about their mobilities in an inert gas (nitrogen, argon, etc.,), which is related to their shapes (details about the experiments can be found in Revesz A. et al., 2011). The experiments revealed that the arrival times for most of the studied ions are linearly dependent on their m/z ratio. However, the mobilities for [(2)CuO]þ and [(2-H2O)Cu]þ were significantly greater than it was expected. Such observation could be explained by conformational changes caused by the hydroxylation of the side chain by the reactive copper(III) oxo precursor (Scheme 8). In order to test this hypothesis a series of ligands 3-5 was synthetized and subjected to the ion mobility studies in a water/ methanol solution of Cu(NO3)2. The ions [(3)Cu]þ, [(4)Cu]þ, and [(5)Cu]þ showed similar mobilities to [(2)CuO]þ suggesting that the ion [(2)CuO]þ in fact represents a mixture of the hydroxylated copper (I) complexes. Finally, based on the observations described above, a catalytic cycle was proposed (Scheme 9).

SCHEME 8. Oxygen insertion into a C-H bond of [(2)CuO]þ to yield the complexes of the corresponding alcohols 3–5.


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SCHEME 9. Gas-phase reactivity and theoretical completion of catalytic cycle. Adapted from ref. (Shaffer et al., 2012).

B. Copper Catalysis in Coupling Reactions Copper catalyzed coupling reactions represent a broad and highly promising class of transformations for modern synthesis as they usually require mild reaction conditions and can be performed in ambient atmosphere. Below we have tried to summarize the gas-phase studies performed for the investigation of such reaction mechanisms. Although some of these studies did not succeed in finding strong evidence for the proposed mechanistic pathways, all of them are interesting from a scientific perspective and may inspire other scientists to search for answers to the unsolved questions.

1. Copper-Catalyzed C-N Coupling Between aryl Halides and Amines Tseng et al. (2011b) have reported on the investigation of copper-catalyzed C-N coupling reaction between arylhalides and amines (Scheme 10). They have analyzed the reaction mixture by means of ESI-MS and assigned the observed peaks as [Cu(phen)2]þ, [Na(phen)2]þ, and K[Cu(phen)(NPh2)(p-tolyl)]þ in positive ion mode. Based on the observation of the latter copper (II) complex, they suggested the participation of a radical path in the catalytic cycle and proposed a mechanistic scheme shown in Scheme 11. A radical [CH3C6H4]• could be formed upon the elimination of iodide from the radical anion [CH3C6H4I]- generated from 4iodotoluene by a single electron transfer from sodium tertbutoxidee.

SCHEME 10. Cu(I) catalyzed C–N coupling reaction.

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Although the intermediates Na[Cu(NPh2)2(p-tolyl)]þ or [Cu(NPh2)2(p-tolyl)I] were not directly observed in the ESI spectra, it was suggested, based on the presence of [Cu(NPh2)I]-, that a two-electron oxidative addition may be involved in the mechanism. Briefly, the catalytic cycle starts with the generation of [Cu(NPh2)2] upon the reaction between N-phenylaniline, a base (t-BuONa or K2CO3), and CuI. The anion reacts with 4iodotoluene to form A, and reductive elimination of the product molecule from A produces [Cu(NPh2)I] which can further react with NPh2 and complete the catalytic cycle. The alternative free-radical path includes ligand redistribution reactions and leads to the formation of the neutral complex [Cu(phen)(NPh2)]. Its reaction with p-tolyl radical generates a copper(II) complex [Cu(phen)(NPh2)(p-tolyl)] which, in association with another single-electron transfer, eliminates the product. When 1 equivalent of a radical scavenger (2,2,6, 6-tetramethylpiperidin-1-yl) oxidanyl (TEMPO) had been added to the reaction mixture, the yield of the coupled product was reduced from 93% to 64%. These observations supported the existence of the free radical path and suggested that it contributes about one third to the whole catalytic reaction. However, changing the reaction conditions (e.g., use of a different base or ligand), changed the influence of TEMPO on the yield of the product indicating that the mechanism of the reaction is strongly dependent on the reaction conditions. The complex [Na(phen)3Cu(NPh2)2] suggested to be formed in the first step of reaction was synthetized (Scheme 12), isolated and its catalytic activity was studied in a greater detail (Tseng et al., 2011a). If the complex [Na(phen)3Cu(NPh2)2] were an intermediate, it should react with 4-iodotoluene yielding the product (N-4methylphenyl-N,N-diphenylaniline). This reaction was tested and yielded 71% of the final product. In addition, the complex was found to be an effective catalyst in the coupling reaction itself. For instance, when 10 mol% of the complex was added to the reaction mixture, the C-N coupling reaction gave 99% of the Mass Spectrometry Reviews DOI 10.1002/mas

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SCHEME 11. Proposed catalytic cycle. Adapted from ref. (Tseng et al., 2011b).

product. These observations suggest that [Na(phen)3Cu(NPh2)2] truly is an intermediate.

2. Copper-Catalyzed Coupling of Thioesters and Boronic acids In 2002 Villalobos et al. found a copper catalyzed coupling reaction of thioethers with arylboronic acids under aerobic conditions—a convenient pathway for the synthesis of nonsymmetrical ketones (Scheme 13) (Villalobos, Srogl, &, Liebeskind, 2007). Tsybizova et al. applied ESI-MS for on-line monitoring of the coupling reaction between the substrate 1 and 4-tolylboronic acid in the presence of copper acetate (Scheme 14) (Tsybizova et al., 2014b). The ESI-MS of the reaction mixture revealed the formation of various sodium complexes: (e.g., [(1)Na]þ, [(1)2Na]þ, [(4) Na]þ, [(4)2Na]þ), copper complexes (e.g., [(1)Cu]þ, [(1) CuOAc]þ, [(4)Cu]þ), and also some intermediates (e.g., [(int)

Cu]þ with m/z 305). No intermediates containing all three reaction components, i.e., substrate 1, the boronic acid, and copper as well as no complexes containing the ketone product were observed. It was possible to determine the appearance energy of 121 kJ mol1 for the fragmentation of [(1)CuOAc]þ to [(int)Cu]þ (cf. Scheme 14) which corresponds to the formation of BzOAc. As this product was not observed in the condensed phase, it could be considered as an upper limit for the energy barrier for the observed C-C coupling. From the monitoring of the abundances of the sodium complexes in time it was possible to determine the activation energy for the reaction according to the Arrhenius equation as 81 5 kJ mol1. In agreement, this value is substantially lower than the determined upper limit. As to a possible mechanism, it was suggested that the transmetallation to form the key intermediate proceeds in a neutral state. Hence, the [(1)Cu(OAc)2] probably reacts with TolB(OH)2 to form [(1)Cu(OAc)(Tol)] which finally eliminates the ketone product.

SCHEME 12. The formation of the complex [Na(phen)3Cu(NPh2)2] through different reaction routes. Adapted from ref. (Tseng et al., 2011a).


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SCHEME 13. Aerobic coupling of thioesters and boronic acids.

3. Copper Catalyzed Coupling of Thiols With aryl Halides Shao-Wen Cheng and co-workers have employed ESI-MS to study a C-S cross coupling reaction between thiols and aryl halides, catalyzed by copper (I) (Scheme 15) (Cheng et al., 2011). ESI-MS of the reaction mixture led to the formation of [Cu(SPh)2], [Cu(SPh)I], and K[Cu(SPh)2(Ph)]þ in negative and positive modes, respectively. Based on these observations a catalytic cycle was proposed (Scheme 16). It was suggested that formation of the cation K[Cu(SPh)2(Ph)]þ could result from the fragmentation of neutral K[Cu(SPh)2(Ph)I] into I and K[Cu(SPh)2(Ph)]þ. These ionic species were considered as indirect evidence for the formation of the proposed Cu (III) species in the reaction cycle (the key intermediate A was not observed). It should be noted that the complex K[Cu(SPh)(Ph-S-Ph)]þ containing the product of the studied reaction would have the same m/z ratio and would represent a copper (I) species. This is often a problem in searching for copper (III) intermediates and more studies are necessary in this direction.

4. Copper Catalyzed Disproportionation of Iminedisulfides Srogl et al. have investigated copper catalyzed disproportionation of iminedisulfides (Scheme 17) from both synthetic and gas-phase perspectives (Srogl et al., 2009). For the ESIMS studies the reactant 1 was mixed with a copper(I) catalyst and sprayed into the a mass spectrometer. The spectrum revealed the formation of the ion [(1)Cu]þ which then was subjected to collision induced dissociation experiments.

The CID spectrum (Fig. 9) reveals the dominant formation of [(3)Cu]þ associated with the elimination of the neutral product 2. This fragmentation is fully consistent with the reaction mechanism in which a single Cu atom is sufficient to complete a catalytic cycle. The synthetic experiments and kinetic studies showed an agreement with the mass spectrometric experiments and a tentative mechanistic scheme for the investigated reaction was proposed (Scheme 18). The reaction mechanism was further investigated by theoretical calculations. Possible pathways for the transformation of the initial adduct of Cu(I) and disulfide substrate ([(1) Cu]þ) to the [(2)Cu]þ product ions were pursued (Fig. 10) (Rokob et al., 2011). It was shown that Cu(III) species are likely to be involved in the reaction. The same computational analysis was done for the fragmentation of complexes E, which corresponds to the loss of neutral 2 and subsequent formation of the copper (I) complex F (cf. Fig. 11). Several possible structures of the copper (I) complex can be suggested (FS, FN, and FC, Fig. 11). Theoretical calculations revealed that there is a preference for the formation of (FS þ 2) which lies only 25.4 kcal mol1 higher in energy than reactant A. The most energetically demanding step is represented by the formation of the first heterolytic product in the complex ES. The IRMPD spectrum of [(1)Cu]þ is in a good agreement with the theoretical spectrum for the Cu(I)-adduct of the disulfide (Fig. 12a). The structure of the daughter ions [(3)Cu]þ was also tested by means of IRMPD spectroscopy. The direct measurement of [(3)Cu]þ was impossible because of an insufficient amount of its fragmentation induced by the laser, but the experiment could be performed with its adduct with background water. To this end, the water adduct [(3)Cu(H2O)]þ was subjected to IRMPD, and an experimental IRMPD spectrum was obtained upon the elimination of the water molecule (Fig. 12b).

5. Copper-Promoted Oxidative Cyclization of Enaminones In 2013 Hyvl et al. reported their investigation in the mechanism of copper-catalyzed cyclization of enaminones (Hyvl et al.,

SCHEME 14. Observed copper complexes. Adapted from ref. (Tsybizova et al., 2014b).

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SCHEME 15. Copper catalyzed coupling of thiols with aryl halides.

2013). It was known that with combined palladium and copper catalysis in DMF the reaction yielded indoles (W€urtz et al., 2008), while the reaction in acetonitrile using a copper catalyst yields only pyrazoles (Scheme 19) (Neumann, Suri, & Glorius, 2010). The selectivity of the reaction with copper attracted the attention of the authors. Their investigation started with the analysis of a mixture of enaminone 1 and Cu(OAc)2 in acetonitrile at room temperature. ESI-MS showed the formation of copper(II) complexes of the deprotonated substrate bearing either an additional acetonitrile ligand or another neutral enaminone molecule: [(1H)Cu(CH3CN)]þ and [(1H)Cu(1)]þ. Other copper complexes corresponded to copper acetate ions with neutral enaminone or acetonitrile: [(1)Cu(OAc)]þ and [Cu(OAc)(CH3CN)2]þ. After heating of the reaction mixture, formation of new complexes containing the product molecule 2 was observed: [2H]þ, [(2)Cu(CH3CN)]þ, and [(2)2Cu]þ. Also complexes with both reactant and product molecules appeared in the spectrum: [(1H)Cu(2)]þ and [(1)Cu(2)]þ. The mass spectra also showed a series of signals containing a new component X. Reactions with labeled compounds were carried out to reveal the structure of X, followed by its isolation from the reaction mixture and characterization using NMR spectroscopy. Based on these experiments a structure for intermediate X was suggested (Scheme 20). It was shown that mixing intermediate X with the copper catalyst in the acetonitrile under the identical conditions does not lead to the formation of the product. Therefore, it was

SCHEME 16. Proposed catalytic cycle for the coupling reaction of thiols with aryl halides. Adapted from ref. (Cheng et al., 2011).


SCHEME 17. Cu(I)-catalyzed transformation of imine disulfide.

suggested that X was a side product that could have been formed due to partial oxidation of starting compound 1 during the reaction (Scheme 21). Although no direct intermediates for the reaction were observed, a possible mechanistic scheme was proposed for the formation of pyrazoles (Scheme 22).

C. Copper Mediated Naphthol Coupling ESI-MS coupled with ion spectroscopy and tandem mass spectrometry helped to reveal a mechanism of naphthol coupling, catalyzed by copper (II). Oxidative coupling of naphtholes is an important class of reactions providing a route to the formation of chiral compounds that are frequently used in stereoselective synthesis (Clavier & Pellissier, 2012) or as fluorescent sensors for enantioselective recognition (Pu, 2012). Numerous synthetic procedures exists for such coupling reactions including catalysis by copper, iron, or vanadium oxides (Scheme 23) (Klussmann & Sureshkumar, 2010). The reaction mechanism of the coupling was studied with a mixture of methyl-3-hydroxy-2-naphtholate (3) and Cu(OH)ClTMEDA catalyst in a series of ESI-MS experiments (see Scheme 24) (Roithova & Schr€oder, 2008). The spectra revealed the formation of two complexes that could be assigned as [(3-H) Cu(TMEDA)]þ and [(3-H)2Cu2Cl(TMEDA)2]þ. Previous mechanistic studies suggested mononuclear copper species such as [(3-H)Cu(TMEDA)]þ as the key intermediates in this catalytic cycle. These intermediates were suggested to behave as carbon-centered radicals with respect to the second naphthol molecule in order to yield binol 4. The reactivity of the complex [(3-H)Cu(TMEDA)]þ as a carbon-centered radical was tested in the gas phase in reactions with CH3–S–S–CH3 and CH3–Se–Se–CH3. While C-radicals are capable of cleaving the S–S or Se–Se bond, no reactivity was observed for [(3-H) Cu(TMEDA)]þ (Stirk et al., 1992), which suggested that the complex [(3-H)Cu(TMEDA)]þ cannot react with a second inactivated naphthol molecule to yield the binol 4. The structure of the [(3-H)Cu(TMEDA)]þ cation was further characterized by IRMPD spectroscopy and compared with the theoretical spectrum of the most stable isomer found for this complex (Fig. 13a) (Roithova & Milko, 2010). The C-O vibration of the naphthoxy ligand is found at about 1320 cm1, which is consistent with the unpaired electron remaining localized at the copper (II) center and the naphthoxy ligand does not represent a C-radical (see above Fig. 5 and the related discussion). On the other hand, the binuclear complex [(3-H)2Cu2Cl(TMEDA)2]þ can serve as a potential reaction intermediate. The collisional activation experiments with this complex revealed three fragmentation channels: (i) dissociation into two monomeric complexes [(3-H)Cu(TMEDA)]þ and [(3-H) 97

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SCHEME 18. Proposed mechanistic cycle for Cu(I)-catalyzed transformation of imine disulfide. Adapted from ref. (Srogl et al., 2009).

CuCl(TMEDA)], (ii) loss of the TMEDA ligand, and (iii) elimination of the binol 4. Comparison of the IRMPD spectrum of [(3-H)2Cu2Cl(TMEDA)2]þ with the theoretical spectra showed that the complex contains two separate naphthoxo ligands. The elimination of 4 is thus a result of the C-C coupling reaction induced by activation (collisional activation or irradiation) of the complex. Under CID conditions, elimination of binol 4 was much less abundant than the cluster cleavage of the [(3-H)2Cu2Cl(TMEDA)2]þ ion, whereas it became dominant, when the fragmentation was induced by the absorption of IR photons. This observation suggests that the coupling reaction proceeds over a tight transition state and therefore a “slow heating” of the reaction complex favors binol formation.

IV. COPPER AS A LEWIS ACID A. Copper-Platinum Transmetallation Transmetallation is a key step in many cross-coupling reactions catalyzed by transition metals (Meijere de and Diederich, 2004). Moret et al. used ESI-MS to investigate platinum-copper transmetallation (Moret et al., 2010). The catalytic species were prepared directly in the electrospray process from a solution containing equimolar amounts of [(dmpe)PtMe2], copper (I) triflate and monodentate phosphine PR3 (where R ¼ Me, Ph, Cy, and t-Bu) (Scheme 25). Crystallization of the corresponding triflate salt of the Pt-Cu complex (in the case of R ¼ t-Bu) helped to gain more insight into its structure. The crystal structure showed that a platinum atom is connected to copper by a short bond and a bridging methyl group. Consequent gas-phase studies of the corresponding heterometallic cations revealed a series of possible transformations (Scheme 26) depending on the substituent group: Their reactivity involved transmetallation reactions and a methyl transfer from platinum to copper. The energy resolved CID experiments allowed for the determination of the activation energies for the transmetallation step.

B. Copper-Mediated Wolff Rearrangements

FIGURE 9. CID spectrum of mass-selected [(1)Cu]þ showing the highly preferential loss of neutral 2 to afford [(3)Cu]þ. The protonated benzothiazole [2H]þ (m/z 212) arises from a consecutive loss of neutral CuH from [(3)Cu]þ. The inset shows the measured and calculated isotope pattern of the [(1)Cu]þ precursor ion. Adapted from ref. (Srogl et al., 2009).

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In 2003 Julian et al. reported a mechanistic and computational study of copper mediated Wolff rearrangements (Julian et al., 2003). Although the gas phase synthesis of metallocarbenoids was attempted many times (for example in 2000 Adlhart et al. reported on a similar study of ruthenium carbene complexes (Adlhart et al., 2000) it was the first example of the study of copper carbenes (Batiste & Chen, 2014). Diazomalonates (known to be capable of Wolff rearrangement) served as model substrates for this study (Scheme 27). To Mass Spectrometry Reviews DOI 10.1002/mas

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FIGURE 10. Calculated energy profile for the possible transformations of the reactant complex A ([(1)Cu]þ). Reprinted with permission from ref. (Rokob et al., 2011). Copyright (2011) American Chemical Society.

FIGURE 11. Computed energy profiles for the loss of phenylbenzothiazole 2 to form the ions F (m/z 276). (The pathway between the reactant complex A and product complexes E is shown in Figure 12, hence only the largest barriers are shown here). Reprinted with permission from ref. (Rokob et al., 2011). Copyright (2011) American Chemical Society.


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FIGURE 12. a) Experimental IRMPD spectrum of [(1)Cu]þ (m/z 487, black) and the computed IR spectrum of reactant complex A (red) in the range from 1000 to 1900 cm-1. The numbers indicate the positions of the maxima. b) Experimental IRMPD spectrum of the fragment ion formed by benzothiazole loss and water uptake (m/z 294, black) and the computed IR spectrum of FSH2O (red) in the range from 1000 to 1900 cm-1. The numbers indicate the positions of the maxima. Reprinted with permission from ref. (Rokob et al., 2011). Copyright (2011) American Chemical Society.

SCHEME 19. Copper-promoted oxidative cyclization of enaminones affords different products depending on the chosen catalytic system.

this end, 2-diazodimethylmalonate was mixed with a copper (I)catalyst in a water/methanol mixture with an addition of 0.1% of acetonitrile and sprayed into the mass spectrometer. The obtained mass spectra showed the formation of a copper (I) complex 1 with the malonate ligand, which was subjected to further MSn experiments (Scheme 28). CID of the isolated copper-malonate adduct 1 lead to two sequential losses of 28 Da, where the first loss corresponds to the elimination of the diazo-group. The second loss results from the Wolff rearrangement of fragment 2 accompanied by the loss of CO yielding complex 3. This fragment can undergo the same rearrangement once more leading to a second loss of CO and yielding the stable copper Fischer carbene 4. CID of 4 leads to

the elimination of an acetonitrile molecule with a subsequent addition of either water or methanol molecules that are present as background gases in the given mass spectrometer. Experiments showed that unlike copper(I), copper(II) complexes are incapable of producing Fischer carbenes or undergoing Wolff rearrangement upon CID. Instead, they simply eliminate an acetonitrile molecule. DFT calculations showed that direct elimination of a N2 molecule from 1 is unlikely, because a triplet like conformation is favorable for 1, and the thermal dissociation of N2 must lead to the singlet state. As an alternative, copper(I) insertion into the C-N bond of 1 was suggested, followed by the Wolff rearrangement from 2 to 7 (Fig. 14). Further Wolff rearrangement of 3 leads to a barrierless Cu insertion, yielding a stable Fisher carbene 4 completing the sequence of transformations (for another example see: Comelles et al., 2004).

C. Gas-Phase Synthesis and Reactivity of Cuþ–benzyne Complexes

SCHEME 20. Proposed structure of X based on multidimensional NMR spectroscopy.

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Very recently Y. Chai et al. reported on the synthesis of Cuþ– benzyne complexes in the gas phase (Chai et al., 2014). The synthesis was based on a Cu-mediated decarboxylative reaction in the gas phase (Scheme 29). The parent copper (II) benzoate Mass Spectrometry Reviews DOI 10.1002/mas

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SCHEME 21. Possible mechanism for the formation of intermediate compound X. Adapted from ref. (Hyvl et al., 2013).

SCHEME 22. Suggested pathway for the reaction of [(1-H)Cu(CH3CN)]þ to the pyrazole product. Adapted from ref. (Hyvl et al., 2013).

complexes were generated by electrospray ionization of a mixture of 2-iodobenzoic acid, a copper catalyst, and a nitrogencontaining bidentate ligand L. Upon collisional activation of the benzoates, elimination of CO2 and iodine was observed leading to the desired copper (I)-benzyne complex (Scheme 29). The reactivity of this complex was studied in a coupling with the amino-group of the auxiliary ligand L.

V. ORGANOCUPRATES: SPECIATION AND REACTIVITY A. Speciation of Organocuprates Organocuprates represent an important class of organometallic compounds as they are frequently used in modern synthesis, including C-C coupling with alkyl halides (Krause, 2002; Schlosser, 2013). Lithium cyanocuprates are easily available from transmetallation reactions of CuCN and organolithium compounds:

Lipshutz, Wilhelm, & Kozlowski, 1984; Lipshutz, 1987; Lipshutz et al., 1990; Bertz, 1990; Stemmler, Penner-Hahn, & Knochel, 1993; Stemmler et al., 1995; Snyder et al., 1994; Lipshutz & James, 1994; Barnhart, Huang, & PennerHahn, 1995; Snyder & Bertz, 1995; Bertz, Miao, & Eriksson, 1996; Mobley, M€uller, & Berger, 1998), but after X-ray crystallographic studies the lower ordered structure of cyanocuprates (LiCuR2 • LiCN) was generally accepted (Boche et al., 1998; Kronenburg et al., 1998; Krause, 1999). However, the question of the aggregation state of cyanocuprates in solution still receives continuous attention. Putau and Koszinowski decided to address this question with the ESI-MS studies of cyanocuprates in THF (Putau & Koszinowski, 2010). To this end, solutions were prepared by addition of RLi to a suspension of CuCN in THF under argon atmosphere at 78˚C. After 1 h of stirring the solution was subjected to ESI-MS.

CuCN RLiLiCuRðCNÞ RLiLiCuR2 LiCN Formation of higher order lithium cyanocuprates of the form R2Cu(CN)Li2 has been a subject of controversy for a long time that has led to numerous mechanistic and structural investigations (Lipshutz, Wilhelm, & Floyd, 1981; Mass Spectrometry Reviews DOI 10.1002/mas

SCHEME 23. Transition-metal mediated naphthol coupling.

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SCHEME 24. Mechanism for the naphthol coupling mediated by a binuclear copper complex, where metals are bound via a counterion X (X ¼ NO3, Cl, or Br) and each metal atom bears a TMEDA ligand and deprotonated naphthol. Adapted according to ref. (Roithova & Schr€ oder, 2008).

FIGURE 13. a) IRMPD spectra (black lines) of (a) [(3-H)Cu(TMEDA)]þ and (b) [(3-H)2Cu2Cl (TMEDA)2]þ compared with the theoretical IR spectra (black bars) of the most stable structures of the corresponding complexes calculated at the B3LYP/6-311þG*(Cu):6-31G*(C,O,N,H) level (scaling factor 0.95). The gray areas show the theoretical spectra folded with Gaussian peak shapes with a FWHM (full width at half maximum) of 20 cm-1. The “ball and stick” models show a view of the optimized geometries; copper is given in yellow, oxygen in red, nitrogen in green, and carbon and hydrogen atoms in grey; the hydrogen atoms are removed in (b). Adapted from the ref. (Roithova & Milko, 2010).

SCHEME 25. Generation of a series of Pt-Cu ions, where R¼ Me, Ph, Cy, and t-Bu.

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The studies have shown that the composition of ions strongly depends on the stoichiometry of the mixed reactants. Thus, for the solutions of LiCuR2 • 3LiCN the dominant observed species were [Lin-1CunR2n] (with n ¼ 1 and 3) in negative mode and [Li2(CN)(THF)n]þ in positive mode. In agreement with the generally accepted conclusion, no indication for the formation of high-ordered cuprates was found. MSn experiments on [Li2Cu3R6] suggested that the complex contained of [CuR2] and a neutral dimer 1 (Scheme 30) that is in Mass Spectrometry Reviews DOI 10.1002/mas

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SCHEME 26. Fragmentation patterns for the studied heterometallic cation. Adapted from the ref. (Moret et al., 2010).

SCHEME 27. General scheme of Wolff rearrangement.

agreement with previous NMR studies (Gschwind et al., 2000; John et al., 2000). In this respect, the presence of [Li2(CN)(THF)n]þ complexes was in better agreement with previous IR and X-ray spectroscopic measurements (Huang et al., 1996; Huang, Liang, & Penner-Hahn, 1998; Gerold et al., 1997; Bertz et al., 1998) that suggested the presence of [Li2(CN)]þ motif tied up in contact ion pair 2. Comparison of the effects of different R- groups showed that the more sterically hindered the group was, the lower was the aggregation of cyanocuprates. For solutions of LinCuRn(CN) (where n > ¼ 1) the species [Lin-1CunRn(CN)n] and [Li(THF)n]þ were observed. MS/MS studies of the [Lin 1CunRn(CN)n] anion revealed that [Li2Cu2R2(CN)2] is likely to

be a subunit of a tetrameric complex. These findings provide indirect evidence for the presence of contact ion pair 3 in the THF solution. These observations were later complemented by conductivity measurements and also by a study of the aggregation of cyanocuprates in Et2O (Putau & Koszinowski, 2011). ESI-MS study revealed that the transfer from THF to Et2O changes the polarity of the solution which results in a higher aggregation state of the cuprate species. ESI-MS measurements of cuprates in 2-methyltetrahydrofuran, methyl tert-butyl ether and cyclopentyl methyl ether, and conductivity measurements confirm the effect of polarity of the solvent on the ability to control the association/dissociation behavior of the organocuprates. The influence of temperature on conductivity was also investigated.

SCHEME 28. Fragmentation pathways of the mass selected Cu-malonate complex. Adapted from the ref. (Julian et al., 2003).


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FIGURE 14. An illustration of the energetics of reaction intermediates in Scheme 28. The energies are given in parentheses in kcal/mol. When a neutral gas molecule is lost, the energy of the minimized, separated molecule is added to that of the remaining structure. The barriers at each step have not been calculated but are below the binding energy of the MeCN ligand. Adapted from ref. (Julian et al., 2003). Copyright (2003) American Chemical Society.

SCHEME 29. Gas-phase synthesis of the ligated Cuþ–benzyne complex using ESI mass spectrometry. Adapted from ref. (Chai et al., 2014).

B. Reactivity of Organocuprates The detailed mechanism of coupling between alkyl halides and alkyl cuprates was unknown for a long time. Two pathways are possible (Scheme 31): A side SN2 reaction (Path A) or a mechanism that involves formation of a Cu(III) species (Path B). To distinguish between these two pathways James and O’Hair carried out an extensive study

on the reactivity of organocuprates in the gas phase (James & O’Hair, 2004). The cuprate species were prepared in collision induced dissociation experiments from the precursor anion [Cu(OAc)2] that was generated by electrospray ionization of a Cu(OAc)2 solution. CID of the [Cu(OAc)2] anion leads to sequential losses of two molecules of CO2 thus forming a dialkylcuprate anion (Scheme 32, eq. (1)) (Rijs et al., 2008). The oxidation state

SCHEME 30. Proposed structures of organocopper species present in the solutions of cyanocuprates in ethereal solvents.

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SCHEME 31. Two possible mechanisms for the C-C bond coupling of dialkylcuprates with alkyl halides. Path A follows an SN2 mechanism via the transition state A; Path B involves formation of a neutral Cu(III) intermediate.

SCHEME 32. Reactions occurring in the collision cell.

of the metal had a pronounced effect on the fragmentation: It was impossible to synthetize organometallic species from a Cu(II) precursor (Scheme 32, eq. (2)). The dialkylcuprate anions were subjected to ion-molecule reactions with methyliodide in the collision cell. The reactions proceeded towards the formation of two different anionic products (equations (3) and (4)), with I as the major product. Following this observation a series of labeling experiments were carried out. It was shown that the reaction must involve a cross coupling step, because only [CH3CuI] was observed in the reaction between [(CH3)2Cu] and CD3I, and [CD3CuI] was observed in the reaction of [(CD3)2Cu] and CH3I. Kinetic experiments with the labeled reagents showed the presence of a kinetic isotope effect that further confirmed the occurrence of the cross coupling reaction. Finally, DFT studies were carried out (Fig. 15). The results revealed that the reaction couldn’t proceed via path A in the ion trap, because the key transition state for this path lies higher in energy than reactants. The pathway B features a coordination of methyl iodide to the copper center and is energetically favored. The relevant transition structure has a T-shaped geometry at the copper center and the metal is not oxidized to the copper (III) oxidation state. For further discussion and comparison with other coinage metals see ref. (Rijs et al., 2010a). It was later shown that decarbonylation of copper (I) acetate can be also used in catalytic cycles to form new C-C coupling products (Rijs & O’Hair, 2012). In particular dimethylcuprate anions [CH3CuCH3] were allowed to react with allylacetate in the gas phase. The allyl groups coordinate to the copper center in an h2 fashion. The next step is binding of the allyl group to copper leading to complex [(CH3)2CuIII(CH2CHCH2)] CH3COO. Reductive elimination of CH3CH2CHCH2 is associated with formation of [(CH3COO)CuCH3]. As shown above, Mass Spectrometry Reviews DOI 10.1002/mas

this anion undergoes decarboxylation, which closes the catalytic cycle (Rijs et al., 2012; Sharif Al et al., 2013). Another interesting mode of reactivity of dimethylcuprates is a dyotropic rearrangement (Scheme 33) (Reetz, 1972a b; Gridnev, 2008; Fernandez, Cosso, & Sierra, 2009). It was investigated using tandem mass spectrometry and DFT calculations (Rijs, Yates, & O’Hair, 2010b).

FIGURE 15. MP2/6-31þþG** (with ECPs for Cu) calculated reaction energy profiles for paths A (red) and B (blue) of Scheme 32 for the reaction of dimethylcuprate anion with CH3I. Reprinted with permission from ref. (James & O’Hair, 2004). Copyright (2004) American Chemical Society.

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SCHEME 33. Dyotropic rearrangement of dimethylcuprates.

The dimethylcuprate anion was generated in a mass spectrometer as described above and then subjected to a series of CID experiments (Scheme 33). Upon collisional activation, the dimethylcuprate anion sequentially loses both methyl groups as radicals (Eq. (1) and (2) in Scheme 33). A side fragmentation pathway leads to the formation of a copper hydride anion, which may be the result of a rearrangement of [CH3-Cu-CH3] involving a 1,2-migration reaction leading to [CH3CH2CuH] (Eq. (3) in Scheme 34). Upon a b-hydride elimination from [CH3CH3CuH], the dihydride anion, [HCuH], and ethene are formed. CID of the deuterium-labeled organocuprates confirmed the assignments made for the ions and revealed aspects of their fragmentation reactions. CID spectra of [CD3-Cu-CH3] showed the presence of an isotope effect related to bond homolysis. The observation of [H-Cu-D] is consistent with isomerization of [CD3-Cu-CH3] into a mixture of [CH3CD2Cu-D] and [H-Cu-CH2CD3] that then undergo elimination of CH2¼CD2 via b-hydride and b-deuteride transfer, respectively. Complementary ab initio calculations are fully consistent with the mechanistic scenario of the dyotropic rearrangement leading to the formation of [HCuH] (Fig. 16). For cross coupling reactions between LiCuMe2 LiCN and alkyl halides the observation of tetraalkylcuprates –Cu(III) complexes was reported (Bertz et al., 2007; Bertz et al., 2010). In order to probe the generation and reactivity of the organocopper (III) compounds, ESI-MS, conductivity measurements, and quantum chemical calculations were employed by Putau et al. (Putau, Brand, & Koszinowski, 2012) As shown previously (Putau & Koszinowski, 2010), the solution of LiCuMe2 LiCN in THF leads to the generation of [Lin-1CunMe2n] complexes. When 1 equivalent of allyl chloride is added to this mixture, the conductivity of the solution rapidly decreases (Fig. 17), followed by near complete loss of the [Lin-1CunMe2n] signal. This behavior can be explained by generation of the [LiMe2CuR(CN)] intermediate. The corresponding anion [Me2CuR(CN)] was not observed in the mass spectrum presumably because of a low stability and thus incompatibility with the ESI process. When more MeLi was added to the solution, the conductivity again increased, indicating the formation of new species. Accordingly, ESI-MS detected the

SCHEME 34. Fragmentation reactions occurring with a dimethylcuprate anion during CID experiments.

106

FIGURE 16. Ab initio MP2/SDD6-311þþG(2d,p) calculated energies for the fragmentation of [CH3CuCH3]- and the structures of both minima and transition states relevant to the isomerization to [CH3CH2CuH]- and fragmentation via b-hydride elimination [Eq. (3)]. Adapted from ref. (Rijs et al., 2010b)

formation of a tetraalkylcuprate anion [Me3CuR], which can be formed by ligand exchange in the formerly suggested intermediate [LiMe2CuR(CN)] (Scheme 35). The fragmentation of the mass selected [Me4Cu] leads to the formation of [CuMe2] and ethane. DFT calculations showed that the activation energies for reductive elimination from tetraalkylcuprates are much larger than those for neutral Cu(III) species (Fig. 18). Addition of a methyl anion to neutral CuMe3 leads to a large stabilization of the copper(III) species, which can be explained as a stabilization of the highly electron deficient Cu(III) center by a strong Lewisbasic Me anion. Such stabilization is not present in neutral CuMe3 which results in a lower energy barrier for the

FIGURE 17. Time profile of the electrical conductivity of a solution of LiCuMe2LiCN in THF (generated by the addition of 2 equiv. of MeLi to CuCN) at 202 K upon consecutive treatment with RCl (R ¼ allyl, 1 equiv.) and MeLi (2 0.2 equiv). Reprinted with permission from ref. (Putau et al., 2012). Copyright (2012) American Chemical Society.


COPPER CATALYSIS

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SCHEME 35. Formation of lithium tetraalkylcuprates probed by ESI-MS.

FIGURE 18. Schematic potential energy surfaces for the reductive elimination of ethane from neutral [CuMe3] and anionic [CuMe4]-. Reprinted with permission from ref. (Putau et al., 2012). Copyright (2012) American Chemical Society.

reductive elimination of ethane. This observation strongly suggests that tetraalkylcuprates rather than neutral organocopper(III) species should be taken into account as intermediates in copper(III) mediated reactions.

VI. CONCLUSION AND OUTLOOK As we have shown in this review, electrospray ionization mass spectrometry is a versatile tool that is intensively used for studying reaction mechanisms. Next to the detailed studies using various classical tools of mass spectrometry such as energyresolved CIDs, MSn experiments, or reactivity studies, there are emerging studies combining these classical tools with techniques such as ion mobility or ion spectroscopy. All these approaches can help build very detailed pictures of possible reaction intermediates, their reactivities and their involvement in the reaction mechanisms. Many mechanistic studies aim to detect highly reactive species that are not easily transferred from reaction mixtures or cannot survive the ESI process. In the case of copper catalyzed reactions, this is often case for elusive copper(III) intermediates. As discussed in the beginning of this review, the ionization process can significantly influence the overall picture of the reaction mixture. Fragmentation of the ions in the ion-transfer region or reactions with water or other background gases can modify the detected ions. Although some of the studies demonstrated successful characterization of highly reactive species, in many other cases spectacular intermediate structures were suggested relying only on their m/z ratios. Such tentative claims should probably be avoided and more experimental studies carried out. Mass Spectrometry Reviews DOI 10.1002/mas

At present, ESI-MS begins to penetrate into synthetic laboratories as a common tool for monitoring reaction mixtures. While this tendency is certainly very promising for mass spectrometry, it will also be a challenge to establish a good practice for the use of ESI-MS in this direction; especially when possible electrospray ionization artifacts and exaggerative interpretations of source ESI-MS spectra are taken into account. In copper-mediated reactions, the studies presented here open a whole new area of research. Many studies did not initially succeed at resolving all details of the reaction mechanisms and novel approaches need to be found for detecting these reaction intermediates. Copper offers interesting chemistry and often different possible rationales for the observed reactivities exist. Given that copper complexes are usually easily transferred to the gas phase by the electrospray ionization, it can be expected that many more studies will appear in future.

ACKNOWLEDGEMENT Financial support from the European Research Council (StG ISORI) and the Grant Agency of the Czech Republic (1420077S) is gratefully acknowledged.

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Gas-phase ion-molecule reactions of the CH3O (+) cation.

ion reactions.

Folding of Protein Ions in the Gas Phase after Cation-to-Anion Proton-Transfer Reactions.

The α-effect and competing mechanisms: the gas-phase reactions of microsolvated anions with methyl formate.

Probing the mechanisms and dynamics of gas phase hydrogen-deuterium exchange reactions of sodiated polyglycines.

2-Butoxyethanol and Benzyl Alcohol Reactions with the Nitrate Radical: Rate Coefficients and Gas-Phase Products.

Investigation of the gas-phase structure of electrosprayed proteins using ion-molecule reactions.

ion Reactions.

A new approach for the study of gas-phase ion-ion reactions using electrospray ionization.

molecule reactions with diethylamine.

ion reactions.

Resonant laser ablation as a selective metal ion source for gas-phase ion molecule reactions.

Protonation of ferrocene in the gas phase.

Tautomers of Gas-Phase Erythrose and Their Interconversion Reactions: Insights from High-Level ab Initio Study.

Gas-phase reactions of alcohols with hexamethylene triperoxide diamine (HMTD) under atmospheric pressure chemical ionization conditions.

An investigation of site-selective gas-phase reactions of amino alcohols with dimethyl ether ions.

Negatively-charged helices in the gas phase.

Stable stoichiometry of gas-phase cerium oxide cluster ions and their reactions with CO.

Functional group selective derivatization and gas-phase fragmentation reactions of plasmalogen glycerophospholipids.

AlH3 and ammonia: theoretical study.

gas phase photocatalytic reactions by electron ionization mass spectrometry.

Assessment of density-functionals for describing the X(-) + CH3ONO2 gas-phase reactions with X = F, OH, CH2CN.

Rate Coefficients for the Gas-Phase Reactions of Hydroxyl Radicals with a Series of Methoxylated Aromatic Compounds.

ion reactions with "onium" reagents: an approach for the gas-phase transfer of organic cations to multiply-charged anions.