Fluorinated Organic Paramagnetic Building Blocks for Cross-Coupling Reactions

New stable polyfluorinated nitroxide radicals for use in cross-coupling reactions, namely, N-tert-butyl-N-oxyamino-2,3,5,6-tetrafluoro-4-iodobenzene and N-tert-butyl-N-oxyamino-2,3,5,6-tetrafluoro-4-ethynylbenzene, were prepared from perfluoroiodobenzene. The reaction of the polyfluoro derivative with tert-butylamine under autoclaving conditions leading to the formation of N-tert-butyl-2,3,5,6-tetrafluoro-4-iodoaniline proved to be the key stage of the whole process. The fluorinated tert-butyl iodophenyl nitroxide was found to form in a solid state via N–O···I halogen bonds, a one-dimensional assembly of the radicals. The acceptor role of the nitroxide group in the halogen bonding changes to a donor role when the nitroxide reacts with Cu(hfac)2. In the last case, zero-dimensional assembly prevails, giving a three-spin complex with axial coordinated nitroxide groups and, as a consequence, causing ferromagnetic intramolecular exchange interactions between Cu(II) and radical spins.


Introduction
tert-Butylarylnitroxides and corresponding polynitroxides are an important class of paramagnets that have been actively used in different fields of research. A typical method for the preparation of tert-butylarylnitroxides involves an interaction of an appropriate aromatic organometallic compound with tert-nitrosobutane, thus giving aryl tert-butylhydroxylamine, followed by its oxidation to the target radical product. Less commonly, the oxidation of N-tert-butylanilines is performed to obtain nitroxide radicals [1,2].
Recently, we proposed a new synthetic approach to obtaining functionalized tertbutylphenylnitroxides by sequential substitution of a fluorine atom in polyfluorinated arenes with tert-butylamine or lithium tert-butylamide and oxidation of resultant N-tert-butylanilines with meta-chloroperoxybenzoic acid (m-CPBA). This approach has been found to generate nitroxide mono-and diradicals in high yields ( Figure 1) [3,4]. Moreover, it turned out that polyfluorinated tert-butylarylnitroxides are much stable than nonfluorinated analogs. Therefore, the nitroxides of this type can serve as paramagnetic building blocks for diverse applications. In particular, one of the tasks of our current project aimed at obtaining spin-labeled graphene nanostructures is to search for stable paramagnetic blocks suitable for introduction into polycondensed aromatic structures and capable of efficiently injecting spin density into such structures [5][6][7][8].
Because the above-mentioned polyfluorinated tert-butylarylnitroxides satisfy all these requirements, within the framework of this work, we studied the possibility of obtaining their iodo and ethynyl derivatives that may be next subjected to the Sonogashira cross-coupling reaction.

Results and Discussion
Following the newly developed approach, we carried out the reaction of perfluoroiodobenzene with tert-butylamine in chloroform at room temperature (r.t.). As opposed to perfluorotoluene and perfluorobenzonitrile, the iodo derivative did not possess enough reactivity, and the reaction with the amine did not proceed. The use of tert-butylamine under autoclaving conditions at 120 • C led to the substitution of the fluorine atom in perfluoroiodobenzene and the formation of N-tert-butyl-2,3,5,6-tetrafluoro-4-iodoaniline (1) in a high yield. Formation of other isomeric amines was not detectable (Supplementary Materials). The oxidation of diamine 1 with m-CPBA was performed in CHCl 3 at r.t. and gave one of the target nitroxide radicals, 4, in a yield of~60% (Scheme 1). 4-Iodoaniline 1 was cross-coupled with trimethylsilyl acetylene in dry Et 3 N in the presence of Pd(PPh 3 ) 2 Cl 2 (5 mol%) and CuI (10 mol%) as catalysts. The reaction was carried out at r.t. in a tightly closed Schlenk flask in an argon atmosphere. The process was terminated after the disappearance of 19 F NMR signals belonging to the starting compound to obtain alkynyl derivative 2 with a yield of 92%. The resulting compound 2 was cleaved by the action of K 2 CO 3 in MeOH at r.t., thus producing fluorinated ethynyl-derivative 3 with an almost quantitative yield (Supplementary Materials). At the final stage, amine 3 was oxidized with m-CPBA in CHCl 3 at r.t. and gave ethynyl-substituted nitroxide 5 as a red oily compound in a yield of~58%. Both nitroxide radicals 4 and 5 were found to be stable and were purified by thin-layer chromatography (TLC). Electron spin resonance (ESR) spectra (Figures 2 and 3) for diluted (~10 −4 M) and oxygen-free toluene solutions of radicals 4 and 5 showed triplet patterns at g iso = 2.0065 and g iso = 2.0064, respectively. The spectra were simulated with the following sets of parameters: For 4, A N = 1.283 mT and A 2F = 0.078 mT; for 5, A N = 1.278 mT. In the case of nitroxide 5, a high-resolution ESR spectrum was recorded to achieve more complex splitting of the central line of its triplet. The spectrum was well simulated, taking into account nine hyperfine structure (hfs) constants for the protons of the tert-butyl   Even though both freshly prepared radicals 4 and 5 were red oils, repeated efforts were made to obtain them in a crystalline form. Eventually, by crystallization from a cold n-heptane solution, nitroxide radical 4 was isolated as high-quality crystals that allowed to solve its molecular and crystal structure by X-ray diffraction (XRD) analysis ( Figure 4). It was revealed that radical 4 crystallizes in the orthorhombic Pbca space group (Table 1). Bond lengths of the tert-butylnitroxide moiety ( Table 2) are fully consistent with those of previously described radicals of this family [3]. The nitroxide groups in diradical 4 are twisted at a large angle (~64 • ) relative to the aromatic ring. The observed twisting is due to, first, steric repulsion between the tert-butyl group and ortho-fluorine atoms and, second, electrostatic repulsion of dipoles C-F and N-O. In this regard, the analogous dihedral angle in nonfluorinated tert-butylphenylnitroxides is twofold smaller and has experimental and calculated values of 23-34 • [9]. The X-ray analysis revealed an assembly of radicals 4 into zigzag chains via halogen bonds between the nitroxide oxygen and iodine atom (Figure 4b,c). If we consider so-called conjugated nitroxides [2], there are very few cases when halogen bonding induces one-dimensional self-or supra-organization of paramagnetic species. Moreover, the halogen bonding with the participation of an iodine atom has been described only for the family of nitronyl nitroxides [10][11][12][13]. For tert-butylphenylnitroxides, this type of halogen bonding was shown for the first time. In addition, the halogen bonds observed in nitroxide 4 are very strong, as indicated by the short I1· · · O1 distance (2.967 Å, >15% shorter than the sum of van der Waals radii of O and I [14]) and almost linear C-I· · · O angles (~164 • ). The N-O (1.278(4) Å) bond distance is typical of nitronyl nitroxide moieties, indicating that the presence of the halogen bond has little impact on electronic properties of the free radicals. This is a consequence of the essentially electrostatic nature of the halogen bond interaction. An interaction of half an equivalent of bis(hexafluoroacetylacetonato)copper(II) (abbreviated as Cu(hfac) 2 ) with radical 4 in CHCl 3 gave rise to the [Cu(hfac) 2 (4) 2 ] complex (Supplementary Materials). Its recrystallization from n-hexane generated well-shaped crystals suitable for X-ray analysis. If an equivalent amount of Cu(hfac) 2 was used in the reaction, complex [Cu(hfac) 2 (4) 2 ] also formed along with the crystallization of excess complex Cu(hfac) 2 . Attempts to prepare a similar complex with nitroxide 5 every time led to the formation of dense intergrowths of crystals of complex [Cu(hfac) 2 (5)]. Due to the low quality of the crystals, the structure of the complex was solved with R-factor 8.76% and is considered a tentative result here.
According to XRD analysis, coordination compound [Cu(hfac) 2 (4) 2 ] crystallizes in the triclinic crystal system (space group P-1) with two independent molecules per asymmetric unit, as shown in Figure 5a. In the distorted octahedron around the copper ion, two O NO atoms occupy axial positions with d Cu-O = 2.380 and 2.400 Å in the independent molecules. Equatorial Cu-O hfac distances in both molecules are in the range of 1.933 to 1.955 Å ( Table 2).
In the crystal structure of [Cu(hfac) 2 (4) 2 ], the independent molecules are bound via two van der Waals interactions of the C-F···C Ph type (contacts i and ii). One of the fluorine atoms attached to the aromatic cycle engages in an intermolecular contact (iii) with the H atoms of the tert-butyl group, thereby binding the dimers into a layer (Figure 5b). Temperature dependences of the effective magnetic moment (µ eff ) and inverse magnetic susceptibility (1/χ) for complex [Cu(hfac) 2 (4) 2 ] are shown in Figure 6. The µ eff value is 3.17 µ B at 300 K and increases with decreasing temperature to 3.55 µ B at 4 K. The 1/χ(T) dependence is linear in the temperature range 100-300 K and obeys the Curie-Weiss law with best-fit values C = 1.218 ± 0.002 K·cm 3 /mol and θ = 9.1 ± 0.3 K. The µ eff value at 300 K and Curie constant C are in good agreement with theoretical spin-only values of 3.00 µ B and 1.125 K·cm 3 /mol for three paramagnetic centers: Two nitroxides and one Cu(II) ion. The increase in µ eff with decreasing temperature and positive Weiss constant θ indicate the domination of ferromagnetic exchange interactions between spins of paramagnetic centers. An analysis of experimental µ eff (T) dependences was performed via a model of a three-spin exchange cluster (spin Hamiltonian H = −2J Cu-R × (S R1 S Cu + S Cu S R2 ) − 2J R-R × S R1 S R2 ), taking into account intermolecular exchange interactions zJ in the mean field approximation. Best-fit values of g Cu and exchange interaction parameters J Cu-R , J R-R and zJ are 2.21, 15.9 cm −1 , −8.7 cm −1 and 0.15 cm −1 , respectively. g-Factors for the nitroxides were fixed at g R = 2 to avoid overparametrization. The observed ferromagnetic exchange interactions between the unpaired electrons in [Cu(hfac) 2 (4) 2 ] are consistent with the XRD data on the axial coordination of the nitroxide groups to the Cu 2+ ion [15][16][17][18].

Conclusions
The development of the chemistry of nitroxides opens up new areas of their practical application. Recently, we devised a new synthetic approach to functionalized tert-butylphenylnitroxides via substitution of a fluorine atom in polyfluorinated arenes by tert-butylamine with subsequent oxidation of the obtained N-tert-butylanilines with m-CPBA [3]. With highly activated polyfluorinated compounds, the substitution reaction proceeds smoothly, with the formation of the corresponding aniline. In the case of less activated polyfluorinated aromatics, we proposed the use of lithium tert-butylamide, which allowed, for example, to synthesize a necessary diamine precursor for the N,N -(perfluorobiphenyl-4,4 -diyl)bis(N-tert-butyl-N-oxyamine) diradical [4]. In the present work, we employed the third version of the reaction, namely, the process was carried out in an autoclave at 120 • C, using tert-butylamine both as a reagent and a solvent. Under these conditions, the reaction of perfluoroiodobenzene with tert-butylamine proceeded regioselectively and gave N-tert-butyl-2,3,5,6-tetrafluoro-4-iodoaniline in high yields. The obtained iodo derivative was converted via a multistep procedure into an ethynyl-substituted aryl nitroxide, which was oxidized into the corresponding tert-butylphenylnitroxide. The latter radical crystalizes with the formation of the structure in which free radicals are bound into one-dimensional chains by relatively strong halogen bonds N-O···I. If upon the formation of the halogen bond the nitroxide group acts as an acceptor, then in the reaction with Cu(hfac) 2 it becomes an electron pair donor. The reaction produces a molecular complex of 1:2 composition with axial coordination of the paramagnetic ligands. The result of such coordination gives rise to ferromagnetic intramolecular exchange interactions between Cu(II) and radical spins.
Both synthesized nitroxides, N-tert-butyl-N-oxyamino-2,3,5,6-tetrafluoro-4-iodobenzene and N-tert-butyl-N-oxyamino-2,3,5,6-tetrafluoro-4-ethynylbenzene, represent stable paramagnetic building blocks for the Sonogashira cross-coupling reaction. This reaction is being evaluated for the synthesis of functional paramagnets with potential application in the fields of molecular magnetism and spintronics. In particular, in the course of preliminary experiments, it was shown that the paramagnetic iodo derivative can be successfully used to introduce a spin-bearing group into the planar hexabenzocoronene backbone.

Materials and Measurements
Cu(hfac) 2 was prepared according to previously described procedures [19]; before use, the Cu(hfac) 2 complex was sublimated and stored in a desiccator charged with NaOH. The starting materials were obtained from commercial sources (Merck KGaA, Darmstadt, Germany) and were used without further purification. All solvents were purified according to standard procedures. Preparative TLC was performed on Merck precoated silica gel 60 PF254 containing gypsum. The visualization of developed chromatograms was performed by means of UV light.
Continuous-wave ESR spectra were acquired on a commercial Bruker X Band (9 GHz) spectrometer, Elexsys E 540 (Bruker Corporation, Billerica, MA, USA), at r.t. in dilute (~10 −4 M) toluene solutions degassed by means of repeated freeze-pump-thaw cycles. ESR spectra were recorded with the following settings: Frequency, 9.87 GHz; microwave power, 2.0 mW; modulation amplitude, 0.01 mT for radical 4 and 0.005 mT for radical 5; time constant, 20.5 ms; and conversion time, 20 ms. Simulations of solution ESR lines were carried out in the EasySpin software (5.2.28) [20], which is available at http://www.easypin.org.
Masses of molecular ions were determined by high-resolution mass spectrometry (HRMS) on a DFS Thermo Scientific instrument at an ionization energy of 70 eV (Thermo Fisher Scientific, Waltham, MA, USA). Melting points were recorded on a Mettler-Toledo FP81 Thermosystem apparatus (Mettler-Toledo, Greifensee, Switzerland). IR spectra were acquired by means of a Bruker Vector 22 spectrometer in KBr pellets or thin films (Bruker Optik GmbH in Ettlingen). Elemental analyses were performed on a Carlo Erba 1106 CHN elemental analyzer.
Magnetic susceptibility was measured with a MPMSXL SQUID magnetometer (Quantum Design, San Diego, CA) in the temperature range 2 to 300 K with a magnetic field of up to 5 kOe. Diamagnetic corrections were made via Pascal constants. The effective magnetic moment was calculated as follows: µ eff (T) = ((3k/N A µ B 2 )χT) 1/2 ≈ (8χT) 1/2 .