Direct Investigation of Covalently Bound Chlorine in Organic Compounds by Solid-State 35Cl NMR Spectroscopy and Exact Spectral Line-Shape Simulations''

Cl NMR spectroscopy studies of organic systems are very rare, with only a few neat liquids having been studied. The lack of chlorine NMR spectroscopy data may be explained by the fact that Cl and Cl are quadrupolar (spin I= 3/2) and low-frequency isotopes. The quadrupole moments of the chlorine nuclei couple with the electric field gradient (EFG) tensor at the nuclei; this phenomenon is known as the quadrupolar interaction (QI). The quadrupolar coupling constant, CQ, and the quadrupolar asymmetry parameter, hQ, describe the magnitude and asymmetry of the QI. In solution, one of the consequences of the QI is fast relaxation, which means that the Cl NMR signals for covalently bound chlorines are very broad and are of low intensity. For these reasons, chemically distinct chlorine sites are very difficult to distinguish with solution NMR spectroscopy. However, in the solid state, nuclear spin relaxation is typically slower, thus enabling higher quality Cl NMR spectra to be collected, at least in principle. Unfortunately, the magnitude of the QI for covalently bound chlorines is very large because of the substantial, anisotropic EFG at the Cl atom, owing mainly to its electronic configuration when it forms a chlorine–carbon bond. Conventional wisdom is that such chlorine sites cannot be studied in powders by solid-state NMR spectroscopy as the central transition (CT; mI= 1/2$ 1/2) can span tens of megahertz in typical commercially available magnetic fields. For this reason, only ionic chlorides and inorganic chlorides have been studied, as the EFG at these chlorides is often an order of magnitude smaller than at covalently bound chlorine atoms in organic molecules. The bonding environments for these types of chlorine atoms are substantially different from the environments in those chloride-containing molecules that have been studied previously. A partial Cl NMR spectrum for hexachlorophene has been briefly mentioned in the literature. On the other hand, most of the interesting chlorine chemistry occurs when Cl is covalently bound to a carbon atom, where the chlorine atom often acts as a leaving group. Chlorine atoms are also important in many organic pharmaceuticals as well as in crystal design applications where they can form halogen bonds. Recent studies show that covalently bound chlorine is also important in biological chemistry where, for example, the tryptophan 7-halogenase was found to selectively chlorinate tryptophan moieties. Herein, we show that with the combination of an ultrahigh magnetic field (B0= 21.1 T) and the state-of-the-art WURSTQCPMG pulse sequence, it is possible to acquire highquality Cl NMR spectra of organic compounds that contain a covalently bound chlorine atom in powder samples in a reasonable amount of time. We have acquired Cl NMR spectra of 5-chlorouracil (1); the pesticide 2-chloroacetamide (2); sodium chloroacetate (3); a,a’-dichloro-o-xylene (4); chlorothiazide (5), a diuretic pharmaceutical also known as diuril; 2,4’-dichloroacetophenone (6); and p-chlorophenylalanine (7), a chlorinated amino acid, which is used as an inhibitor of tryptophan hydroxylase. These were chosen as a representative subset of compounds wherein chlorine is bound to spor sp-hybridized carbons. The molecular structures are shown in Figure 1 along with the NMR spectra. The Cl CT NMR spectra span on the order of 7 MHz at 21.1 T, necessitating the variable-offset cumulative spectral (VOCS) acquisition approach. Interpretation of the broad spectra of the CT requires line-shape simulations. Such line shapes are typically simulated by using second-order perturbation theory, where theQI is assumed to act as a perturbation to the Zeeman interaction. It is known from nuclear quadrupole resonance (NQR) studies that the values of CQ( Cl) for covalently bound chlorine atoms are on the order of 70 MHz. As the Larmor frequency (n0) for the nucleus Cl at 21.1 T (corresponding to a 900 MHz H n0) is only 88.2 MHz, the ratio of n0/nQ is around 2.5, where nQ represents the quadrupolar frequency. It is generally assumed that the high-field approximation is only valid if this ratio is higher than 10; thus, second-order perturbation theory is not expected to be valid to model the Cl NMR spectra shown herein, and an exact description needs to be used. Presently, we have written a new fast and graphical exact NMR simulation program, the technical details of which will be described elsewhere. The spectral simulations of the chlorine NMR spectroscopy data obtained with our QUEST (“QUadrupolar Exact SofTware”) program are shown in Figure 1. To demonstrate the critical importance of using exact Hamiltonian diagonalization for the interpretation of these NMR spectra, we have [*] F. A. Perras, Prof. Dr. D. L. Bryce Department of Chemistry and CCRI, University of Ottawa 10 Marie Curie Private, Ottawa, Ontario (Canada) E-mail: [email protected] Homepage: http://mysite.science.uottawa.ca/dbryce/