Supercritical CO 2 DOI: 10.1002/anie.201303819 Supercritical Carbon Dioxide: A Promoter of Carbon–Halogen Bond Heterolysis** Thais Delgado-Abad, Jaime Martínez-Ferrer, Ana Caballero, Andrea Olmos, Rossella Mello, María Elena Gonzµlez-NfflÇez,* Pedro J. PØrez, and Gregorio Asensio Supercritical carbon dioxide (scCO 2 ) is an alternative medium for sustainable chemistry [1] that is competitive in a variety of chemical processes of technological impor- tance. [1, 2] Carbon dioxide has zero dipole moment and very low polarizability, [3] and most polarity studies describe scCO 2 as a nonpolar medium with a very low dielectric constant and no hydrogen-bonding behavior, comparable to n-hexane or carbon tetrachloride. [3] These properties limit the applications of scCO 2 in chemical processes. However, carbon dioxide has a strong quadrupolar moment (À14.3  10 À4 8Cm 2 ) [4] arising from two opposed dipoles in the linear molecule, which allows for significant interactions with bond dipoles in solute molecules and justifies the ability of scCO 2 to dissolve solutes carrying structural motifs such as perfluorinated chains, sulfonate and phosphate groups, or carboxylic acid esters. [4] These peculiar properties prompted us to investigate strongly solvent-dependent reactions in scCO 2 as a method for probing intermolecular solute–solvent interactions, [5] which may con- tribute to expand the range of applications of this medium. Unimolecular nucleophilic substitution (S N 1, Scheme 1) is a strongly solvent-sensitive reaction [3] as the leaving group departs from the carbon atom prior to the entrance of the nucleophile. Polar protic solvents with high dielectric con- stants promote polar bond heterolysis by providing effective H-bonding and electron-pair donation interactions to the leaving group and the incipient carbocation, respectively. Then, the solvent captures the carbocation intermediate to give the corresponding S N 1 products. Conversely, polar non- nucleophilic solvents, such as dichloromethane, nitrome- thane, SO 2 ClF, or SO 2 F 2 , which are commonly used for the generation and observation of carbocations, [6] are unable to ionize polar covalent bonds and require the presence of strong Brønsted or Lewis acids to promote the departure of the leaving group. According to these features, scCO 2 is far from being an ideal solvent for S N 1 reactions in the absence of strong acids. Acid-catalyzed reactions, such as Friedel–Crafts alkylation with alcohols, [7] alkane isomerization, [8] glycosidation, [9] and etherification, [10] are known to proceed efficiently in scCO 2 , although the involvement of carbocation intermediates has not been specifically ascertained. As these reports suggest that scCO 2 is able to sustain ionic processes, they prompted us to test the ability of scCO 2 to promote S N 1 reactions in the absence of acid catalysts. 1-Chloro-1-phenylethane (1 aCl), a secondary benzylic substrate with well-known reactivity under conventional S N 1 conditions, [11] was first selected as the ionogen. 1,3- Dimethoxybenzene (2), a highly activated aromatic com- pound that is unable to assist polar s-bond ionization through hydrogen bonding, was selected to trap any electrophilic species formed. Nucleophiles, such as azide or halide anions, which are commonly used to trap carbocationic intermediates in S N 1 reactions, are not appropriate in this case as their salts are insoluble in scCO 2 . The reaction was performed at 60 8C and 250 bar by pressurizing with CO 2 a stainless-steel reactor containing 1-chloro-1-phenylethane (1 aCl, 0.03 m) and 1,3- dimethoxybenzene (4 equiv). After 5 h under these condi- tions, the reactor was depressurized at 0 8C and the products were collected at À78 8C. The organic residues in the reactor and the trap were dissolved into diethyl ether and treated with sodium hydrogen carbonate. The GC and GC-MS analyses of the solution showed the complete conversion of 1 aCl into a mixture of the corresponding Friedel–Crafts adducts, 2,4- dimethoxy-1-(1-phenylethyl)benzene (3a o,p ) and 1,3-dime- thoxy-2-(1-phenylethyl)benzene (3a o,o ) [Eq. (1)]. Substrate Scheme 1. Reaction conditions for S N 1 reactions. [*] T. Delgado-Abad, Dr. J. Martínez-Ferrer, Prof.Dr. R. Mello, Prof. Dr. M. E. Gonzµlez-NfflÇez, Prof. Dr. G. Asensio Departamento de Química Orgµnica, Universidad de Valencia Avda. Vicente AndrØs EstellØs s.n., 46100-Burjassot, Valencia (Spain) E-mail: elena.gonzalez@uv.es Prof. Dr. A. Caballero, Dr. A. Olmos, Prof. Dr. P. J. PØrez Laboratorio de Catµlisis HomogØnea, Unidad Asociada al CSIC, CIQSO-Centro de Investigación en Química Sostenible, Universi- dad de Huelva Campus El Carmen, 21007-Huelva (Spain) [**] Financial support from the Spanish Dirección General de Inves- tigación (CTQ2010-21172, CTQ2011-28942-C02-02), Consolider Ingenio 2010 (CSD2007-00006), and Generalitat Valenciana (ACOMP/2012/217) is gratefully acknowledged. T.D.A. thanks the Spanish Ministerio de Educación y Ciencia for a fellowship. We thank the SCSIE (Universidad de Valencia) for access to their instrumental facilities. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201303819. . Angewandte Communications 13298  2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2013, 52, 13298 –13301