2,2,2-Trifluoro-N-(isoquinolin-5-ylmethyl)acetamide

The molecular structure of the title compound at 123 K, C12H9F3N2O, presents a rotationally disordered CF3 group. Hydrogen bonds between the amide NH group and the N atom of the isoquinoline form a chain in the b-axis direction. The packed structure forms alternate layers of isoquinoline and amide groups parallel to the ab plane.


Related literature
In the search for biologically active compounds in the area of anti-inflammatory and pain relief drugs, we have found a class of compounds that act as potent antagonists or agonists of the vanilloid VR1 receptor. These have been shown to be useful in the treatment and prevention of inflammatory and other pain conditions in mammals, see: Jetter et al. (2007Jetter et al. ( , 2008; Codd et al. (2003). The title compound was prepared as a precursor for more complex compounds. For analysis of the structures of analogous naphthalenes, see: Weinstein & Leiserowitz (1980). For a discussion on disorder in crystal structures, see: Mü ller (2009 Table 1 Hydrogen-bond geometry (Å , ).

Comment
In the search for novel biologically active compounds in the area of anti-inflammatory and pain relief drugs, we have found a class of compounds acting as potent antagonists or agonists of the vanilloid VR1 receptor. These have been shown to be useful in the treatment and prevention of inflammatory and other pain conditions in mammals (Jetter et al., 2007;Jetter et al., 2008;Codd et al., 2003). The title compound was prepared as an important precursor for more complex compounds.
Surprisingly, reaction of n-hydroxymethyl trifluoroacetamide with isoquinoline in the presence of sulfuric acid afforded a single positional isomer after purification by column chromatography.
The plane of the quinolene ring forms a dihedral angle of 76.2 (2) ° with the amide plane, see A major difference between the naphthalene derivatives and the present compound is seen in the intermolecular contacts.
The naphthalenes bond through amide to amide (N-H···O) hydrogen bonds. However, in the quinolene, the presence of a hetero atom enables N-H···N bonds. These form extended chains running along the b direction, see Fig. 2.
The packing diagram, Fig. 3, illustrates the layered nature of this structure. Traveling along the c direction there are alternate quinolene layers and amide layers. The closest π interaction, connecting molecules along the a direction, in the quinolene layer is slightly outside the sum of van der Waals distances (C5···C12 3.486 (4) Å).

Experimental
Isoquinoline (1.29 g, 10 mmol) in concentrated sulfuric acid (50 ml) was cooled to 293 K. n-Hydroxymethyl trifluoroacetamide (1.43 g, 10.00 mmol) was added in portions. After 15 min, the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The clear light-brown reaction mixture was then poured onto 200 g of ice, then concentrated ammonium hydroxide was added dropwise until the reaction mixture was basic to pH paper. After extraction with 100 ml of dichloromethane, the organic layer was washed (2 x 100 ml brine), dried over MgSO 4 and then evaporated under reduced

Refinement
The F atoms of the CF 3 group are disordered by rotation about the C2-C1 bond. After several trial calculations, a model with three separate groups of F atom positions was adopted. Site occupancy factors are 0.5 for F1 to F3, 0.3 for F4 to F6 supplementary materials sup-2 and 0.2 for F7 to F9. Only F1 to F3 were refined anisotropically. Restraints were placed on the C-F distances (1.33 Å) and to encourage similarity in the F atom U ij values (Müller, 2009).
The amide-H atom was found by difference synthesis and refined isotropically. All other H atoms were positioned geometrically at distances of 0.95 and 0.99 Å from the parent C atom for CH and CH 2 groups respectively. For these atoms, a riding model was used with U iso (H) values constrained to be 1.2 times U eq of the parent C atom.