cis-1,5-Diaminocyclooctane: the most basic gaseous primary amine? John C. Poutsma,* a Erica J. Andriole, a Tristan Sissung b and Thomas Hellman Morton* b a Department of Chemistry, The College of William and Mary, Williamsburg, VA, USA 23187-8795. E-mail: jcpout@wm.edu; Fax: 1 (757) 221-2715; Tel: (757) 221-2548 b Department of Chemistry, University of California, Riverside, CA, USA 92521-0403. E-mail: morton@citrus.ucr.edu; Fax: 1 (909) 787-4713; Tel: 1 (909) 787-4735 Received (in Corvallis, OR, USA) 9th May 2003, Accepted 26th June 2003 First published as an Advance Article on the web 4th July 2003 The gas phase basicity of the title compound has been determined to be greater than that of putrescine, making it the most basic primary diamine measured to date. Enzymic catalysis often includes removal of a proton from a site on the substrate that does not have high acidity. Given that amino acid side chains do not contain functional groups any more basic than primary amines or guanidino groups, it is not obvious what can accomplish this. One hypothesis suggests that two basic groups in the protein can be held so closely together that strong hydrogen bonding stabilizes their conjugate acid. Fig. 1 portrays a model for this sort of behavior. In the neutral base the nitrogens are positioned at a distance D NN . Upon protonation they move towards one another to a distance d NN , where strong hydrogen bonding stabilizes the conjugate acid. The two N–H distances, r NH and r HN , remain unequal. As has long been known, 1 strong hydrogen bonds favor a linear arrangement of the hydrogen bond donor, the bridging proton, and the hydrogen bond acceptor (angle q = 180°). The increased basicity of linear diamines (such as 1,4-diaminobu- tane, 1, and 1,5-diaminopentane, 2) has been viewed as a result of strong hydrogen bonding. 2 The conjugate acids have cyclic structures. Ring constraints make 1 the most basic of the linear diamines. Ab initio and DFT calculations agree with this view of the protonated diamines. The theoretical picture of the neutral diamines is more complicated. Although internally hydrogen bonded geometries (as Fig. 1 depicts) represent energetic minima for linear diamines, entropy does not favor them. Thus, hydrogen-bonded geometries (D NN in Table 1) constitute minor species for gaseous, neutral diamines. The entropy change for making an internal hydrogen bond in HO(CH 2 ) 4 OCH 3 in solution has been reported as 216.2 e.u. at 298 K, 3 which does not differ greatly from the reported entropy change for transferring a proton from a monoamine to 1, 214.3 e.u. 4 Hence it seems likely that the topological change from a chain to a ring accounts for most of the entropy change upon protonation of a linear diamine. This reasoning implies that more rigid, cyclic diamines might display greater basicity than linear diamines, because of a less unfavorable entropy change (so long as the nitrogens can get close to one another in the conjugate acid). To test this hypothesis, we have synthesized cis-1,5-diaminocyclooctane, 3, and here report its gas phase basicity relative to that of 1. Ab initio (MP2/6-311G**) geometry optimization predicts that the lowest energy conformation of neutral 3 places the amino groups too far apart to hydrogen bond to one another, as eqn. 1 illustrates. By contrast, the conjugate acid, 3H + , changes conformation to form a strong internal hydrogen bond. Our experiments show that the gas phase basicity for 3 (GB, which is defined as 2DG for protonation) is greater than that for 1, although its proton affinity (PA, which is defined as 2DH for protonation) is slightly lower. (1) Compound 3 was synthesized in a straightforward fashion starting with the ditosylate of cis-1,5-cyclooctanediol, 5 as eqn. 2 depicts. The neutral diamine (bp 60–61 °C/0.25 Torr) forms a crystalline hydrobromide salt, which exhibits the expected m/z 143 MH + ion by electrospray mass spectrometry. The only reference base that was found to form proton-bound dimer ions with 1, 2, and 3, was canavanine, 4, a non-protein amino acid analog of arginine. Collision-induced dissociation of these cluster ions was used to assess the gas phase basicities of the diamines. (2) The 1·H·4 + cluster ion happens to have the same mass as the proton-bound trimer of 1. To rule out that interference, isotopically labeled 1 was prepared by catalytic deuteration of succinonitrile. Contrary to a previous literature report, 6 this reduction does not give pure d 4 product, but a 1 : 8 : 1 mixture of d 3 : d 4 : d 5 isotopomers. Since these are easily resolved in the mass spectrometer, the presence of these impurities presents no obstacle. Mass spectrometric measurements were performed on a Finnigan LCQ-DECA ion trap instrument using procedures described in detail elsewhere. 7 Proton affinities were obtained using the extended kinetic method. 8–11 In this approach, cluster ions of various amines B with 4H + are produced by electrospray injection into a quadrupole ion trap, where they are mass selected and then dissociated by collisions with background helium gas at several collision energies. The partner that retains the proton more often is judged to be the more basic. Dissociation of the 1·H + ·4 cluster ion gives more 4H + than 1H + . As expected, the 2·H + ·4 cluster gives an even greater ratio (499% 4H + ), which is too large to be of use in quantitative assessments. In contrast to clusters of 4 with monoamines or with linear diamines, collision-induced dissociation of the 3·H + ·4 cluster ion gives less 4H + than 3H + . This means that 3 is more basic than canavanine (which, in turn, is more basic than Fig. 1 Geometric features of neutral and protonated diamines. Table 1 Distances (Å) and angles (°) a for diamines (MP2/6-311G**) D NN d NN r NH r HN q PA expt b 1 2.95 2.63 1.13 1.52 165 240.3 c 2 3.30 2.64 1.13 1.51 177 238.9 c 3 3.17 2.65 1.12 1.53 174 239.5 d a For definitions, see Fig. 1. b kcal mol 21 c Ref 14. d This work. This journal is © The Royal Society of Chemistry 2003 2040 CHEM. COMMUN. , 2003, 2040–2041 DOI: 10.1039/b305239g