Ring-strain effects on the oxidation potential of enediynes and enediyne complexes Kim K. Baldridge,* a,b Bernadette T. Donovan-Merkert,* c Joseph M. O’Connor,* a Linda I. Lee, a Adam Closson, a Daniel Fandrick, a Tuan Tran, a Kevin D. Bunker, a Mouffouk Fouzi c and Peter Gantzel a a Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093-0358, USA. E-mail: jmoconno@ucsd.edu; Fax: 858 534 5383; Tel: 858 534 5836 b San Diego Supercomputer Center, La Jolla, California 92093-0505, USA c Department of Chemistry, University of North Carolina, Charlotte, North Carolina USA Received 26th September 2002, Accepted 28th January 2003 First published as an Advance Article on the web 12th February 2003 The metal–enediyne complexes [(η 5 -C 5 H 5 )Fe{η 5 -1,2- C 5 H 3 C   C(CH 2 ) n C   C}] (4, n  4; 5, n  5) and [(η 5 -C 5 H 5 )- Fe{η 5 -1,2-C 5 H 3 (C   CMe) 2 }] (6) were prepared from 1,2-diethynylferrocene (3). Complexes 4 and 5 were char- acterized in the solid state by X-ray crystallographic analysis. The structures of 4 and 6 were determined by computation using ab initio methods. A correlation was observed between ring-strain and increased ease of electrochemical oxidation along the series 6 (0.164 V) to 5 (0.152 V) to 4 (0.123 V). A similar trend in ionization potentials was identified in both the gas phase and in solution by computational methods. The effect of cycloalkyl-annelation on the structure, properties, and reactivity of aromatic rings has attracted the attention of organic chemists for over 50 years. 1,2 A particularly fascin- ating aspect of strained-ring annelation is the observation that the oxidation potentials within a series of naphthalenes becomes more positive as ring-strain is increased. To illustrate, oxidation of 1,2-dihydrocyclobuta[b]naphthalene (1, E ½ =  1.59 V vs. SCE) occurs at 50 mV more positive potential than for 2,3-dimethylnaphthalene (2, E ½ = 1.54 V; Fig. 1). 2a This, and related phenomena, have been attributed to a strain- induced rehybridization of the ring-junction carbons (*). 1,2 Thus, ring-strain results in increased p-character in the atomic orbitals used in the strained-ring and, conversely, increased s-character in the atomic orbitals used to form the sigma bond to the sp 2 -carbon α to the strained-ring. Enediynes are of great interest due to the potent antitumor activity exhibited by naturally occurring strained-ring enediynes, 3 and the widespread use of enediynes as important units for the construction of carbon-rich systems. 4 Strained- ring alkynes have been widely studied from the perspective of reactions at the alkyne π-system; 5 however, the influence of cycloalkynyl-annelation on redox behaviour has not previously been reported. Here we report synthetic, electrochemical, and computational studies which establish a relationship between enediyne ring-strain and the electronic properties of enediynes and enediyne–metal complexes. Sequential treatment of a THF solution (125 mL) of 1,2- diethynylferrocene 6 (3; 383 mg, 1.64 mmol) with n-BuLi (4.1 mmol) and 1,4-diiodobutane (0.54 g, 1.64 mmol) gave the enediyne complex [(η 5 -C 5 H 5 )Fe{η 5 -1,2-C 5 H 3 C   C(CH 2 ) 4 C   C}] Fig. 1 (4) as a yellow–orange air-stable solid in 26% yield (Scheme 1). 7–9 The 11-membered ring analogue 5 and the acyclic dipropynyl analogue 6 were prepared from 3 in a similar fashion. A DEPT NMR spectrum (CDCl 3 ) of 4 supports the assignment of carbon resonances at δ 80.0 and 96.2 to the alkyne sp-carbons. For comparison, the alkyne carbons in 5 are observed at δ 80.2 and 91.8; whereas, for 6 these resonances are located farther upfield at 76.0 and 84.3. The 13 C NMR spectroscopic data are consistent with an increase in p-character at the alkyne–cyclopentadienyl bonds proceeding across the series from 6 to 5 to 4. The structural details for 3–6 were established by X-ray crystallography (4, 5; Table 1; Fig. 2) 10 and by computation using ab initio methods (4, 6; Table 1). 11 The validity of the computational results is supported by the remarkably close agreement between the crystallographic and computational data for 4 (Table 1). For the series of compounds 4–6, the bond distances of the enediyne unit (α, β, γ) are similar within the experimental uncertainty; however, large geometric differences in the enediyne angles are observed along this series. Angular distortions at the proximal alkyne carbons in the 10-membered ring enediyne 4 are significantly greater (B = 163.5) than at the distal alkyne carbons (C = 172.7; 171.8 calc). In contrast, the B/C angles for the 11-membered ring compound 5 are 168.6 and 171.0, respectively. Both 4 and 5 fit the structural criteria for angle-strained alkynes, 7 with the average angle about the sp-carbons bound to the Cp-ring in 4 and 5 determined to be 163 and 168, respectively. The cd-distance in 4 (3.4 Å, 3.5 Å calc) and in 5 (3.8 Å) is significantly shorter than the corresponding distance calculated for 6 (4.6 Å). Scheme 1 DOI: 10.1039/ b209285a This journal is © The Royal Society of Chemistry 2003 Org. Biomol. Chem. , 2003, 1, 763–766 763