Structure and thermal reactivity of a novel Pd(0) metalloenediyne

Article abstract of DOI:10.1021/ja9944094

We report the X-ray diffraction structure and thermal reactivity of the metalloenediyne compound bis(1,2- bis(diphenylphosphinoethynyl)benzene)palladium(0) (Pd(dppeb)₂, 1). The structure of 1 features a tetrahedral Pd(0) center with four phosphorus atoms from two chelating ligands. The P - Pd - P bond angles nearly match the idealized 109.5°geometry expected for a d¹⁰ metal center in a tetrahedral ligand field. The tetrahedral geometry of the metal center forces the alkyne termini separation of the enediyne ligand to a distance of 3.47 A, which results in a thermally stable compound at room temperature. However, at 115 °C 1 exhibits solvent-dependent reactivity. In o-fluorotoluene, 1 decomposes via ligand dissociation, while in o-dichlorobenzene, carbon-halide bond activation of solvent occurs leading to the oxidative addition product trans- Pd((2-chlorophenyl)diphenylphosphine)₂Cl₂ and free (2- chlorophenyl)diphenylphosphine. The thermal reactivity of 1 is markedly more endothermic (44 kcal/mol) than that of the known Pd(dppeb)Cl₂ analogue (12.3 kcal/mol). The diminished reactivity can be attributed to two factors: the increased alkyne termini separation in 1 (3.47 vs 3.3 A) due to the metal- mandated tetrahedral geometry of the Pd(0) center, and the resistance of the Pd(0) to adopting a planar transition state geometry to promote Bergman cyclization. Overall this study demonstrates that metal binding can impose structural consequences upon the enediyne ligand governed by the oxidation state and corresponding ligand field geometry of the metal center.

Full text of DOI:10.1021/ja9944094

3112
J. Am. Chem. Soc. 2000, 122, 3112-3117
Structure and Thermal Reactivity of a Novel Pd(0) Metalloenediyne
Nicole L. Coalter,† Thomas E. Concolino,‡ William E. Streib,† Chris G. Hughes,†
Arnold L. Rheingold,‡ and Jeffrey M. Zaleski*,†
Contribution from the Department of Chemistry, Indiana UniVersity, Bloomington, Indiana 47405, and
Department of Chemistry and Biochemistry, UniVersity of Delaware, Newark, Delaware 19716
ReceiVed December 17, 1999
Abstract: We report the X-ray diffraction structure and thermal reactivity of the metalloenediyne compound
bis(1,2-bis(diphenylphosphinoethynyl)benzene)palladium(0) (Pd(dppeb)2, 1). The structure of 1 features a
tetrahedral Pd(0) center with four phosphorus atoms from two chelating ligands. The PsPdsP bond angles
nearly match the idealized 109.5° geometry expected for a d10 metal center in a tetrahedral ligand field. The
tetrahedral geometry of the metal center forces the alkyne termini separation of the enediyne ligand to a distance
of 3.47 Å, which results in a thermally stable compound at room temperature. However, at 115 °C 1 exhibits
solvent-dependent reactivity. In o-fluorotoluene, 1 decomposes via ligand dissociation, while in o-
dichlorobenzene, carbon-halide bond activation of solvent occurs leading to the oxidative addition product
trans-Pd((2-chlorophenyl)diphenylphosphine)2Cl2 and free (2-chlorophenyl)diphenylphosphine. The thermal
reactivity of 1 is markedly more endothermic (44 kcal/mol) than that of the known Pd(dppeb)Cl2 analogue
(12.3 kcal/mol). The diminished reactivity can be attributed to two factors: the increased alkyne termini
separation in 1 (3.47 vs 3.3 Å) due to the metal-mandated tetrahedral geometry of the Pd(0) center, and the
resistance of the Pd(0) to adopting a planar transition state geometry to promote Bergman cyclization. Overall
this study demonstrates that metal binding can impose structural consequences upon the enediyne ligand governed
by the oxidation state and corresponding ligand field geometry of the metal center.
Introduction
molecules.26 The key feature of these natural products is the
1,5-diyne-3-ene unit that undergoes Bergman cyclization to form
the potent 1,4-phenyl diradical intermediate27,28 in the presence
of biological reducing equivalents. The singlet diradical inter-
mediate is proposed to be the species responsible for the DNA-
cleaving activity of the enediynes,29 which occurs via H-atom
abstraction from the deoxyribose ring of the DNA backbone.30
Ironically, it is this inherently facile reactivity that promotes
toxicity problems in the pharmacological applications of these
compounds.
The discoveries of the unique structural motifs1-3 and striking
antitumor activities of the enediyne antibiotics have spawned
extensive interest in the mechanisms4-25 of these intriguing
* To whom correspondence should be addressed. E-mail: zaleski@
indiana.edu.
† Indiana University.
‡ University of Delaware.
(1) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Siegal, M. M.; Morton, G.
O.; Ellestad, G. A.; McGahren, W. J.; Borders, D. B. J. Am. Chem. Soc.
1992, 114, 985.
(2) Golik, J.; Clardy, J.; Dubay, G.; Greoenewold, G.; Kawaguchi, H.;
Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J. Am.
Chem. Soc. 1987, 109, 3461.
(3) Golik, J.; Clardy, J.; Dubay, G.; Greoenewold, G.; Kawaguchi, H.;
Konishi, M.; Krishnan, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J. Am.
Chem. Soc. 1987, 109, 3462.
(15) Depew, K. M.; Zeman, S. M.; Boyer, S. H.; Denhart, D. J.; Ikemoto,
N.; Danishefsky, S. J.; Crothers, D. M. Angew. Chem., Int. Ed. Engl. 1996,
35, 2797.
(16) Nicolaou, K. C.; Tsay, S.-C.; Suzuki, T.; Joyce, G. F. J. Am. Chem.
Soc. 1992, 114, 7555.
(4) Takahashi, T.; Tanaka, H.; Yamada, H.; Matsumoto, T.; Sugiura, Y.
Angew. Chem., Int. Ed. Engl. 1996, 35, 1835.
(5) Nicolaou, K. C.; Smith, A. L.; Wenderborn, S. V.; Hwang, C.-K. J.
Am. Chem. Soc. 1991, 113, 3106.
(6) Nicolaou, K. C.; Dai, W.-M.; Wendeborn, S. V.; Smith, A. L.;
Torisawa, Y.; Maligres, P.; Hwang, C.-K. Angew. Chem., Int. Ed. Engl.
1991, 30, 1032.
(7) Nicolaou, K. C.; Zuccarello, G.; Riemer, C.; Estevez, V. A.; Dai,
W.-M. J. Am. Chem. Soc. 1992, 114, 7360.
(8) Nicolaou, K. C.; Ogawa, Y.; Zuccarello, G.; Kataoke, H. J. Am. Chem.
Soc. 1988, 110, 7247.
(9) Zein, N.; Sinha, A. M.; McGahren, W. J.; Ellestad, G. A. Science
1988, 240, 1198-1201.
(10) Lee, M. D.; Dunne, T. S.; Siegal, M. M.; Chang, C. C.; Morton, G.
O.; Borders, D. B. J. Am. Chem. Soc. 1987, 109, 3464.
(11) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegal, M.
M.; Morton, G. O.; McGahren, W. J.; Borders, D. B. J. Am. Chem. Soc.
1987, 109, 3466.
(17) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497.
(18) Walker, S.; Landovitz, R.; Ding, W. D.; Ellestad, G. A.; Kahne, D.
Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 4608.
(19) Li, H.; Zeng, Z.; Estevez, V. A.; Baldenius, K. U.; Nicolaou, K.
C.; Joyce, G. F. J. Am. Chem. Soc. 1994, 116, 3709.
(20) Liu, C.; Smith, B. M.; Ajito, K.; Komatsu, H.; Gomez-Paloma, L.;
Li, T.; Theodorakis, E. A.; Nicolaou, K. C.; Vogt, P. K. Proc. Natl. Acad.
Sci. U.S.A. 1996, 93, 940.
(21) Nicolaou, K. C.; Li, T.; Nakada, M.; Hummel, C. W.; Hiatt, A.;
Wrasidlo, W. Angew. Chem., Int. Ed. Engl. 1994, 33, 183.
(22) Ho, S. N.; Boyer, S. H.; Schreiber, S. L.; Danishefsky, S. J.; Crabtree,
R. G. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 9203.
(23) Shair, M. D.; Yoon, T.; Chou, T. C.; Danishefsky, S. J. Angew.
Chem., Int. Ed. Engl. 1994, 33, 2477.
(24) Nicolaou, K. C.; Smith, B. M.; Ajito, K.; Komatsu, H.; Gomez-
Paloma, L.; Tor, Y. J. Am. Chem. Soc. 1996, 118, 2303.
(25) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991,
30, 1387.
(12) Aiyar, J.; Danishefsky, S. J.; Crothers, D. M. J. Am. Chem. Soc.
1992, 114, 7552.
(13) Aiyar, J.; Hitchcock, S. A.; Denhart, D.; Liu, K. K. C.; Danishefsky,
S. J.; Crothers, D. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 855.
(14) Drak, J.; Iwasawa, N.; Danishefsky, S.; Crothers, D. M. Proc. Natl.
Acad. Sci. U.S.A. 1991, 88, 7464.
(26) Smith, A. L.; Nicolaou, K. C. J. Med. Chem. 1996, 39, 2103.
(27) Jones, R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660.
(28) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
(29) Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184.
(30) Paloma, L. G.; Smith, J. A.; Chazin, W. J.; Nicolaou, K. C. J. Am.
Chem. Soc. 1994, 116, 3697.
10.1021/ja9944094 CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/17/2000

ReactiVity of a NoVel Pd(0) Metalloenediyne
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3113
been reported46,47 to document the utility of transition metals
for affecting enediyne cyclizations. Within this theme, our efforts
have focused on preparing and structurally characterizing
metalloenediynes to investigate the limits to which enediyne
cyclization can be modulated and controlled. We are specifically
interested in determining the role of the metal center oxidation
state and geometry in governing enediyne ligand disposition
and the activation energy for Bergman cyclization. To date, no
studies have been published comparing and contrasting the
effects of metal center oxidation state and geometry on enediyne
cyclization temperatures. Moreover, no crystallographic struc-
tures of enediyne ligands chelated to transition metals have been
elucidated to correlate detailed geometric features with thermal
Bergman cyclization reactivities.48
Herein we report the X-ray diffraction crystal structure and
thermal reactivity of a mononuclear Pd(0) metalloenediyne
compound with two chelating 1,2-bis(diphenylphosphinoeth-
ynyl)benzene ligands (dppeb). The structure is the first example
of a metal-chelated enediyne compound and in conjunction with
its thermal reactivity serves as a key model for understanding
the factors that control metal-assisted Bergman cyclization
reactions.
Figure 1. Modulation of the distance (d) between alkyne termini of
the dppeb ligand by chelation to transition metal centers.
The ability to control formation of 1,4-phenyl diradical
intermediates characteristic of the enediyne antitumor antibiot-
ics26,31 leads to the potential for designing novel compounds
with pharmacological utility. To this end, a number of unique
synthetic,32,33 photochemical,6,34-38 and electrochemical35 ap-
proaches have been explored to initiate Bergman cyclization
of organic enediynes in a controlled manner. One of the
prominent themes to emerge from the original synthetic work
was the empirical correlation between the alkyne termini
separation distance (d ) 3.2-3.31 Å, Figure 1) and the
temperature for thermal cyclization.7 Correlation of activation
energies for Bergman cyclization with crystallographically
determined alkyne termini distances has shown in contrast no
direct relationship between distance and activation energy.39-43
Rather, differential molecular ring strain in the ground and
transition states is proposed to be the dominant contribution to
the thermal barrier height for cyclic enediyne systems. More
recent computational studies have confirmed the absence of an
exclusive relationship between alkyne termini separation and
activation enthalpy, and suggest that ring strain contributions
to the thermal barrier are indeed important to Bergman cycliza-
tion reactivity.29 However, ring strain is not the sole factor in
determining the activation barrier. Density functional results also
suggest that if structural perturbations were to reduce d to 2.9-
3.4 Å, cyclization should occur spontaneously (i.e. room
temperature or below) baring very large olefin ring strain.29,44
Thus, although d may not be the exclusive contributor to the
reaction coordinate, it appears to play a more coarsely defined
supporting role in affecting enediyne cyclization temperatures.
Recently, Buchwald et al. have shown that chelation of the
metal binding enediyne 1,2-bis(diphenylphosphinoethynyl)-
benzene (dppeb) to Pd2+, Pt2+, and Hg2+ can modulate the
critical distance by using the metal as a scaffold to poise the
alkyne termini at a distance governed by the atomic radius of
the ion (Figure 1).45 Since this seminal work, remarkably few
examples of metal-assisted thermal enediyne cyclizations have
Experimental Section
Materials. 1,2-Bis(diphenylphosphinoethynyl)benzene was prepared
according to a literature procedure. Pd(dppeb)2 was prepared according
to a modified literature procedure for Pd(dppm)3. Pd(PPh3)2Cl2, Pd(CH3-
CN)2Cl2, and Pd(CH3CN)4BF4 were purchased from Strem and used
as received. All solvents were dried and distilled according to standard
procedure except o-dichlorobenzene which was dried over 4 Å sieves
prior to use. 1,4-Cyclohexadiene was purchase from Aldrich and used
as received.
Physical Measurements. A nitrogen atmosphere drybox was used
1
for all air-sensitive manipulations. H, 13C{1H}, and 31P{1H} studies
were performed on a Varian Unity I400 spectrometer. 1H and 13C{1H}
spectra were referenced to the residual proton signal of the solvent,
while 31P{1H} spectra were referenced with an 85% phosphoric acid
standard. Differential Scanning Calorimetry (DSC) measurements were
made on a TGA 910 DSC system with a TA Instruments thermal
analyzer. Samples of Pd(dppeb)2 were scanned at a rate of 10 °C min-1
.
Synthesis of Pd(dppeb)2 (1). dppeb (5 g, 0.01 mol) in 10 mL of
benzene was added to 3.55 g (0.005 mol) of Pd(PPh3)2Cl2 in 50 mL of
benzene. The solution was heated and stirred at 60 °C until dissolution
(16 h). Without cooling, hydrazine was added dropwise until the
evolution of gas ceased, resulting in a red solution with an orange
precipitate. The solvent was removed in vacuo, and then the residue
was dissolved in a minimum amount of CH2Cl2 (10 mL) and
reprecipitated in cold ethanol (50 mL). The solution was filtered, and
the solid collected and dried (yield: 50%). Crystals for X-ray diffraction
were grown from slow evaporation of CH2Cl2.1H NMR (CD2Cl2): δ
7.5-7.4 (m, 4H), 7.3 (br S, 16H), 7.0 (t, 8H), 6.8 (t, 16H). 31P{1H}
NMR (CD2Cl2): δ -5.6. 13C{1H} NMR (CD2Cl2): δ 138.9, 134.0 (d,
20 Hz), 132.1, 130.3, 128.9 (d, 18 Hz), 128.0, 127.3, 109.1, 96.5 (d, 9
Hz).
(31) Nicolau, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30,
1387.
(32) Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci.,
U.S.A. 1993, 90, 5881.
(33) Maier, M. E. Synlett 1995, 13.
(34) Wender, P. A.; Zercher, C. K.; Beckham, S.; Haubold, E.-M. J.
Org. Chem. 1993, 58, 5867.
(35) Ramkumar, D.; Kalpana, M.; Varghese, B.; Sankararaman, S. J.
Org. Chem. 1996, 61, 2247.
(36) Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan, M. F.;
Cecil, T. L. J. Am. Chem. Soc. 1996, 118, 3291.
(37) Turro, N. J.; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett. 1994,
35, 8089.
(38) Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120, 1835.
(39) Magnus, P. J.; Carter, P. A. J. Am. Chem. Soc. 1988, 110, 1626.
(40) Magnus, P.; Lewis, R. T.; Huffman, J. C. J. Am. Chem. Soc. 1988,
110, 6921.
(41) Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J. P. J. Am. Chem. Soc.
1990, 112, 4986.
Crystallographic Structure Determination for 1. A suitable crystal
of 1 was mounted with silicone grease, transferred to a goniostat, and
cooled to 105 K for data collection. A preliminary search for peaks
followed by analysis using programs DIRAX and TRACER revealed
(45) Warner, B. P.; Millar, S. P.; Broene, R. D.; Buchwald, S. L. Science
1995, 269, 814.
(46) Konig, B.; Pitsch, W.; Thondorf, I. J. Org. Chem. 1996, 61, 5258.
(47) Basak, A.; Shain, J. C. Tetrahedron Lett. 1998, 39, 3029.
(48) A search of the Cambridge Structure Database revealed no metal-
loenediyne structures with chelating enediyne ligands. The closest structural
analogues known are the π-complexed Os(II) metal-enediyne trans-[Os-
(en)2(η2-L)Br]+Br-, L ) cis-1,6-bistrimethylsilyl-3-ene-1,5-diyne (Hase-
gawa, T.; Pu, L. J. Orgmet. Chem. 1997, 527, 287), and a bridging Pd(II)
bisacetylide Pd2L(PR3)4Cl2, L ) o-diethynylbenzene (Onitsuka, K.; Yama-
moto, S.; Takahashi, S. Angew. Chem., Int. Ed. Engl. 1999, 38, 174).
(42) Snyder, J. P. J. Am. Chem. Soc. 1990, 112, 5367.
(43) Snyder, J. P. J. Am. Chem. Soc. 1989, 111, 7630.
(44) Nantz, M. H.; Moss, D. K.; Spence, J. D.; Olmstead, M. M. Angew.
Chem., Int. Ed. Engl. 1998, 110, 470.

3114 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Coalter et al.
Scheme 1. Synthesis and Solid State Thermal Reactivity of 1
a triclinic cell. The choice of space group P1h was later confirmed by
the successful solution of the structure. Data processing produced a
set of 9866 unique intensities and an Rav ) 0.029 for the averaging of
3876 of these which had been measured more than once. The structure
was solved using a combination of direct methods (MULTAN 78) and
Fourier techniques. The position of the palladium atom was obtained
from an initial E-map. The positions of the remaining non-hydrogen
atoms were obtained from iterations of the least-squares refinement
followed by a difference Fourier calculation. There was evidence in
the difference maps for a molecule of CH2Cl2 solvent near a center of
of kobs vs t. The activation energy for the decomposition of 1 was
obtained from the slope of an Arrhenius plot of kobs vs 1/T (R2 ) 0.95).
B. o-Fluorotoluene. Thermal activation of 1 in o-fluorotoluene was
conducted according to the procedure described above in subsection
A. At 115 °C the reaction went to completion within 24 h, while at
lower temperatures, the reaction time increased from 2 to 7 days. The
only products derive from decomposition of the starting compound
which yielded unreacted dppeb (31P{1H}: δ -32.1 ppm).
Results and Discussion
3
1
symmetry at 0, 0, 0 and another at /2, /2, 1. In addition, these atoms
were disordered because of their close proximity to a symmetry element.
Eventually, two half-weight molecules were included. Hydrogens were
included in fixed calculated positions with thermal parameters fixed at
one plus the isotropic thermal parameter for the parent carbon atom.
In the final cycles of refinement, the non-hydrogen atoms for the Pd
complex were varied with anisotropic thermal parameters that, with a
scale and extinction parameter, gave a total of 659 variables. In the
final difference map the largest peak was 1.8 e/Å3, located 0.7 Å from
Cl(77), and the deepest hole was -1.5 e/Å3.
Crystallographic Structure Determination for 2. The single-crystal
X-ray diffraction experiments were performed on a Siemens P4/CCD
diffractometer for 2. Systematic absences and diffraction symmetry are
consistent for the space groups P1 and P1h. The E-statistics suggested
the centrosymmetric option, which yielded chemically reasonable and
computationally stable results of refinement. The structure was solved
by the Patterson function, completed by subsequent difference Fourier
syntheses, and refined by full-matrix, least-squares procedures. All non-
hydrogen atoms were refined with anisotropic displacement coefficients.
The CH2Cl2 solvate carbon atom is positionally disordered over an
inversion center. Hydrogen atoms were treated as idealized contribu-
tions, except on the disordered carbon atom of the CH2Cl2 solvate which
were ignored in the refinement but not in the global refinement
parameters. All software and sources of the scattering factors are
contained in the SHELXTL (5.10) program library (G. Sheldrick,
Siemens XRD, Madison, WI).
Thermal Reactivity of 1 in Selected Solvents. A. o-Dichloroben-
zene. An NMR tube was charged with 20 mg of Pd(dppeb)2, 5 equiv
of cyclohexadiene as H-donor, and 0.5 mL of o-dichlorobenzene. The
sample was heated to 115 °C for 24 h followed by 31P{1H} NMR
analysis. Identification of the reaction product as trans-Pd((2-chloro-
phenyl)diphenylphosphine)2Cl2 (31P{1H} -5.1 ppm) (2) was made by
obtaining crystals of the dibromide analog49 via slow evaporation from
CH2Cl2. The (2-chlorophenyl)diphenylphosphine ligand (3) was identi-
fied by mass spectrometry HMRS (FAB) m/z 296.1 (100) M+ and 13C-
{1H} NMR (CDCl3): δ 139.1 (d, 26.9 Hz), 136.9 (d, 11.9 Hz), 135.7
(d, 11.2 Hz), 133.9 (d, 21.7 Hz), 133.7 (d, 22 Hz), 129.9, 129.5, 129.0,
128.6 (d, 7.4 Hz), 128.4 (d, 7.3 Hz). Psuedo-first-order rate constants
for the decay of 1 were obtained by integration of the 31P{1H} resonance
at -5.6 ppm as a function of reaction time (t) and subsequently plotting
Synthesis and Structure of 1. The dppeb ligand and the
corresponding zerovalent Pd(dppeb)2 compound were synthe-
sized according to modified literature procedures.50-52 Briefly,
2 equiv of the ligand were reacted with Pd(PPh3)2Cl2 in benzene
to produce 1 as an orange solid in 50% yield (Scheme 1). The
compound is thermally stable (vide infra) and only mildly
susceptible to air oxidation over a 24 h period in solution.
The structure of 1 features a tetrahedral Pd(0) center with
four phosphorus atoms from two bound ligands that complete
the coordination sphere (Table 1, Figure 2). The PsPdsP bond
angles nearly match the idealized 109.5° geometry expected for
a d10 metal center in a tetrahedral ligand field (Table 2). The
most important feature of the structure is the alkyne termini
separation distance d ) 3.47 Å. Although d is comparable in
magnitude to the alkyne termini separation distance in the
enediyne antitumor antibiotic dynemicin A triacetate (d ) 3.54
Å)53 and related synthetic analogues (d ) 3.6-3.7 Å),8,31 it is
greatly reduced from the proposed free ligand distance of 4.1
Å.45 Thus, the structure documents the ability of the metal to
reduce the alkyne termini separation from that of the free ligand
while maintaining the thermal stability of the uncyclized bis-
(chelate) for structure determination.
Several geometric characteristics observed in the structures
of other enediyne motifs are also apparent in the structure of 1.
The first of these is the >12° deviation from linearity of the
P-CtC bond angles. The structure of dynemicin A triacetate
(49) Elemental analysis of 1 reveals trace amounts (0.23%) of Br- ion
although all reagents used in the synthesis, purification, and characterization
were the chloride halo-form. The structure of 2 prompted elemental analyses
of all reagents used in the preparation and subsequent thermal reactivity of
1. Trace amounts of Br- ion were indeed found in PdCl2 (0.02%) and
o-dichlorobenzene (0.05%) used despite the fact that all reagents were the
highest purity commercially available.
(50) Warner, B. Personal Communication.
(51) McFarlane, H. C. E.; McFarlane, W. Polyhedron 1988, 7, 1875.
(52) Stern, E. W.; Maples, P. K. J. Catal. 1972, 27, 120.
(53) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.;
Clardy, J. J. Am. Chem. Soc. 1990, 112, 3715.

ReactiVity of a NoVel Pd(0) Metalloenediyne
Table 1. Crystallographic Data for 1
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3115
formula
C69H50Cl2P4Pd
formula weight
color of crystal
crystal system
space group
a, Å
b, Å
c, Å
1180.38
yellow
triclinic
P1h
13.326(5)
21.332(8)
11.601(4)
105.72(1)
115.88(1)
93.56(2)
2793.42
2
R, deg
â, deg
γ, deg
V, Å3
Z
F
T, K
calcd, g/cm3
1.403
105
λ, Å
0.71069
0.070
0.073
R(Fo)a
Rw(Fo)b
a R ) ∑|Fo| - |Fc|/∑|Fo|. b Rw ) [∑w(|Fo| - |Fc|)2/∑w|Fo|2]1/2, where
w ) 1/σ2(|Fo|).
Figure 3. Thermal ellipsoid plot of 2 drawn at 30% probability.
Hydrogen atoms and solvate molecules have been omitted for clarity.
Table 2. Selected Bond Distances (Å) and Angles (deg) for 1
Pd-P(2)
2.3354(18) C(15)-C(16)
2.3326(17) C(23)-C(24)
2.3334(17) C(51)-C(52)
2.3373(17) C(59)-C(60)
1.195(8)
1.175(9)
1.197(9)
1.206(8)
110.99(6)
109.42(6)
109.69(7)
Pd-P(25)
Pd-P(38)
Pd-P(61)
P(2)-Pd-P(25)
P(2)-Pd-P(38)
P(2)-Pd-P(61)
109.64(6)
109.50(6)
107.53(6)
P(25)-Pd-P(38)
P(25)-Pd-P(61)
P(38)-Pd-P(61)
P(2)-C(15)-C(16) 166.9(6)
P(25)-C(24)-C(23) 167.7(6)
P(38)-C(51)-C(52) 167.3(6)
P(61)-C(60)-C(59) 167.6(6)
C(15)-C(16)-C(17) 169.4(8)
C(22)-C(23)-C(24) 171.5(7)
C(51)-C(52)-C(53) 171.7(7)
C(58)-C(59)-C(60) 169.0(8)
observed in the X-ray structure of dynemicin A triacetate (160-
172°)53 and synthetic analogues (169-173°).8,31 Additionally,
although some in-plane distortion of the enediyne ligand is
apparent in the structure of 1, the alkyne carbons within each
ligand are nearly eclipsed revealing no out-of-plane bending in
the molecule.
Ligand-ligand steric contributions to the structure of 1 are
also evident in the X-ray diffraction analysis as two different
interligand phenyl ring interactions are observed. The closest
contact derives from a coplanar slipped π-stacking interaction
at a 3.3 Å inter-ring separation between two phenyl groups (rings
A and B in Figure 2) bound to phosphorus centers P25 and
P38, respectively. Perpendicular to one of these partners (ring
A) is an additional phenyl substituent (ring C) from a third
phosphine (P61) of the PdP4 tetrahedron at a 3.6 Å closest
contact distance. Although these contributions to the structure
of 1 are likely small, they do suggest the potential for using
ligand-ligand steric interactions to influence the structure and
thermal reactivities of metalloenediynes.
Thermal Reactivity of 1. Compound 1 is stable under
ambient conditions and only reacts at significantly elevated
temperatures. In the solid state, 1 exhibits a single exothermic
phase transition at 209 °C (∆H° ) 54.7 kcal/mol) consistent
with the thermal cyclization of the enediyne ligands (Scheme
1).45 No phase transition is detected in a second heating cycle
following sample cooling to room temperature, indicative of
an irreversible thermal reaction. In solution, 1 is stable at
temperatures up to 100 °C over a 24 h period. Above this
temperature, the compound readily decomposes to solvent-
dependent products (Scheme 2). Heating of 1 in o-dichloroben-
Figure 2. (a) ORTEP of the X-ray crystal structure of 1 (hydrogen
atoms removed for clarity) as viewed down the 2-fold axis of a PdP4
tetrahedron. Phenyl rings labeled A-E correspond to those with inter-
ring closest contact interactions. (b) Thermal ellipsoid plot of 1 (phenyl
rings removed for clarity) illustrating the planarity of the enediyne
ligand and out-of-plane disposition (0.89 Å) of the Pd(0) center.
as well as those of biomimetic enediyne analogues also exhibit
bending of the sp carbon that links the enediyne bridgehead to
the remainder of the molecule. In general, angles ranging from
162 to 168° are observed in the structures of the antibiotic53
and synthetic models,31 suggesting that enediyne chelation to
the metal in 1 qualitatively reproduces the geometric disposition
of the alkyne termini within cyclic organic enediyne systems.
Also noteworthy are the comparable deviations (∼10°) in the
CtC-C angles of the enediyne skeleton, which are once again

3116 J. Am. Chem. Soc., Vol. 122, No. 13, 2000
Scheme 2. Thermal Reactivity of 1 in Solution
Coalter et al.
Table 3. Crystallographic Data for 2
Table 4. Selected Bond Distances (Å) and Angles (deg) for 2
formula
formula weight
color of crystal
crystal system
space group
a, Å
C37H30Br2Cl4P2Pd
944.57
pale brown plock
triclinic
P1h
9.4510(2)
9.6419(2)
11.6018(3)
110.5270(9)
109.0990(9)
98.4086(12)
893.99(4)
1, 1/2
Pd-P(1)#1
2.350(2)
2.4232(13) C(2)-C(3)
3.416(4)
1.822(10)
1.847(9)
1.838(10)
C(1)-C(2)
1.389(16)
1.39(2)
1.35(2)
1.402(16)
1.374(15)
Pd-Br(1)
Pd-Cl(1)
C(3)-C(4)
C(4)-C(5)
C(5)-C(6)
P(1)-C(18)
P(1)-C(12)
P(1)-C(6)
b, Å
c, Å
P(1)#1-Pd(1)-P(1)
P(1)#1-Pd(1)-Br(1)
180.000(1) C(18)-P(1)-C(6) 104.9(5)
88.08(7)
C(18)-P(1)-C(12) 102.1(4)
C(12)-P(1)-C(6) 103.5(4)
R, deg
P(1)#1-Pd(1)-Br(1)#1 91.92(7)
â, deg
Pd(1)-P(1)-C(18)
Pd(1)-P(1)-C(12)
112.1(3)
120.5(3)
γ, deg
V, Å3
Z, Z′
resulting Pd(II) phosphide could then be stabilized by formation
of a mixed-valence Pd(0,II) dinuclear complex in which the
phosphide occupies a bridging position. Subsequent oxidative
addition of the aryl-halide at the Pd(0) center generates a
species in which the aryl halide and phosphide can reductively
eliminate to give the uncomplexed compound 3. In contrast to
the solvent activation chemistry in o-dichlorobenzene, heating
of 1 in the more robust solvent o-fluorotoluene at 115 °C for 2
h results in simple decomposition of 1 to yield uncyclized dppeb
(31P{1H} -32.1 ppm). No Bergman cyclization products are
detected under these reaction conditions.
Structure/Reactivity Correlation. Comparison of the cy-
clization temperature for 1 with that of the previously reported
Pd(dppeb)Cl2 analogue reveals a striking dependence of the
thermal barrier to cyclization on metal site geometry. The origin
of this reactivity originates from two convoluted geometric
factors: (1) the direct distance between the alkyne termini and
(2) the ability of the metal center to adopt a planar transition
state geometry leading to efficient Bergman cyclization. Ex-
perimental evidence for the first derives from thermal reactivity
studies of dppeb with metal chlorides.45 While the Hg2+ complex
is reported to be unreactive due to a large alkyne termini
separation (d ) 3.4 Å), the solid state thermal reactivities of
the Pd2+ and Pt2+ complexes show remarkable decreases in the
cyclization temperatures of the bound dppeb relative to uncom-
plexed enediyne (DSC: Pd2+, 61 °C; Pt2+, 81 °C; dppeb, 243
F
calcd, g/cm3
T, K
1.754
193
0.71069
0.0827
0.2059
λ, Å
R(F)a
R(wF2)a
a Quantity minimized ) R(wF2) ) [∑w(Fo - Fc2)/∑(wFo )2]1/2; R
2
2
) ∑∆/∑(Fï), ∆ ) |Fo - Fc| where w ) 1/[σ2(Fo ) + (aP)2 + bP], P
2
) [2Fc2 + max(Fo, 0)]/3.
zene at 115 °C for 2 h in the presence of cyclohexadiene (CHD)
as an H-atom donor yields three products with 31P{1H} NMR
resonances at -32.1, -10.6, and -5.1 ppm in a 1:3:1 ratio,
respectively. The farthest upfield chemical shift corresponds to
dissociation of uncyclized dppeb from 1. The remaining oxi-
dative addition product trans-Pd((2-chlorophenyl)diphenyl-
phosphine)2Cl2 (2, -5.1 ppm), which has been identified by
crystallographic characterization of the dibromide analogue
(Tables 3 and 4),49 and the corresponding free ligand (2-
chlorophenyl)diphenylphosphine (3, -10.6 ppm),54 derive from
aryl-halide bond activation of the solvent. The mechanism
responsible for the formation of these products is not clear55
but may involve initial dissociation of dppeb from Pd(0) and
subsequent oxidative addition of the phosphinoacetylide yielding
phosphorus-carbon bond rupture. Within this framework, the
(54) Grim, S. O.; Yankowsky, A. W. Phosphorus Sulfur 1977, 3, 191.
(55) Garrou, P. E. Chem. ReV. 1985, 85, 171.

ReactiVity of a NoVel Pd(0) Metalloenediyne
J. Am. Chem. Soc., Vol. 122, No. 13, 2000 3117
°C). In solution, the Pd2+ complex has a half-life of 42 min at
35 °C, and the rate of cyclization can be measured at temper-
atures as low as 5 °C.45 The facile reactivity of Pd(dppeb)Cl2
is partially reflective of the 3.3 Å critical distance calculated
for this compound, which compares favorably with organic
analogues exhibiting similar distances and thermal cyclization
temperatures.7 Although crystallographic structure characteriza-
tion of Pd(dppeb)Cl2 has not been reported, the d8 Pd2+
geometry is expected to be square planar with P-Pd-P angles
close to 90°. In this case, the ligand field geometry of the metal
center governs the disposition of the bound enediyne causing a
reduction in the alkyne carbon termini separation and a
consummate lowering of the thermal barrier to cyclization.
In addition to influencing the alkyne termini separation of
the enediyne, evidence for the importance of the specific metal
center geometry to cyclization reactivity can be obtained by
comparison of activation energies for Bergman cyclization with
theoretically determined transition state structures. The activation
energy for Bergman cyclization of Pd(dppeb)2Cl2 has been
determined experimentally to be a modest 12.3 kcal/mol.45 For
this process the dppeb ligand chelated to Pd can be viewed as
a nine-membered metallocycle where the ligand field geometry
of the metal center controls the P-Pd-P angle and consequently
the alkyne termini separation distance. However, that is not the
only structural influence the metal ion has on the enediyne unit.
The geometry of the metal center also controls the overall
planarity of the nine-membered ring. This is an important
geometric consideration as density functional calculations for
nine-membered carbocyclic enediynes have shown that the
transition-state structure for Bergman cyclization possesses a
planar ring geometry with a reduced alkyne termini separation
(1.96 vs 2.91 Å).56 The model suggests that the square-planar
ground-state geometry of the Pd(II) center in Pd(dppeb)Cl2
serves to more closely approach the transition state geometry
required for facile Bergman cyclization, thereby contributing
to the low thermal barrier to reactivity for this molecule.
Examination of the X-ray structure of 1 shows that the
tetrahedral Pd(0) center is positioned 0.89 Å above the plane
formed by the enediyne ligand (Figure 1b), making this system
geometrically analogous to nine-membered carbocyclic ene-
diynes. These organic compounds typically possess activation
energies for Bergman cyclization from ∼10 to 30 kcal/mol
depending upon the steric interactions between substituents on
the three tetrahedral carbons closing the ring.41 One of the
prominent differences between the structures of the metallocycle
and the carbocyclic enediynes is the elongated ring closing
P-Pd-P bond distances (2.33 Å vs 1.4 Å) which partially
relieve some of the steric interactions between the three adjacent
tetrahedral centers. Based exclusively on this argument, 1 may
be expected to exhibit a comparable or diminished activation
barrier for Bergman cyclization relative to the carbocyclic
enediyne analogues. Since 1 does not undergo Bergman
cyclization in solution, an accurate measurement of the activa-
tion energy for this process is not possible. However, a lower
limit can be estimated by determining the activation energy for
the thermal decomposition of 1 in solution by NMR (Scheme
2). For this process, Ea has been determined to be 44 kcal/mol
in o-dichlorobenzene by temperature-dependent rate constant
measurements. The activation energy for Bergman cyclization
of 1 in solution must therefore be > 44 kcal/mol, which is
consistent with the enhanced alkyne termini separation and the
resistance of the stable tetrahedral Pd(0) center to formation of
a planar transition state that would favor Bergman cyclization.
In relation to Pd(dppeb)2Cl2, this value is ∼30 kcal/mol more
endothermic, and nearly 20 kcal/mol more endothermic than
the nine-membered carbocyclic enediynes. Based on these
results, we propose that the dramatic increase in the cyclization
temperature of 1 relative to the dichloride analogue results
directly from the increased alkyne termini distance in 1 (d )
3.47 Å vs 3.3 Å) caused by the increase in the P-Pd-P angle
and the resistance of the ligand field stabilized tetrahedral Pd-
(0) geometry to bringing the alkyne carbons into close proximity
for σ-bond formation in the transition state.57
Conclusion
Herein we report the unique X-ray crystal structure of a
chelated metalloenediyne compound and its corresponding solid
state and solution thermal reactivity. The tetrahedral geometry
imposed by the d10 Pd(0) center forces the alkyne termini to a
rigid separation distance of 3.47 Å. The ligand field stabilized
geometry of the metal center also inhibits formation of a planar
transition state that would bring the alkyne carbons into close
proximity for σ-bond formation. As a result of these geometric
influences, 1 is remarkably stable with no propensity to undergo
Bergman cyclization. Our work demonstrates that metal binding
can impose structural consequences upon the enediyne ligand
governed by the ligand field mandated geometry of the metal
center. The thermal reactivity of such systems can thus be
modulated over a wide temperature range simply by judicious
choice of metal-ligand geometry. Overall, this study provides
conceptual insights into opportunities for modulating enediyne
reactivity using transition metals and leads to considerable
possibilities for designing novel metalloenediynes with potential
biological utility.
Acknowledgment. We thank Drs. Mark Pagel and Ulrike
Werner-Zwanziger of the Indiana University NMR Facility for
technical assistance. The generous support of the American
Cancer Society (RPG-99-156-01-C), the donors of the Petroleum
Research Fund (PRF No. 33340-G4), administered by the
American Chemical Society, and Research Corporation (Re-
search Innovation Award No. RI0102 for J.M.Z) is gratefully
acknowledged.
Supporting Information Available: Crystallographic data
for 1 and 2 including tables of bond distances angles, final
fractional coordinates and thermal parameters (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA9944094
(57) It is impossible to rule out contributions to the activation energy
for Bergman cyclization arising from steric clashes of the phenyl groups
on adjacent ligands during progression to the transition state. However,
sterically demanding tetrakis(diphenylphosphine) compounds of square-
planar Pd(II) are synthetically established, and the X-ray structure of Pd-
2+
[dppn]2 documents the ability of four phenyl groups to adequately pack
about a square-planar Pd(II) center (Oberhauser, W.; Backmann, C.; Stampfl,
T.; Haid, R.; Bru¨ggeller, P. Polyhedron 1997, 16, 2827). Moreover, since
loss of dppeb is the initial step in the solution thermal reactivity of 1,
Bergman cyclized products arising from a Pd(0) monochelated intermediate
might be expected to form if phenyl ring interactions were inhibiting the
cyclization process at elevated solution temperatures. However, under these
conditions no Bergman cyclization products are detected thereby suggesting
that steric contributions from phenyl ring interactions are not the primary
factor in determining the activation energy for the reactivity of 1.
(56) Koseki, S.; Fujimura, Y.; Hirama, M. J. Phys. Chem. A 1999, 103,
7672.