Synthesis, thermal reactivity and structure of 1,2-bis(4-hydroxy-3- methoxyphenylethynyl)benzene

Article abstract of DOI:10.1007/s10870-005-1674-1

The crystal structure of the new enediyne 3 was determined by X-ray diffraction. 3 crystallizes in the orthorhombic space group Pbca (No. 61) with a = 12.7148(9) A, b = 7.4872(8) A, c = 38.890(4) A, α = β = γ = 90° and Z = 8. The three-dimensional structu

Full text of DOI:10.1007/s10870-005-1674-1

ꢀC
Journal of Chemical Crystallography, Vol. 35, No. 5, May 2005 ( 2005)
DOI: 10.1007/s10870-005-1674-1
Synthesis, thermal reactivity and structure of
1,2-bis(4-hydroxy-3-methoxyphenylethynyl)benzene
Michael Schmittel,(1,3)∗ Guido Morbach,(1) Wolfdieter A. Schenk,(2) and Michael Hagel(2)
Received May 21, 2004; accepted December 1, 2004
The crystal structure of the new enediyne 3 was determined by X-ray diffraction. 3
˚
crystallizes in the orthorhombic space group Pbca (No. 61) with a = 12.7148(9) A,
◦
˚
˚
b = 7.4872(8) A, c = 38.890(4) A, α = β = γ = 90 and Z = 8. The three-dimensional
structure is characterized by an 8-membered cyclic array linking four molecules of 3 by
hydrogen bonding between phenolic and methoxy groups. Furthermore, stabilization by
π–π-stacking and CH · · · π interactions is present. The important cd distance (between
the two terminal acetylene carbons of the enediyne) which is relevant for the Bergman
cyclization, was determined to 401 pm, being in good agreement with the high cyclization
barrier (ꢀG = 147.9 kJ mol−1 at 220◦C) that was determined by differential scanning
‡
calorimetry (DSC).
KEY WORDS: Enediyne; V-shaped molecule; Bergman cyclization; Hydrogen bond; π–π-Stacking, CH · · · π
Interactions.
Introduction
tial heating. En route to investigate the influence
of the substitution at enediynes we decided to pre-
The antibacterial and antitumor properties
pare enediyne 3. Herein, we describe the prepara-
tion, thermal reactivity and interesting solid state
structure of the hitherto unknown compound.
of naturally occurring enediynes have aroused
great interest.1a Their ability to effect highly
specific DNA cleavage via the formation of σ-
biradicals2 is thought to be responsible for their
potent activity.1 At present, considerable research
is focused on the synthesis of simple enediyne
model compounds1b–d,3 that mimic the above
property under physiological conditions. While
simple acyclic enediynes can cleave DNA photo-
Synthesis
4-Bromo-2-methoxyphenol was converted
into the trimethylsilylalkynyl-substituted com-
pound 1 using Sonogashira coupling conditions.5
After the removal of the trimethylsilyl group by
potassium hydroxide, the resulting 4-ethynyl-2-
methoxyphenol (2) was coupled with half an
equivalent of 1,2-diiodobenzene to form the
enediyne 3 (Scheme 1).
4
chemically, their thermal Bergman cyclization
with ensuing DNA cleavage will require substan-
(1) University of Siegen, Center of Micro and Nanochemistry and
Engineering, Organic Chemistry I, Adolf-Reichwein-Str., D-
57068 Siegen, Germany.
(2) University of Wu¨rzburg, Department of Chemistry, Inorganic
Chemistry, Am Hubland, D-97074 Wu¨rzburg, Germany.
∗ To whom correspondence should be addressed; e-mail: schmittel
@chemie.uni-siegen.de.
Experimental
4-Bromo-2-methoxyphenol was purchased
from Lancaster and trimethylsilylacetylene from
373
ꢀ
C
1074-1542/05/0500-0373/0 2005 Springer Science+Business Media, Inc.

374
Schmittel, Morbach, Schenk, and Hagel
Scheme 1. Synthesis of the enediyne 3.
◦
−1
Aldrich. DSC measurements were done on a
DSC7 of Perkin Elmer at heating rates of
10◦C min−1.
---
M.p: 93 C. IR(NaCl, ν˜/cm ): 3384 (m, O H),
---
2958 (m, C H), 2152 (m, C C), 1594 (m,
---
---
O Hdeform.), 1511 (s), 1454 (m), 1248 (s, C O),
1157 (m), 1118 (m), 1031 (m), 939 (w), 848 (s).
1H NMR (200 MHz, CDCl3): δ 0.23 (s, 9H),
Synthesis of 1
3
3.88 (s, 3H), 5.72 (s, 1H), 6.82 (d, J = 8.1 Hz,
4
3
1H), 6.95 (d, 1H, J = 1.8 Hz), 7.02 (dd, J =
Under nitrogen atmosphere 4-bromo-2-
methoxyphenol (2.40 g, 11.8 mmol), copper(I)
iodide (462 mg, 2.43 mmol) and tetrakis(triphenyl-
phosphine)palladium(0) (1.40 g, 1.21 mmol) were
suspended in anhydrous triethylamine (40 mL)
and placed in a sealing tube. Then trimethylsi-
lylacetylene (4.84 g, 49.3 mmol, 6.34 mL) was
added and the reaction mixture was allowed
to stir at 100◦C for a total of 6 d. The mix-
ture was concentrated, the remaining residue dis-
solved in dichloromethane (150 mL), washed
twice with a 2.5% aq. potassium cyanide solu-
tion (70 mL) and three times with water (70 mL).
Evaporation of the solvent and chromatographic
purification on silica gel furnished a slightly
brown solid that was purified by sublimation at
100◦C under reduced pressure. The 2-methoxy-
4-trimethylsilylethynylphenol (1) (2.04 g, 9.26
mmol, 78%) was received as colorless crystals.
TLC (CH2Cl2/petrolether(30/50), 1:1): Rf = 0.2.
4
8.1 Hz, J = 1.8 Hz, 1H). 13C NMR (63 MHz,
CDCl3): δ 0.02, 55.9, 91.9, 105.4, 114.1, 114.4,
114.7, 126.0, 145.8, 146.4. Anal. for C12H16O2Si
(220.3): Calcd. C 65.43, H 7.33. Found C 65.12,
H 7.30.
Synthesis of 2
2-Methoxy-4-trimethylsilylethynylphenol (1)
(188 mg, 853 µmol) was dissolved in a mixture
of methanol (2 mL) and tetrahydrofuran (2 mL).
A solution of potassium hydroxide (500 mg)
in water (2 mL) was added and the mixture
was stirred at ambient temperature for 2 h. The
solution was neutralized with 1 M hydrochloric
acid, treated with diethyl ether (20 mL), and the
aqueous layer was extracted three times with
ether (15 mL). The combined organic layers were
dried over magnesium sulfate and the solvent

1,2-bis(4-hydroxy-3-methoxyphenylethynyl)benzene
375
---
---
was removed under reduced pressure at ambient
temperature. 4-Ethynyl-2-methoxyphenol (2)
(126 mg, 852 µmol, >99%) was received as
an orange-brown oil and was used for the next
step without further purification. TLC (CHCl3/n-
hexane): Rf = 0.3. IR (NaCl, ν˜/cm−1): 3389 (s,
O H), 2938 (w, C H), 2204 (w, C C), 1590
---
(m, C H), 1514 (s, CH), 1451 (m), 1418 (m),
1317 (m), 1255 (s, C O), 1206 (m), 1118 (m),
1031 (m). H NMR (200 MHz, CDCl3): δ 3.79
---
1
3
(s, 6H), 5.76 (s, 2H), 6.86 (d, J = 8.1 Hz,
4
3
2H), 7.03 (d, J = 1.8 Hz, 2H), 7.13 (dd, J =
4
---
---
O H), 3286 (s, C CH), 2919 (s, C H), 2097
8.1 Hz, J = 1.8 Hz, 2H), 7.27 (m, 2H), 7.51
(dd, 2H). 13C NMR (CDCl3, 63 MHz): δ 55.9,
86.8, 93.8, 113.9, 114.5, 115.0, 125.6, 126.0,
127.7, 131.3, 146.2, 146.4. Anal. for C24H18O4
(370.4): Calcd. 370.1205. Found 370.1200
(correct HRMS).
---
(w, C C), 1593 (s, O Hdeform.), 1511 (s), 1455
(m), 1419 (m), 1373 (m), 1274 (s), 1237 (m,
---
C O), 1202 (m), 1143 (m), 1121 (s), 1032 (s),
1
855 (w), 820 (w), 791 (w). H NMR (200 MHz,
CDCl3): δ 2.97 (s, 1H), 3.88 (s, 3H), 6.84 (d,
4
3J = 8.1 Hz, 1H), 6.97 (d, J = 1.7 Hz, 1H),
3
4
7.04 (dd, J = 8.1 Hz, J = 1.7 Hz, 1H). 13C
NMR (CDCl3, 63 MHz): δ 56.0, 75.3, 76.5,
113.6, 114.3, 114.5, 126.2, 146.1, 146.6. Anal.
for C9H8O2 (148.2): Calcd. 148.0524. Found
148.0520 (HRMS).
X-ray crystallography
X-ray diffraction intensity collection was
carried out with graphite-monochromatized
MoKα radiation on an Enraf-Nonius-CAD4
diffractometer (filter factor 15.41, λ =
˚
0.71073 A). Crystal data and details of
Synthesis of 3
measurement and refinement are summarized in
Table 1. According to the µ × r < 0.05 criterion,
no absorption correction had to be applied. The
crystal structure was solved by direct methods
(Program SHELXS 97) in the space group Pbca
(Nr. 61).6 The hydrogen atoms were included in
idealized positions coupled to their respective
carbon atoms. Least-squares cycles for the
structure refinement (Program SHELXL 97)6
with 258 parameters and 3253 used reflections
resulted in a reflex/parameter ratio of 13/1.
The refinement converged at R1(3) = 0.0450,
wR2 = 0.0975.
1,2-Diiodobenzene (125 mg, 379 µmol,
50.0 µl) was added under nitrogen to a suspen-
sion of copper(I) iodide (7.40 mg, 38.9 µmol)
and bis(triphenylphosphine)palladium(II) chlo-
ride (13.3 mg, 18.9 µmol) in anhydrous tri-
ethylamine (1.5 mL). After the addition of 2-
methoxy-4-ethynylphenol (126 mg, 850 µmol)
in anhydrous triethylamine (2 mL) the reaction
mixture was allowed to stir for 5 h at ambient
temperature. The solvent was evaporated under
reduced pressure, the remaining residue was dis-
solved in dichloromethane (25 mL) and the or-
ganic layer was washed twice with an 1% aq.
potassium cyanide solution (20 mL) and three
times with water (20 mL). After drying over
magnesium sulfate and evaporation of the sol-
vent, the crude product was purified by column
chromatography on silica gel. The fraction (TLC
[CH2Cl2]: Rf = 0.1) causing a fluorescent spot on
the TLC was isolated and purified by recrystal-
lization from chloroform. 1, 2-Bis(4-hydroxy-3-
methoxyphenylethynyl)benzene (3) was received
(60.0 mg, 162 µmol, 43%) as colorless crys-
tals. M.p. 123◦C. IR (NaCl, ν˜/cm−1): 3510 (m,
Discussion
Enediyne 3 (Pearson symbol oP368) crys-
tallizes in the orthorhombic system in the space
group Pbca with eight molecules in the unit cell.
All atoms of 3 (Fig. 1) are placed on general po-
sitions 8c (1). Along [100] the crystal displays
a layer structure (Fig. 2), which is stabilized by
hydrogen bonds (Fig. 3) and by aromatic π–π-
interactions (Fig. 4).

376
Schmittel, Morbach, Schenk, and Hagel
Table 1. Crystal Data and Structure Refinement Details for 3a,b
Parameter
3
Empirical formula
Crystal dimension/mm3
M
C
24H18O4
0.4 × 0.2 × 0.2
370.38
Crystal system
Space group
Orthorhombic
Pbca
12.7148(9)
7.4872(8)
38.890(4)
3.7022(6)
˚
a(A)
˚
b(A)
˚
c(A)
V/nm3
Z
8
T/K
293(2)
1.329
0.71073
0.090
Dc/Mg m−3
˚
λ(A)
µ(mm−1
)
F(000)
1552
θ Range for data collection/◦
2.09–24.98
0 ≤ h ≤ 15, 0 ≤ k ≤ 8,
−46 ≤ l ≤ 46
6440
Limiting indices
Reflections collected
Independent reflections
Completeness to θ = 24.98
Max., min. transmission
Data, restraints, parameters
Goodness-of-fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
3253
99.9
Fig. 1. Structure of enediyne 3. Distance provided in pm.
Thermal ellipsoids are drawn at the 50% probability level.
0.9822, 0.9648
3253, 0, 258
1.038
R1 = 0.0450, wR2 = 0.0975
R1 = 0.0925, wR2 = 0.1222
0.0043(5)
Extinction coefficient
Largest diff. peak and
0.183 and −0.159
−3
˚
hole/e A
aFull-matrix, least squares refinement on F2.
bSee here for full crystallographic data (CCDC 236788).
The solid state structure of enediyne 3 ex-
hibits a remarkable inter- as well as intramolecu-
larly hydrogen bonded 8-membered array (Fig. 3)
in which phenolic and methoxy groups are en-
gaged. The pivotal hydrogen bonding pattern
is formed by four molecules of 3, each of
which participates with only one of its two 2-
hydroxyanisole units. Two molecules of 3 use
the methoxy and hydroxy groups in the hydro-
gen bonding, while the two remaining molecules
participate only with their hydroxy group. For the
former molecules, the methoxy group acts as an
acceptor and the hydroxy group as a donor giving
rise to a bifurcated hydrogen bonding. For the
latter molecules the hydroxy group acts as both
donor and acceptor. Based on Etter7 classification
the OH · · · O hydrogen bonded ring structure
Fig. 2. Crystal system along [100].

1,2-bis(4-hydroxy-3-methoxyphenylethynyl)benzene
377
Fig. 3. Picture depicting the tetramer formed by bifurcated hydrogen bonding leading
to an 8-membered cyclic array. Distances are provided in pm. Further distances and
angles are furnished in Table 2.
could be assigned to the graph set designation
R44 (8).
Hydrogen bonding involving the methoxy
groups results in intermolecular MeO · · · HO
(231.3(2) pm) and intramolecular MeO · · · HO
(231.4(2) pm) interactions of similar strength. In
contrast, the · · · HO · · · HO hydrogen bonding in-
teraction between hydroxy groups was slightly
stronger (227.6(2) pm).
Interestingly, the two molecules that are
only involved with their hydroxy groups in
the central hydrogen bonding pattern have their
Fig. 4. Crystal system along [010] with a look at the hydrogen bonded 8-membered array.

378
Schmittel, Morbach, Schenk, and Hagel
◦
---
---
---
ortho-methoxy group participating in moderate
to weak intramolecular CH · · · π interactions with
their two phenylalkyne units (310.8, 322.8, 304.2,
324.0(3) pm).
and C(21) C(22) C(11) C(12) = 12.64(21) )
but nevertheless furnish a distinct delocalized
π-system. The distance between the two terminal
acetylenic carbon atoms C1 and C4 (Fig. 1:
called cd distance in enediynes) was determined
to 401 pm. It is much longer than the cd distance
(344 and 350 pm) of analogous benzoenediynes
that are incorporated into 11-membered ring
systems,8 while it is comparable to that of
other acyclic diphenylsubstituted enediynes (cd
distances 377–423 pm).9
Moreover, the aromatic subunits are arranged
in a coplanar π–π-stacking fashion with an aver-
˚
age inter-planar distance of 3.7 A. To realize this
arrangement the aromatic systems are twisted by
about 20◦ (Fig. 4).
Because of nonlinear acetylene groups the V-
shaped molecule differs from t◦he ideal geometry
--- ---
--- ---
( C2 C1 C11 = 177.35(25) , C22 C2 C1
Like other diaryl substituted benzoenediynes
3 is expected to undergo Bergman cyclization
at elevated temperature.8–10 Indeed, differential
scanning calorimetry (DSC) measurements indi-
cated a cyclization onset temperature of 189◦C,
◦
= 179.07(25)◦, C4 C3 C21 = 178.06(25)
--- ---
◦
--- ---
and C31 C4 C3 = 176.3(26) ) (Table 2).
The phenyl rings within 3 are not coplana◦r
---
---
---
( C(36) C(31) C(21) C(22) = 24.06(25)
Table 2. Selected Bond Distances (pm) and Angles (◦) of 3
Phenyl-I
Phenyl-II
----
----
O(1) C(14)
136.5(2)
139.5(2)
142.8(3)
139.2(3)
139.4(3)
137.2(3)
137.9(3)
138.0(3)
137.8(3)
O(3) C(34)
137.1(3)
136.6(3)
142.5(3)
139.5(3)
140.5(3)
139.5(3)
137.2(3)
137.9(4)
137.7(3)
----
O(2) C(13)
----
O(4) C(33)
----
----
O(2) C(5)
O(4) C(6)
----
----
C(11) C(16)
C(21) C(26)
----
----
C(11) C(12)
C(21) C(22)
----
C(12) C(13)
----
C(22) C(23)
----
----
C(13) C(14)
C(23) C(24)
----
----
C(14) C(15)
C(24) C(25)
----
----
C(15) C(16)
C(25) C(26)
Phenyl-III
Acetylene-bridge
----
----
C(31) C(36)
138.4(3)
139.9(3)
137.6(3)
139.0(3)
137.3(3)
137.5(3)
C(1) C(2)
119.7(3)
119.0(3)
143.7(3)
143.2(3)
143.5(3)
143.5(3)
401.1(3)
----
C(31) C(32)
----
C(3) C(4)
----
----
C(32) C(33)
C(4) C(31)
----
C(33) C(34)
----
C(1) C(11)
----
----
C(34) C(35)
C(2) C(22)
----
C(35) C(36)
----
C(3) C(21)
----
C(1) C(4)
Angles
----
----
----
----
----
C(2) C(1) C(11)
177.35(25)
179.07(25)
120.3(2)
12.64(21)
38.61(20)
C(4) C(3) C(21)
178.06(25)
176.3(26)
---- ----
----
C(22) C(2) C(1)
C(31) C(4) C(3)
---- ----
----
----
C(22) C(21) C(3)
(I, II)
C(21) C(22) C(2) 120.6(2)
(II, III)
24.06(25)
(I, III)
Angles of bifurcated hydrogen bonds
O(2) · · · H(1) · · · O(3)
H(1) · · · O(2) · · · H(3)
O · · · O distances
O2 · · · O3
d(O · · · O)
291.7(2)
275.4(2)
298.8(2)
99.07(6)
143.80(7)
O1 · · · O2
O1 · · · O3
H-bondsa
O2 · · · H1
O2 · · · H3
O3 · · · H1
d(O H)
----
231.4(2)
231.3(2)
227.6(2)
1
2
aSymmetry operators: 1) x + 21 , y − 21 , z; 2) −x + 1, y − 1, −z + 12 ; 3) −x + 21 , y + 12 , −z +
.

1,2-bis(4-hydroxy-3-methoxyphenylethynyl)benzene
379
2. Jones, R.R.; Bergman, R.G. J. Am. Chem. Soc. 1972, 94, 660.
3. Schreiner, P.R. J. Am. Chem. Soc. 1998, 120, 4184; Bru¨ckner,
R.; Suffert, J. Synlett 1999, 657; Kim, C.-S.; Diez, C.; Russell,
K.C. Chem. Eur. J. 2000, 6, 1555; Rawat, D.S.; Zaleski, J.M. J.
Am. Chem. Soc. 2001, 123, 9675; Suzuki, I.; Tsuchiya, Y.;
Shigenaga, A.; Nemoto, H.; Shibuya, M. Tetrahedron Lett.
2002, 43, 6779; Alabugin, I.V.; Manoharan, M. J. Phys. Chem.
A 2003, 107, 3363; Klein, M.; Ko¨nig, B. Tetrahedron 2004, 60,
1087.
being in good agreement with thermal cyclization
conditions for related systems. Closer inspection
of the DSC11 data allowed to derive an activation
‡
barrier ꢀG = 147.9 kJ mol−1 at 220◦C.
Acknowledgments
4. Funk, R.L.; Young, E.R.R.; Williams, R.M.; Flanagan, M.F.;
Cecil, T.L. J. Am. Chem. Soc. 1996, 118, 3291; Evenzahav, A.;
Turro, N.J.J. Am. Chem. Soc. 1998, 120, 1835; Schmittel, M.;
Viola, G.; Dall´Acqua, F.; Morbach, G. Chem. Comm. 2003, 646.
5. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 50, 4467; de Meijere, A.; Meyer, F.E. Angew. Chemie
1994, 106, 2473; Angew. Chem. Int. Ed. Engl. 1994, 33, 2379;
Rossi, R.; Carpita, A.; Bellina, F. Organic Preparations and
Procedures Inc. 1995, 27, 127; Heck, R.F. Palladium Reagents
in Organic Synthesis, Academic Press London, 1995.
6. Sheldrick, G.M. SHELXS-97, A Program for Crystal Structure
Solution, University of Go¨ttingen: Germany, 1997; Sheldrick,
G.M. SHELXL-97-2, A Program for the Refinement of Crystal
Structures, University of Go¨ttingen, Germany, 1997.
7. M.C. Etter, J.C. MacDonald, J. Bernstein, Acta Cryst. B 1990,
46, 256–262.
Financial support from the Deutsche
Forschungsgemeinschaft and Fonds der Chemis-
chen Industrie is gratefully acknowledged. More-
over, we are indebted to Prof. Mormann (Siegen)
for providing access to the DSC facilities and
Mukul Lal for discussions on the hydrogen bond-
ing pattern.
References
8. Wandel, H.; Wiest, O. J. Org. Chem. 2002, 67, 388.
9. Chandra, T.; Kraft, B.J.; Huffman, J.C.; Zaleski, J.M. Inorg.
Chem. 2003, 42, 5158.
10. Schmittel, M.; Kiau, S. Chem. Lett. 1995, 10, 953.
11. Borchardt, H.J.; Daniels, F. J. Am. Chem. Soc. 1957, 79, 41.
1. a) Nicolaou, K.C.; Dai, W.-M. Angew. Chem. 1991, 103, 1453;
Angew. Chem. Int. Ed. Engl. 1991, 30, 1387; b) Maier, M.E.
Synlett 1995, 13; c) Basak, A.; Mandal, S.; Bag, S.S. Chem.
Rev. 2003, 103, 4077; d) Rawat, D.S.; Zaleski, J.M. Synlett
2004, 393.