Toward an Artificial Oxidative DNA Photolyase

Article abstract of DOI:10.1021/jo0354600

The design, synthesis, structure, and binding affinity of two dioptic receptors for the selective molecular recognition of the cis,syn cyclobutane pyrimidine dimer are reported. The design is based on two 2,6-di(acetamino)pyridine recognition units that are covalently linked via triple bonds to an anthraquinone functional spacer unit. The convergent synthesis uses a modified Sonogashira reaction involving a zinc transmetalation as the key step. The crystal structure of one of the receptors reveals a supramolecular 1D polymer with strong interactions mediated by shape self-complementarity, π-stacking, and hydrogen bonding between adjacent molecules. Hydrogen bonding between adjacent strands enforces a parallel orientation, which leads to a noncentrosymmetric crystal structure of the highly polar compound. The receptor has an association constant of K _a = 1.0 × 10³ M^-1 with the cis,syn pyrimidine dimer, whereas binding of the trans,syn isomer is approximately 1 order of magnitude weaker.

Full text of DOI:10.1021/jo0354600

Tow a r d a n Ar tificia l Oxid a tive DNA P h otolya se
Mickae¨l Pauvert, Patrick Laine, Marco J onas, and Olaf Wiest*
Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556-5670
owiest@nd.edu
Received October 5, 2003
The design, synthesis, structure, and binding affinity of two dioptic receptors for the selective
molecular recognition of the cis,syn cyclobutane pyrimidine dimer are reported. The design is based
on two 2,6-di(acetamino)pyridine recognition units that are covalently linked via triple bonds to
an anthraquinone functional spacer unit. The convergent synthesis uses a modified Sonogashira
reaction involving a zinc transmetalation as the key step. The crystal structure of one of the receptors
reveals a supramolecular 1D polymer with strong interactions mediated by shape self-complemen-
tarity, π-stacking, and hydrogen bonding between adjacent molecules. Hydrogen bonding between
adjacent strands enforces a parallel orientation, which leads to a noncentrosymmetric crystal
structure of the highly polar compound. The receptor has an association constant of Ka ) 1.0 × 103
M-1 with the cis,syn pyrimidine dimer, whereas binding of the trans,syn isomer is approximately
1 order of magnitude weaker.
In tr od u ction
chemistry because one can envision hydrogen bonding
patterns that are related to the molecular recognition
phenomena that play a key role in maintaining genetic
integrity (e.g. Watson-Crick pairing). Consequently, the
use of noncovalent interactions for the nucleotide bases
of DNA, based mainly on hydrogen bonding, has become
an important field of research and the development of
new receptors for the binding of molecules of biological
interest is a main focus of supramolecular chemistry.5-7
The structure of the biologically relevant cis,syn CPD
would allow an extension of these concepts by using more
than three hydrogen bonds for molecular recognition by
appropriately positioned multiple receptor units.
Upon irradiation of DNA with UV light of wavelengths
between 260 and 320 nm, two adjacent pyrimidines
undergo a photochemical [2+2] cycloaddition, leading to
the formation of cyclobutane pyrimidine dimers (CPD),
the most important among several possible photoprod-
ucts.1 These photolesions are mutagenic and cause all of
the three major types of skin cancer.2 Many organisms,
but not humans, have developed a protection mechanism
to regenerate the damaged genetic information by using
enzymes called CPD photolyases that use a unique
photoinduced electron-transfer-catalyzed mechanism to
achieve DNA repair. Although CPD photolyase uses a
reductive single electron transfer to initiate the cyclo-
reversion, it was shown that the cycloreversion of the
CPD can also be achieved in vitro through an oxidative
pathway.3 The development of artificial models for this
reaction has been a very active and attractive field of
research in recent years and has yielded valuable infor-
mation about CPD photolyase.4
There have been a number of different approaches to
the problem of molecular recognition of CPD. Several
research groups have developed artificial receptors for
CPD and the corresponding TpT dinucleotide. Rebek and
co-workers8 achieved a binding constant of 4800 M-1 for
(4) (a) Goodman, M. S.; Rose, S. D. J . Org. Chem. 1992, 57, 3268-
3270. (b) Harzfeld, D. G.; Rose, S. D J . Am. Chem. Soc. 1993, 115,
850-854. (c) Carell, T.; Epple, R.; Gramlich, V. Angew. Chem., Int.
Ed. Engl. 1996, 35, 620-623. (d) Epple, R.; Carell, T. J . Am. Chem.
Soc. 1999, 121, 7318-7329. (e) Carell, T.; Burgdorf, L.; Butenandt, J .;
Epple, R.; Schwogler, A. In Bioorganic Chemistry; Diederichsen, U.,
Ed.; Wiley-VCH: New York, 1999; pp 337-345.
(5) (a) Dervan, P. B. Bioorg., Med. Chem. 2001, 9, 2215-2235. (b)
Deans, R.; Niemz, A.; Breinlinger, E. C.; Rotello, V. R. J . Am. Chem.
Soc. 1997, 119, 10863-10864.
(6) (a) Sessler, J . L.; Wang, R. J . Org. Chem. 1998, 63, 4079-4091.
(b) Sessler, J . L.; Wang, R. Angew. Chem., Int. Ed. 1998, 37, 1726-
1729.
The first step toward a successful CPD photolyase
model is the selective molecular recognition of CPD. This
is a particularly interesting problem in supramolecular
(1) For monographs, see e.g.: (a) Friedberg, E. C. DNA Repair; W.
H. Freeman & Co.: New York, 1985; Chapters 1-5, 2-1, and 2-2. (b)
Cadet, J .; Vigny, P. The Photochemistry of Nucleic Acids. In Bioorganic
Photochemistry; Vol. I, Photochemistry and Nucleic Acids; Morrison,
H., Ed.; Wiley & Sons: New York 1990; pp 53-100. (c) Fischer, G. J .;
J ohns, H. E. Pyrimidine photodimers. In Photochemistry and Photo-
biology of Nucleic Acids; Wang, S. Y.;, Ed.; Academic Press: New York,
1976; Vol. I, pp 226-295. (d) Patrick, M. H.; Rahn, R. O. Photochem-
istry of DNA and Polynucleotides: Photoproducts. In Photochemistry
and Photobiology of Nucleic Acids; Wang, S. Y.; Ed.; Academic Press:
New York, 1976; Vol. I, pp 35-95.
(2) (a) Taylor, J .-S. Pure Appl. Chem. 1995, 67, 183-190. (b) Taylor,
J .-S. Acc. Chem. Res. 1994, 27, 76-82.
(3) (a) Begley, T. P. Compr. Nat. Prod. Chem. 1999, 5, 371-399. (b)
Sancar, A. Chem. Rev. 2003, 103, 2203-2238. (c) Heelis, P. F.;
Hartman, R. F.; Rose, S. D. Chem. Soc. Rev. 1995, 24, 289-297.
(7) Tecilla, P.; J ubian, V.; Hamilton, A. D. Tetrahedron 1995, 51,
435-448.
(8) Park, T. K.; Schroder, J .; Rebek, J ., J r. J . Am. Chem. Soc. 1991,
113, 5125-5127. It is possible that the cis,syn derivative has in fact a
higher association constant than the reported value because the
procedure used for the synthesis of the CPD derivative used was later
shown to yield the trans,syn derivative: (b) Cochran, A. G.; Su-
gasawara, R.; Schultz, P. G. J . Am. Chem. Soc. 1988, 110, 7888-7890.
(c) J acobsen J . R.; Cochran, A. G.; Stephans, J . C.; King, D. S.; Schultz,
P. G J . Am. Chem. Soc. 1995, 117, 5453-5461.
10.1021/jo0354600 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/25/2003
J . Org. Chem. 2004, 69, 543-548
543

Pauvert et al.
SCHEME 1. Design of th e System for Molecu la r
a CPD derivative in chloroform by covalently linking the
widely used 2,6-bis(acetamino)pyridine recognition unit
to a xanthene spacer. Hamilton used the same recogni-
tion unit for binding of thymines and CPD with binding
constants between 520 and 2200 M-1.9 By linking 2,6-
bis(acetamino)pyridine with indoles, which can induce a
reductive electron transfer upon irradiation with visible
light, Rose and co-workers10 obtained the first artificial
photolyase. More recently, Inouye et al. measured a
binding constant of 45 M-1 for a dioptic receptor, origi-
nally designed for the binding of TpT, to a CPD derivative
in chloroform/DMSO 85:15.11
Recogn ition
The structural similarity of some of these receptor
units to the approach studied in our laboratories as well
as our recent results on the very interesting crystal
structure of one of our receptors prompted us to report
the design, synthesis, X-ray analysis, and binding studies
for two new receptor units that are selective for the
binding of cis,syn-CPD (cis,syn-1) at this time.
Syn th esis The formal retrosynthesis of 14 and 15
leads to 1,8-diethynylanthracene 11 and 2,6-diamino-4-
halogenopyridine, followed by a Sonogashira-type cou-
pling of those units in the key step of the convergent
synthesis. The 2,6-diaminopyridine units 6, 7, and 8 were
prepared in four steps from 2 or 318 according a modified
literature procedure.11,13,19,20 Conversion of 2 and 3 to the
di(carboxylic acid chloride) is followed by nucleophilic
substitution under phase transfer conditions with 2 equiv
of sodium azide, which gave the di(acyl azide) intermedi-
ate. This unstable intermediate undergoes a Curtius
rearrangement19-21 and alcohol capture of the reactive
isocyanate intermediate with tert-butyl alcohol leads to
the formation of the bis(Boc-protected) diaminopyridine
4. The bis-Boc derivatives 4 and 5 was then treated with
TFA to obtain the 2,6-diamino-4-halopyridine. It was
found that the electron-rich unprotected diamino pyridine
is prone to oxidation and electrophilic attack. These
unwanted side reactions made it necessary to quench the
tert-butyl cation formed during deprotection and to
reprotect the free amine without isolation. Therefore,
anisole was added and the diamino pyridine, without
isolation, was reprotected as the desired acylamino
derivatives, using either Ac2O or valeryl chloride in the
presence of pyridine, leading to the formation of three
different 2,6-diaminopyridine recognition units 6, 7, and
8 (Scheme 2). The total yields for this five-step pathway
from commercially available starting material chelidamic
acid range from 40% for 8 to 66% for 7.
Resu lts a n d Discu ssion
Design The 2,6-bis(acylamino)pyridine unit is well-
known in the literature and has been widely used for the
molecular recognition of pyrimidine bases, as discussed
above.7,10-13 By modifying the alkyl side chain of the acyl
group, the solubility of the molecule can be fine-tuned.
The binding affinity is mediated through three hydrogen
bonds in a DAD/ADA system, leading to the formation
of a strong pyridine-pyrimidine complex. The search for
the ideal spacer unit to link the two recognition units
led to the 1 and 8 positions of an anthracene moiety. This
specific linkage provides a rigid framework for a biden-
tate ligand, with an ca. 0.5 nm bridging distance with
minimal steric interference from the anthracene ring.14,15
This distance between these positions is very close to the
distance between the two pyrimidine units in cis,syn-CPD
(∼0.51 nm). An entropically favorable, rigid preorienta-
tion can be achieved by using ethynyl linker units to
position the DAD recognition unit. The anthracene-triple
bond assembly has been previously used for the rigid
positioning of receptor units.6,11 It was then envisioned
that the previously described anthracene spacer can be
modified to provide the desired function, i.e., the ability
to serve as an electron-transfer catalyst in the excited
state. This can be achieved by oxidation to the an-
thraquinone, which was shown to be efficient in inducing
cycloreversion of CPD, using an oxidative, photoinduced
electron transfer.16,17 The overall design concept is sum-
marized in Scheme 1.
The 1,8-diethynylanthracene moiety was prepared in
five steps from 1,8-anthraquinonedisulfonicacid potas-
sium salt according to a modified literature procedure.15
After reduction of the 1,8-anthraquinone disulfonicacid
potassium salt with zinc dust,22 the new anthracene
compound is melted with KOH pellets under an argon
atmosphere to lead to the formation 1,8-dihydroxyan-
thracene 9.23 Activation of the two hydroxyl substituents
by reaction with triflate anhydride gave the correspond-
ing triflate derivatives that were suitable for Sonogashira
(9) (a) Hirst, S. C.; Hamilton, A. D. Tetrahedron Lett. 1990, 31,
2401-2404. (b) Hamilton, A. D.; Little, D. J . Chem. Soc., Chem.
Commun. 1990, 297-300. (c) Hamilton, D. A.; VanEngen, D. J . Am.
Chem. Soc. 1987, 109, 5035-5036.
(10) (a) Goodman, M. S.; Rose, S. D. J . Org. Chem. 1992, 57, 3268-
3270. (b) Van Camp, J . R.; Young, T.; Hartman, R. F.; Rose, S. D.
Photochem. Photobiol. 1987, 45, 365-370. (c) Kim, S. T.; Young, T.;
Goodman, M. S.; Forrest, C.; Hartman, R. F.; Rose, S. D. Trends
Photochem. Photobiol. 1990, 1, 81-87.
(11) Takase, M.; Inouye, M. J . Org. Chem. 2003, 68, 1134-1137.
(12) Inouye, M.; Takase, M. Angew. Chem., Int. Ed. 2001, 40, 1746-
1748.
(17) Sasson, S.; Elad, D. J . Org. Chem. 1972, 37, 3164-3167.
(18) Pryor, K. E.; Shipps, G. W.; Skyler, D. A.; Rebek, J ., J r.
Tetrahedron 1998, 54, 4107-4124.
(19) Nettekoven, M. Synlett 2001, 12, 1917-1919.
(20) Nettekoven, M.; J enny, C. Org. Proc. Res. Dev. 2003, 7, 38-
43.
(13) Inouye, M.; Hyodo, Y.; Nakazumi, H. J . Org. Chem. 1999, 64,
2704-2710.
(14) Murty, K. V. S. N.; Vasella, A. Helv. Chim. Acta 2001, 84, 939-
(21) Yao, Y.; Lamba, J . J . S.; Tour, J . M. J . Am. Chem. Soc. 1998,
120, 2805-2810.
963.
(15) Katz, H. E. J . Org. Chem. 1989, 54, 2179-2183.
(16) Pouwels, P. J . W.; Hartman, R. F.; Rose, S. D.; Kaptein, R.
Photochem. Photobiol. 1995, 61, 563-574.
(22) Vo¨gtle, F.; Koch, H.; Rissanen, K. Chem. Ber. 1992, 125, 2129-
35.
(23) Lampe, B. Chem. Ber. 1909, 42, 1413-1418.
544 J . Org. Chem., Vol. 69, No. 2, 2004

Toward an Artificial Oxidative DNA Photolyase
SCHEME 2
SCHEME 3
SCHEME 4
coupling with trimethylsilylethyne in the presence of
PdCl2(PPh3)2, CuI, and Et3N, yielding the 1,8-bis-tri-
methylsylilethynylanthracene building block 10.14 The
two TMS protective groups were removed under basic
condition to give the desired 1,8-diethynylanthracene 11
(Scheme 3).
ties of zinc (in contrast to the Sonogashira protocol, which
proceeds by catalytic in situ metalation), this modification
gave us the desired compounds 12 and 13 with excellent
yields in a case where the classical Sonogashira reaction
failed.
Final oxidation of the anthracene derivatives 12 and
13 with chromium oxide in aqueous acetic acid yielded
the two desired models 14 and 1527 with 48-64% yield
depending on the protective group (Scheme 4). The
surprisingly large difference between the two yields is
due to the poor solubility of 12.
The key step of the convergent synthesis of the
designed model is a modification of a Sonogashira
coupling, using a zinc acetylide prepared in situ, which
yields compounds 12 and 13 in 90-96% yield. Although
reaction of the 1,8-diethynylanthraquinone should di-
rectly yield the desired product, a direct coupling of 2,6-
diaminopyridine 6 and 1,8-diethynylanthaquinone was
not successful due to copper-catalyzed self-coupling of the
acceptor-substituted acetylenes. Similarly, coupling of the
anthracene-1,8-bistriflate with 2,6-bis(acetamino)-4-eth-
ynylpyridine was not successful. Although the self-
coupling of acetylenes under copper or palladium cataly-
sis is of course well documented,24 evidence of this
reaction as a side reaction of Shonogashira couplings of
acceptor substituted alkynes appears to be mostly anec-
dotal. Several examples of palladium-coupling reactions
with zinc acetylides have been published recently.25,26
Although this modification needs stoichiometric quanti-
X-r a y Str u ctu r e During our synthetic studies, we
noted the extremely poor solubility of 12, which could be
rationalized by strong intermolecular interactions medi-
ated by either hydrogen bonding in the DAD recognition
unit or π-stacking of the electron-rich anthracene and the
electron-poor pyridine moieties. Although the poor solu-
bility of 12 prevented the growth of suitable crystals, gas
diffusion of diethyl ether into a DMF solution of 14
yielded single crystals that revealed the highly unusual
structure of 14, cocrystallized with one molecule of
solvent (DMF). Three views of the structure of 14 are
shown in Figure 1.
(25) Crisp, G. T.; Turner, P. D.; Stephens, K. A. J . Organomet. Chem.
1998, 570, 219-224.
(26) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979-2017.
(27) Inbasekaran, M.; Witiak, D. T. J . Med. Chem. 1980, 23, 278-
281.
(24) For recent publications, compare e.g.: (a) Liao, Y.; Fathi, R.;
Yang, Z. Org. Lett. 2003, 5, 909-912. (b) Russell, J . M.; Sabat, M.;
Grimes, R. N. Organometallics 2002, 21, 4113-4128. (c) Zhao, Y.;
McDonald, R.; Tykwinski, R. R. J . Org. Chem. 2002, 67, 2805-2812.
J . Org. Chem, Vol. 69, No. 2, 2004 545

Pauvert et al.
F IGURE 1. Three views of the crystal structure of 14: (left) repeating unit of two molecules; (middle) view down the c axis
showing unit cell and two infinite bands; and (right) view down the b axis.
The crystal structure indeed confirms an intercalation
of the electron-rich benzene portion of anthraquinone into
the cleft formed by the two pyridines, as shown on the
left in Figure 1. To allow for this intercalation, the two
triple bonds have to be distorted from linearity by 14°.
It can be expected that the π-stacking interaction would
be even stronger in 12, which is consistent with the lower
solubility of 12 compared to 14.28 Additionally, there is
one hydrogen bond with an O-H distance of 1.97 Å
between the carbonyl carbon of an acetamide of one
molecule to the N-H of the next molecule. Because of
the shape and functionality of 14, the intercalation and
the hydrogen bonding lead to the formation of the infinite
1D-band in the solid that most likely is responsible for
the poor solubility of 12 and 14. This strong, noncovalent
interaction between repeating, self-complementary mono-
mers can be considered a new example of a supra-
molecular polymerization.29
The pyridine rings in 14 are not exactly parallel to each
other, but are at angles of 48° and 68° relative to the
anthraquinone moiety. The two molecules of the repeat-
ing until are therefore rotated against each other by
∼65°. The shape of each of the infinite bands is that of a
parallelogram, as can be seen in the middle of Figure 1.
Adjacent bands are connected in the a and b directions
by one CdO-HN hydrogen bond per unit, enforcing a
parallel orientation of the bands, as shown in Figure 1
on the right. In light of the high dipole moment of 14 of
8.65 D,30 the parallel arrangement of the adjacent
directional bands is unusual and leads to a highly polar,
noncentrosymmetric crystal. Materials with such proper-
ties are of considerable interest because of their potential
as piezoelectrics or second-order harmonic generators in
nonlinear optics.31 Although the formation of noncen-
trosymmetric material based on 1D-networks is more
commonly achieved by using metalorganic coordination
compounds,32 the use of purely organic materials may
lead to improved properties such as high optical nonlin-
earity, fast response times, and the possibility of rational
modification of the physical properties through targeted
synthesis of derivatives.33 The combination of π-stacking
interaction, shape self-complementarity, and hydrogen
bonding34 in the crystal structure of 14 is to the best of
our knowledge a new and promising, albeit unexpected,
motif for the design of polar, noncentrosymmetric organic
crystals based on 1D-networks. Given the relatively
efficient synthesis, future studies will investigate the
optical properties on these interesting compounds.
Bin d in g Affin ity The interactions of the receptor 14
or 15 with the cis,syn-1 were investigated by 1H NMR in
different solvents.35 Titration of the receptor with the
cis,syn-1 led to the formation of hydrogen-bonded com-
plexes that resulted in several characteristic changes in
1
the H NMR spectrum: the signals for the NH protons
of both receptor 14 and 15 and cis,syn-1 are shifted
downfield, thus allowing the measurement of the binding
affinity of these systems. When 14 (4.3 mM) is treated
with cis,syn-1 (4.3 mM) in 10/90 DMSO-d6/ CDCl3, the
NH protons on both compounds were shifted downfield
by 0.12 and 0.34 ppm, respectively. In pure DMSO-d6,
no complex was observed. When 15 (1.4 mM) is treated
with cis,syn-1 (1.4 mM) in CD2Cl2/acetone-d6 50/50, the
NH protons were shifted downfield by 0.11 and 0.44 ppm,
respectively. In pure acetone-d6, shifts are significantly
smaller (<0.01 and 0.04 ppm, respectively). Figure 2
shows the plot of the chemical shift of the NH of model
(32) (a) J ouaiti, A.; Hosseini, M. W.; Kyritsakas, N. Chem. Commun.
2002, 1898-1899. For an example of a purely organic material,
compare: (b) Martz, J .; Graf, E.; Hosseini, M. W.; DeCian, A.; Fischer,
J . J . Chem. Soc., Dalton Trans. 2000, 3791-3795.
(33) (a) Marder, S. R.; Sohn, J . E.; Stucky, G. D. Materials for
Nonlinear Optics; ACS Symp. Ser. 445; American Chemical Society:
Washington, DC, 1991. (b) Nonlinear Optical Properties of Organic
Molecules and Crystals; Chemla, D. S., Zyss, J ., Eds.; Academic
Press: New York, 1987; Vols. 1 and 2.
(34) For examples of two-component complexes with hydrogen
bonding in aromatic compounds, compare also: Muthuraman, M.;
Masse, R.; Nicoud, J .-F.; Desiraju, G. R. Chem. Mater. 2001, 13, 1473-
1479.
(28) This is also in agreement with our observation that addition of
veratrole to a solution of 12 in hot DMF inhibits the normally observed
crystallization upon cooling.
(29) Wu¨rthner, F.; Yao, S.; Beginn, U. Angew. Chem., Intl. Ed. 2003,
42, 3247-3250. (b) Ishada, Y.; Aida, T. J . Am. Chem. Soc. 2002, 124,
14017-14019.
(30) Calculated at the B3LYP/6-31G* level of theory, using the
coordinates from the X-ray structure
(31) E.g.: (a) Curtin, D. Y.; Paul, I. C. Chem. Rev. 1981, 81, 525-
541. (b) Evan, O. R.; Lin, W. Acc. Chem. Res. 2002, 35, 511-522.
(35) Foster, R.; Fyfe, C. A. Prog. Nucl. Magn. Reson. Spectrosc. 1969,
4, 1-89.
546 J . Org. Chem., Vol. 69, No. 2, 2004

Toward an Artificial Oxidative DNA Photolyase
F IGURE 3. Plot of 1/∆ (ppm-1) against 1/[D]0 (M-1) from
equation 1/∆ ) 1/KAD × 1/∆0 × 1/[D]0 + 1/∆0 in conditions of
in the system (15/cis,syn-1) in a mixture of CD2Cl2/acetone-
d6 (50/50) at 25 °C.
F IGURE 2. Plot of 1H chemical shift of NH model 15 against
total equivalent of dimers cis,syn-1 and trans,syn-1 in solution
of CD2Cl2/acetone-d6 (50/50) at 25 °C.
Con clu sion s a n d Ou tlook
15 (1.4 mM) as a function of the amount of dimer cis,syn-1
in solution in a mixture of CDCl2/acetone-d6 (50/50) at
25 °C. We observed a significant characteristic chemical
shift reflecting the formation of a multipoint hydrogen-
bonded complex. The association constant was estimated
to be 1.0 × 103 M-1 for this system (15/cis,syn 1).36
In summary, two new receptors 14 and 15 for the
selective binding of cis,syn cyclobutane pyrimidine dimers
(CPD, cis,syn-1) in organic solvents were synthesized.
The modified Sonogashira coupling, using zinc acetylides
in the key step of a convergent synthesis, provides a
useful alternative to the traditional methods for the case
of acceptor-substituted acetylenes. The final compound
14 was shown to have a fascinating, if unexpected, three-
dimensional structure where 1D-polymers are formed
through supramolecular interactions and are oriented by
interstrand hydrogen bonding in a parallel fashion to
form a noncentrosymmteric material of a highly polar
material. This could have potential implications for
piezoelectric or NLO materials. The binding constant of
cis,syn-1 to 15 in CD2Cl2/acetone-d6 was estimated as
To probe for the selectivity of the molecular recognition,
we also studied the binding of the isomer trans,syn-1
using the same methodology. Due to the lower solubility
of this isomer, only a 9-fold excess of the dimer could be
used. However, it is clear from the data shown in Figure
2 that binding of trans,syn-1 is significantly weaker than
that for cis,syn-1. Although no quantitatively accurate
determination of the binding constant can be performed
with the small number of datapoints in a limited con-
centration range, the difference of binding constants can
be estimated to be approximately one order of magnitude
smaller than that for cis,syn-1.
1000 M-1
.
Current studies investigate the use of the functional
spacer unit as a sensitizer for photoinduced oxidative
electron transfer, leading to the cycloreversion of CPD.
If successful, the systems described would be the first
artificial photolyase using an oxidative pathway. This will
require the study of different solvent systems to balance
the solubility of the functional receptors, the lower
binding constants in hydrogen bond acceptor solvents,
and the solvent-dependent driving force for electron
transfer and might make further fine-tuning and devel-
opment of the receptors necessary. These studies are
currently in progress and will be reported in due course.
The same binding constant estimate was made in pure
acetone-d6 with the complex (15/cis,syn-1) but the as-
sociation constant obtained was too small to be consid-
ered further. Those results are in accordance with the
presence of a solvent competing for binding at both 15
and cis,syn-1.37 Hydrogen bond acceptor solvents such as
DMF and DMSO dramatically decrease the association
constant. The same effect is observed here for the case
of acetone, a competitive hydrogen bond acceptor that is
necessary in our case to enhance solubility. The use of
cosolvent as CD2Cl2 or more commonly CDCl3 decreases
the competitive character of the solvent, and using higher
CD2Cl2 percentage should dramatically increase the
binding affinity to the association constant. In agreement
with previous findings, determination of the binding
constant was not possible for the system (14/cis,syn-1)
in CDCl3/DMSO-d6 (90/10) due to the very low solubility
of the dimer cis,syn-1 in this mixture of solvent.
Exp er im en ta l Section
Meth od s for Estim a tion of th e Associa tion Con sta n t.
The association constant were estimated from a plot of 1/∆
against 1/[D]0 from the equation 1/∆ ) 1/KAD ×1/∆0 × 1/[D]0
+ 1/∆0 under the condition of [D]0 . [A]0 according Foster and
Fyfe35 {[D]0 ) concentration of the donor (dimer 1); [A]0
)
concentration of the acceptor (models 14, 15); KAD ) association
constant; ∆ ) chemical shift of NHacceptor-donor - chemical shift
of NHacceptor alone; ∆0 ) chemical shift for the pure complex (not
measurable)}. The form of this equation is analogous to the
Benesi-Hildebrand equation,39 which has frequently been
used in the determination of association constants from the
analysis of optical data. The plot of 1/∆ against 1/[D]0 from
(36) The equation used to this estimation needs extrapolation to a
solution of high concentration. This is why this equation was used
because of the saturation of donor solubility observed after 25 equiv
of donor was added during the collection of data. But according to
Foster and Fyfe35 if we consider an extrapolation to infinitely dilute
solution, the new equation is ∆/[D]0 ) -KAD∆ + ∆0KAD and the plot of
∆ against ∆/[D]0 gave good linearity and the association constant was
estimated to be 4.3 × 103 M-1
.
(38) Carell, T.; Epple, R.; Gramlich, V. Helv. Chim. Acta 1997, 80,
(37) Kondo, S.; Utsumi, K.; Yano, Y. Internet J . Sci.: Biol. Chem.
[Electronic Publication] 1997, 1, http://www.netsci-journal.com/97v1/
97012/index.htm.
2191-2203.
(39) Benesi, H. A.; Hildebrand, J . H. J . Am. Chem. Soc. 1949, 71,
2703-2707.
J . Org. Chem, Vol. 69, No. 2, 2004 547

Pauvert et al.
the previous equation in the range of 14 to 25 equiv of dimer
cis,syn-1 for the system 15/cis,syn-1 (i.e. under conditions
where [D]0 . [A]0) gave good linearity as shown in Figure 3
and the association constant was estimated to be 1.0 × 103
to O.W. as well as helpful discussions with Prof. R. E.
Taylor of our department.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the synthesis and spectral characterization of some
new compounds as well as X-ray data for 14 in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
M-1
.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support of this work by the National Institutes
of Health (Grant CA073775) and the Dreyfus Founda-
tion through a Camille Dreyfus Teacher-Scholar Award
J O0354600
548 J . Org. Chem., Vol. 69, No. 2, 2004