Probing molecular recognition in the solid-state by use of an enolizable chromophoric barbituric acid

Article abstract of DOI:10.1021/jo800598z

(Chemical Equation Presented) Complex formation of the enolizable chromophor 1-n-butyl-5-(4-nitrophenyl)barbituric acid 1 with multiple binding sites for supramolecular assemblies and its corresponding adducts produced with the Proton Sponge (1,8-bis(dime

Full text of DOI:10.1021/jo800598z

Probing Molecular Recognition in the Solid-State by Use of an
Enolizable Chromophoric Barbituric Acid
Ina Bolz,† Chulsoon Moon,‡ Volker Enkelmann,‡ Gunther Brunklaus,‡ and Stefan Spange*,†
Institut fu¨r Chemie, Technische UniVersita¨t Chemnitz, D-09107 Chemnitz, Germany, and
Max-Planck-Institut fu¨r Polymerforschung, Postfach 3148, D-55021 Mainz, Germany
stefan.spange@chemie.tu-chemnitz.de; brunklaus@mpip-mainz.mpg.de
ReceiVed July 19, 2007
Complex formation of the enolizable chromophor 1-n-butyl-5-(4-nitrophenyl)barbituric acid 1 with multiple
binding sites for supramolecular assemblies and its corresponding adducts produced with the Proton
Sponge (1,8-bis(dimethylamino)naphthalene), PS) and the adenine-mimetic 2,6-diacetamidopyridine (DAC)
have been studied by means of solid-state proton NMR spectroscopy under fast magic-angle spinning,
X-ray analysis, and UV/vis spectroscopy. Both NMR data and X-ray results reveal that the enolic
chromophor undergoes self-aggregation to hydrogen-bonded dimers which are involved in stacked
arrangements. Depending on the nature of the added base, this dimeric assembly is preserved in the
formed enolate anion but can be broken in the presence of complementary hydrogen-bonding pattern
leading to supramolecular complexes. Molecular recognition of these structural different bases significantly
influences the chromophoric π-system of 1.
I. Introduction
affinities at binding adenine or its derivatives, thereby yielding
strongly hydrogen-bonded complexes.4 However, the observed
biological activity of barbiturates is mainly attributed to
tautomerism, acid-base equilibriums, and to the nature of their
substituents.5 Recently, it has been shown that related Mero-
cyanine dyes create new self-assembled structures6 or are
effective sensitizers with interesting photophysical properties.7
More importantly, such dyes exhibit hydrogen-bonding patterns
with an ADA sequence (A ) hydrogen bond acceptor site,
Artificial chromophoric receptors for biologically active
molecules have attracted considerable attention from the view-
point of molecular recognition.1,2 In particular, interactions
mediated by hydrogen-bonding play an important role in both
chemical and biological systems.3 Barbiturates are important
members of the pyrimidine family and show very selective
† Institut fu¨r Chemie, Technische Universita¨t Chemnitz.
‡ Max-Planck-Institut fu¨r Polymerforschung. To whom correspondence
pertaining to NMR and X-ray structure analyses should be addressed.
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10.1021/jo800598z CCC: $40.75
Published on Web 06/10/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4783–4793 4783

Bolz et al.
SCHEME 1. Keto-Enol Tautomerism of 1 Producing
Hydrogen-Bonding Patterns (A ) Hydrogen Bond Acceptor
Site, D ) Hydrogen Bond Donor Site)a
externally induced formation of the enol1 or enol2 form should
cause a significant bathochromic shift in the UV/vis spectrum.
In contrast to the established Merocyanine dyes, the enolizable
barbituric acid serves as a (+M)-substituent which is of
importance for the construction of chromophoric probes relating
to this type of compounds that are still not established for
probing molecular recognition. However, the possible occur-
rence of both tautomeric forms as well as molecular adducts
complicates a clear assignment of observed UV/vis absorption
spectra to a well-defined molecular structure.
Therefore, we have investigated the solid-state structures of
the corresponding assemblies of 1 with the Proton Sponge PS
and the adenine-mimetic base 2,6-diacetamidopyridine DAC to
identify whether mere salt formation occurs or rather genuine
supramolecular complexes are built. The balance between them
is dependent on both the presence of a suitable hydrogen-
bonding pattern of the base and its basicity strength,10 e.g., an
association of nucleobases with synthetic ligands like DAC
mediated by hydrogen bonds has been a longstanding focus of
supramolecular chemistry.11 Proton-transfer reactions of Brøn-
sted acids in the presence of PS have been widely studied.12
The synergism of the two effects and its influence on the
complex (or salt) structures of 1 with different bases is a further
objective of this work. Since various molecular structures can
contribute to the UV/vis response caused by the molecular
recognition, a thorough investigation of the solid-state structures
is required to demonstrate the versatile bonding potential of this
new type of compound toward those structurally different bases.
In order to derive the structure of the various compounds,
we employed both single-crystal X-ray analysis and advanced
solid-state NMR spectroscopy, which in recent years has shown
to be a versatile and powerful tool for the characterization of
materials.13,14 In particular, information about hydrogen-bonding
a Two different enol forms with either vicinal or opposed OH and NH
protons are possible.
D ) hydrogen bond donor site) suitable for selective binding
to bases offering a complementary DAD pattern. Merocyanine
dyes which contain the barbituric acid moiety as an electron-
withdrawing group are well established in the literature.6–8 Due
to the barbituric acid moiety being negatively polarized in
merocyanine-type dyes their UV/vis absorption band is affected
by acids rather than by proton acceptors, which makes them
unsuitable for the recognition of bases with ADA pattern or
related molecules.8
Therefore, in our conceptual development the barbituric acid
moiety should be an electron-donating substituent and has to
be linked to chromophores which bear electron-withdrawing
substituents. These requirements are accomplished, if the
barbituric acid is directly linked at the C5-position to a
chromophoric system under retention of an acid proton suitable
to undergo keto-enol equilibriums. However, these structurally
simple barbiturates are still not established in the literature which
is assigned to the nontrivial structure determination.9 The
occurrence of the tautomeric forms offers two different hydrogen-
bonding patterns ADA and DDA, respectively. Furthermore,
aggregate formation complicates a clear structure assignment
of those dyes even in the pure form. Therefore, the detailed
knowledge of the structural versatility of enolizable barbituric
acid dyes is very important in order to construct novel types of
UV/vis probes for molecular recognition.
In this paper, we report on the synthesis and solid-state
structure of the enolizable chromophor 1-n-butyl-5-(4-nitrophe-
nyl)barbituric acid 1 that features adjustable hydrogen-bonding
properties. The prototropic tautomerism of this dye facilitates
an adjustment to complementary bases containing a DDA or
ADA sequences (Scheme 1).
The switching between the two principle tautomeric forms
of 1 (keto1/keto2 or enol1/enol2, cf. Scheme 1) is associated
with dramatic changes in the extent of π-conjugation. The enol
substituent contributes to a push-pull system due to the para
conjugation with the nitro group, while the keto substituent
belongs to a common nitro-substituted aromatic system. Thus,
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4784 J. Org. Chem. Vol. 73, No. 13, 2008

Molecular Recognition in the Solid-State
FIGURE 1. Molecular structure of dimeric 1 and projection along the b-axis showing the packing of the barbiturate molecules and acetone. Note
that the orientation of the OH-protons is fixed due to hydrogen-bonding to a carbonyl group of a symmetry-produced neighboring 1 molecule.
1
in solids could be obtained by 1D (single-quantum, SQ) H
magic-angle spinning (MAS) NMR and 2D homonuclear dipolar
double-quantum (DQ) techniques.13a,e,15 In such a two-
dimensional experiment, double-quantum coherences due to
pairs of dipolar coupled protons are correlated with single-
quantum coherences resulting in characteristic correlation peaks.
Double-quantum coherences between like spins appear as a
single correlation peak on the diagonal while a pair of cross
peaks that are symmetrically arranged on either side of the
diagonal reflect couplings among unlike spins. In addition, we
exploit the fact that observable DQ signal intensities are
proportional to Dij2 or rij-6, respectively (Dij is the homonuclear
dipolar coupling constant, rij the internuclear distance). Strong
signal intensities in the corresponding double-quantum spectrum
therefore reveal protons in rather close spatial proximity (e.g.,
distances up to 3.5 Å). Protons involved in hydrogen-bonded
1
structures typically exhibit well-resolved H chemical shifts,
mainly between 8 and 20 ppm, thereby providing valuable
1
structural information. Since in solid compounds H chemical
shifts are also affected by subtle packing arrangements, e.g.,
stacking of aromatic moieties,16 the interpretation of experi-
mental data may be facilitated by comparison with density
functional theory (DFT)17 based ab initio chemical shift
calculations. Furthermore, the molecular assemblies of 1 with
PS and DAC were studied by means of differential scanning
calorimetry (DSC) and UV/vis spectroscopy.
FIGURE 2. 1H MAS NMR (top) and 13C CP MAS NMR spectrum of
1 (bottom). The tiny peak at 55 ppm indicates a minor impurity of
keto-type structure of 1. The broadening of the peak at 30 ppm is due
to overlapping signals (methyl groups of acetone and alkyl chains of
1).
II. Results and Discussion
Solid-State NMR Results, Quantum Chemical
Calculations, and X-ray Analyses. Crystallographic Data
of the Barbiturate 1. After recrystallization from acetone tiny
single-crystals of 1 suitable for X-ray analysis were obtained.
It was found that 1 crystallizes in a monoclinic lattice, space
group P21/c (No. 14), with the lattice parameters a ) 11.3856(5)
Å, b ) 7.8718(4) Å, and c ) 19.8518(6) Å. The asymmetric
unit consists of two molecules: one molecule 1 and one acetone
molecule. Two molecules of 1 are linked together by symmetric
and strong hydrogen bonds between the respective CdO and
NH groups of the barbituric acid moieties yielding a centrosym-
metric dimer rather typically found for barbiturates18 (Figure
1).
Solid-State NMR Spectra of 1. An inspection of the 13C
CP MAS NMR spectrum of 1 lacks evidence for the presence
of a methine carbon (expected at about 55 ppm) suggesting an
enol-type structure for 1 (Figure 2). This finding is reminiscent
of a previous study on Schiff bases derived from 5-aminobar-
(16) (a) Wasserfallen, D.; Fischbach, I.; Chebotavera, N.; Kastler, M.; Pisula,
W.; Ja¨ckel, F.; Watson, M. D.; Schnell, I.; Rabe, J. P.; Spiess, H. W.; Mu¨llen,
K. AdV. Funct. Mater. 2005, 15, 1585–1594. (b) Brown, S. P.; Schnell, I.; Brand,
J. D.; Mu¨llen, K.; Spiess, H. W. Phys. Chem. Chem. Phys. 2000, 2, 1735–1745.
(17) Parr, R. G., Yang, W. Density Functional Theory of Atoms and
Molecules; Oxford University Press: Oxford, 1989.
(18) Allen, F. H. Acta Crystallogr. 2002, B58, 380–388.
J. Org. Chem. Vol. 73, No. 13, 2008 4785

Bolz et al.
FIGURE 3. 1H-1H DQ MAS NMR spectrum of 1 at 850 MHz and 59524 Hz MAS, acquired under the following experimental conditions: τ(exc.)
) 33.6 µs, 256 t1 increments at steps of 16.8 µs, relaxation delay 5 s, 32 transients per increment. Sixteen positive contour levels between 4% and
62% of the maximum peak intensity were plotted. The F2 projection is shown on the top.
TABLE 1. Influence of the Chemical Environment on the
Chemical Shifts δ in ppm of 1 and Its Molecular Assemblies with
the Proton Sponge PS and 2,6-Diacetamidopyridine DAC, and
polymorphism, the ability of a compound to crystallize in more
than one crystal structure,19 phase transitions, and molecular
reorientation of alkyl chains,20 are known within the barbiturate
family and thus may complicate the structure refinement.
The 1H MAS NMR spectrum of 1 reveals one high-frequency
shifted proton peak at 11.1 ppm, reflecting that the respective
protons (NH and OH) are indeed involved in hydrogen-bonding.
In order to allow for an assignment of the hydrogen-bonded
a
1
Combination thereof Observed by H MAS NMR Spectroscopy
1
1+DAC
1+PS
1+PS+DAC
barbiturate 1
enol-NH
11.1 (10.2) 11.2 (12.5)
enol-OH
11.1 (4.3)
12.3 (5.3)
enolate-NH
DAC-NH
10.6 (10.5)
18.0 (19.2)
10.2 (11.4)
11.8, 9.9
(12.6, 10.9)
1
protons, we acquired a H-1H DQ MAS NMR spectrum of 1
10.7, 9.7
(11.0, 10.3)
at a rather short dipolar recoupling time (2τR ) 33.6 µs, Figure
3). According to the crystal structure, the distance of the two
NH-protons within the dimer amounts to d ) 2.5283 Å (Dij )
7.43 kHz), while the OH-proton has longer distances to aromatic
protons (d ) 2.9154 Å, Dij ) 4.85 kHz) as well as to methyl
protons of acetone (d ) 2.9657 Å, Dij ) 4.61 kHz). In contrast,
the NH-protons have larger distances to both aromatic (d )
3.3829 Å, Dij ) 3.1 kHz) and aliphatic protons (d ) 3.5561 Å,
Dij ) 2.67 kHz). Since the dipolar couplings among the protons
are very sensitive with respect to the distance (cf. static dipolar
couplings Dij given in parentheses), this should be reflected by
the observed DQ signal intensities. The presence of a strong
DQ peak at 22.2 ppm (11.1 ppm + 11.1 ppm) suggests that it
originates from NH-protons that are involved in dimer formation.
This is also supported by the rather weak cross peak at 19.3
ppm (11.1 ppm + 8.2 ppm) reflecting the contact of the NH-
protons with aromatic protons. However, the fairly strong DQ
cross peaks at 18.3 ppm (11.1 ppm + 7.2 ppm (aromatic)) and
12.3 ppm (11.1 + 1.2 ppm (aliphatic)) indicate that the proton
peak at 11.1 ppm also contains the OH-protons. All observed
DQ peaks (and their respective signal intensities) are in
qualitative agreement with expectations from the given crystal
structure. Nevertheless, the spectral data does not reveal a clear
preference of enol1- vs enol2-type structure in the solid
compound 1. In that respect, we have to refer to the crystal
structure, which contains enol1-type molecules of 1. In cases
PS-NH+
19.3 (19.2)
a
1
Computed ab initio H chemical shifts are given in parentheses.
bituric acid, where the enol form appeared to be more stable
than the keto form.9b Notably, the ordering of the alkyl chains
strongly depends on the (re)crystallization conditions (e.g.,
crystallization rate, polarity of the solvent used). While slow
crystallization from diethyl ether and subsequent recrystallization
from dichloromethane yields substantially disordered alkyl
chains (e.g., revealed as noticeable splitting of the aliphatic 13
signals, see the Supporting Information), crystallization from
acetone produces highly ordered alkyl chains (cf. crystal
structure, Figure 1).
Since in solution a rapid equilibration between both the keto
and enol forms of the enolizable barbiturate 1 occurs, it is
important to distinguish the two possible enol structures in the
solid-state (cf. Scheme 1). In that context, the influence of the
respective morphology (single crystal vs polycrystalline powder)
on the crystallochromic properties of 1 is addressed. A wide
range of crystallographically different properties, such as
C
(19) (a) Cleverley, B.; Williams, P. P. Tetrahedron 1959, 7, 277–288. (b)
Craven, B. M.; Vizzini, E. A. Acta Crystallogr. 1969, B25, 1993–2009. (c)
Craven, B. M.; Vizzini, E. A. Acta Crystallogr. 1971, B27, 1917–1924. (d) Caillet,
J.; Claverie, P. Acta Crystallogr. 1980, B36, 2642–2645. (e) Craven, B. M.;
Fox, R. O., Jr.; Weber, H.-P. Acta Crystallogr. 1982, B38, 1942–1952. (f) Lewis,
T. C.; Tocher, D. A.; Price, S. L. Cryst. Growth Des. 2004, 4, 979–987. (g)
Lewis, T. C.; Tocher, D. A.; Price, S. L. Cryst. Growth Des. 2005, 5, 983–993.
(20) (a) Nichol, G. S.; Clegg, W. Acta Crystallogr. 2005, B61, 464–472. (b)
Nichol, G. S.; Clegg, W. Acta Crystallogr. 2005, C61, o297–o299.
4786 J. Org. Chem. Vol. 73, No. 13, 2008

Molecular Recognition in the Solid-State
FIGURE 4. 1H-1H DQ MAS NMR spectrum of 1+PS at 700 MHz and 29762 Hz MAS, acquired under the following experimental conditions:
τ(exc.) ) 33.6 µs, 128 t1 increments at steps of 33.6 µs, relaxation delay 5 s, 16 transients per increment. Sixteen positive contour levels between 4%
and 63% of the maximum peak intensity were plotted. The F2 projection is shown on the top. The strong (NH/NH) correlation peak at 21.2 ppm
(10.6 ppm + 10.6 ppm) indicates the persistence of the dimeric structure of the enolate anion of 1 reflecting the stability of this arrangement.
where the experimentally observed 1H MAS NMR line shapes
are solely broadened by strong homonuclear dipolar couplings
among abundant protons, high-resolution 1H MAS spectra can
in principle be obtained using so-called homonuclear dipolar
decoupling sequences like windowed phase-modulated
Lee-Goldburg (wPMLG)21,21b or windowed DUMBO-121c that
also constitute the key part of high-resolution DQ spectra (DQ-
CRAMPS15f). However, this approach requires a rather high
degree of local order or crystallinity which is quite difficult to
achieve for a bulk NMR sample of 1.
together, the DQ spectrum of 1+PS is consistent with a dimeric
arrangement of the enolate anion of 1. This behavior is quite
expected since PS does not possess a molecular recognition
sequence suitable for selective binding to an ADA sequence
offered by the enolate anion. A similar packing arrangement is
reported for the complex of barbituric acid with PS whereas
PS cations are orientated in separate π-π stacks.22 However,
the change in 1H chemical shift of the NH-proton of ∆δ ) -0.5
ppm suggests a slight stretching of the NH---OdC hydrogen
bond within the enolate dimer.23
Acid-Base Behavior of 1. To evaluate the stability of the
dimeric unit in 1 with respect to bases, we treated the barbiturate
1 with the so-called Proton Sponge (1,8-bis(dimethylamino)-
naphthalene, PS). Proton sponges show both high thermody-
namic basicity and slow intermolecular proton transfer kinetics12a–c
and thus facilitate complete deprotonation of 1. Indeed, the 1H
MAS NMR spectrum of 1+PS exhibits a high-frequency shifted
resonance at 18.0 ppm that we attributed to a chelated proton12a
resulting from acid-base reaction of PS and the more acidic
OH-proton of 1, while the NH-proton resonates at 10.6 ppm.
This assignment is backed up by ab initio DFT chemical shift
calculations, where the chemical shifts of both the chelated
proton and the NH-proton of the enolate anion are computed
at 19.2 and 10.5 ppm, respectively (cf. Table 1). Notably, the
Hydrogen-Bonding Ability. The complex formation of the
barbiturate 1 and its enolate anion in 1+PS is investigated with
the adenine-mimetic base 2,6-diacetamidopyridine DAC offering
a complementary hydrogen-bonding pattern to the keto1/keto2
and enol2 structure(s) of 1 as well as to the enolate anion. It is
anticipated that the dimer of 1 or its enolate anion will be broken
while forming a hydrogen-bonded complex of 1+DAC or
1+PS+DAC. In particular, we are interested in the expected
reorientation of the self-aggregated enol1-type 1 to a comple-
mentary ADA sequence.
The 1H MAS NMR spectrum of the complex 1+DAC
(recrystallized from acetone) is rather complicated and exhibits
exchangeable proton sites at 16.8, 16.5, 12.3, 11.2, 10.7, and
9.7 ppm, respectively. It is noteworthy to mention that the two
NH-protons in pure DAC resonate at 9.4 ppm and 10.7 ppm
(see the Supporting Information). To elucidate the complex
structure and to facilitate an assignment of the various peaks,
1
corresponding H-1H DQ MAS NMR spectrum (Figure 4) of
1+PS not only shows a strong DQ cross peak at 21.0 ppm (18.0
ppm + 3.0 ppm) between the chelated proton and the methyl
protons of the Proton Sponge but also a strong DQ correlation
peak among the NH-protons at 21.2 ppm (10.6 ppm + 10.6
ppm). Based on this, the deprotonation of 1 appears rather
complete. The aromatic and aliphatic proton signals of both the
Proton Sponge and 1 strongly overlap and, hence, yield no
further insight into the dipolar coupled proton network. Taken
1
we acquired a H-1H DQ MAS NMR spectrum. Notably, we
found no so-called auto-correlation peaks (diagonal peaks)
among the exchangeable protons, suggesting that the former
dimer of the barbiturate 1 is broken. Rather, a new complex
1+DAC was formed revealing itself via characteristic cross
peaks (Figure 5). Assuming that the resonance at 11.2 ppm can
be assigned to the NH-proton of 1, the cross peaks at 21.9 ppm
(21) (a) Leskes, M.; Madhu, P. K.; Vega, S. J. Chem. Phys. 2008, 128,
052309/1–052309/11. (b) Leskes, M.; Madhu, P. K.; Vega, S. J. Chem. Phys.
2006, 125, 124506/1–124506/18. (c) Lesage, A.; Sakellariou, D.; Hediger, S.;
Elena, B.; Charmont, P.; Steuernagel, S.; Emsley, L. J. Magn. Reson. 2003,
163, 105–113.
(22) Nichol, G. S.; Clegg, W. Cryst. Growth Des. 2006, 6, 451–460.
(23) Harris, R. K.; Phuong, Y.; Robert, B.; Ma, C. Y.; Roberts, K. J. Chem.
Commun. 2003, 2834–2835.
J. Org. Chem. Vol. 73, No. 13, 2008 4787

Bolz et al.
FIGURE 5. 1H-1H DQ MAS NMR spectrum of 1+DAC at 850 MHz and 59524 Hz MAS, acquired under the following experimental conditions:
τ(exc.) ) 33.6 µs, 256 t1 increments at steps of 16.8 µs, relaxation delay 10 s, 32 transients per increment. Sixteen positive contour levels between
2% and 35% of the maximum peak intensity were plotted. The F2 projections are given. (Top) Full spectrum. (Bottom) Excerpt highlighting the
important OH/NH cross peaks.
(11.2 ppm + 10.7 ppm) and 20.9 ppm (11.2 ppm + 9.7 ppm)
indicate complexation of 1 with DAC, as they reflect close
contacts of the NH-proton of 1 with the two NH-protons of
DAC. Their comparable signal intensities hint at very similar
distances of the 1-NH-proton to the two DAC-NH-protons. The
rather small peaks at 16.8 ppm and 16.5 ppm, respectively, are
assigned to protons from a 2,6-diacetamidopyridinium cation
DAC-H+, thus suggesting that a minor fraction of the 1+DAC
undergoes an acid-base reaction. In addition, the OH-proton
resonance of 1 is assigned based on its DQ cross peak at 19.6
ppm (12.3 ppm + 7.3 ppm) with adjacent aromatic protons.
Two possible structures of an anticipated complex 1+DAC
have been obtained from ab initio geometry optimizations.
Indeed, the rather simple molecular approach cannot account
for solid-state packing effects possibly present in the compound,
but nevertheless, the computed chemical shifts (cf. Table 1) are
good enough to support the assignment of the NH-peaks in the
1
corresponding H MAS NMR spectrum. In the case of vicinal
4788 J. Org. Chem. Vol. 73, No. 13, 2008

Molecular Recognition in the Solid-State
FIGURE 6. Optimized model geometries of 1+DAC: (a) assuming enol1-type 1 and (b) enol2-type 1 after tautomeric rearrangement. Both structures
and the NMR chemical shieldings have been obtained at BLYP/6-311++G(2df,2pd) and B3LYP/6-311++G(2df,2pd) levels of theory, respectively,
using Gaussian03. NMR chemical shifts were computed with respect to tetramethyl silane (TMS).
NH and OH protons of 1 (cf. Figure 6a), the two NH-protons
of DAC were computed at 11.0 and 8.7 ppm, respectively, while
the 1-NH-proton is predicted at 12.4 ppm. The OH-proton is
computed at 7.3 ppm and, thus, clearly reflects that the optimized
model geometry is only a rough snapshot of the actual structural
arrangement. The initially given model geometry of
1(enol1)+DAC (Figure 6a) is based on the assumption that the
barbituric acid moiety possibly retains its enol1-type structure
and indeed predicts fairly close contact of the 1-OH-proton to
one of the DAC-NH protons (d ) 2.892 Å, Dij ) 5.0 kHz). In
that case, we would expect a strong DQ cross peak at 23.0 ppm
(12.3 ppm + 10.7 ppm), which is not observed in the
corresponding DQ spectrum (cf. Figure 5). Rather, the OH-
proton has a fairly strong DQ peak at 13.7 ppm (12.3 ppm +
1.4 ppm) indicating contact to the alkyl chain protons of 1. This
strongly suggests that the OH-proton is of enol2-type within
the complex 1+DAC, thus hinting at a tautomeric rearrangement
of 1 upon complexation as illustrated in Figure 6b. In this case,
an optimized model geometry of 1(enol2)+DAC yields com-
puted proton chemical shifts of 12.5 ppm (1-NH) as well as
11.0 ppm and 10.3 ppm, respectively, for the two DAC-NH-
FIGURE 7. Molecular structure of the hydrogen-bonded complex of
protons. In addition, the 1-OH-proton is computed at 5.3 ppm.
DAC with the enolate anion of 1 in the presence of PS (asymmetric
Notably, the 1-OH proton shows close contact to the aliphatic
protons of 1 (d ) 1.827 Å, Dij ) 19.7 kHz), which is in rather
good agreement with the experimental data.
unit). Note that the chelated proton PS-H+ populates the two N(CH3)2
units at a 50:50 ratio.
Adding the adenine-mimetic base 2,6-diacetamidopyridine
DAC to the system 1+PS, we offer a complementary hydrogen-
bonding pattern to the enolate anion of 1, which indeed should
allow for complex formation.
implies that the former dimer of the enolate anions in 1+PS is
canceled. Assuming that the 1-NH-proton can be assigned to
the peak at 10.3 ppm, both DQ cross peaks at 22.0 ppm (11.8
ppm + 10.3 ppm) and 20.2 ppm (9.9 ppm + 10.3 ppm),
respectively, indicate successful formation of an enolate
1+DAC complex fulfilling the complementary hydrogen-
bonding pattern. This observation is indeed consistent with the
crystal structure. Again, an analysis of proton-proton distances
within 4 Å facilitates an unambiguous peak assignment: the
crystallographically different DAC-NH-protons are in closest
contact to the 1-NH-proton (d ) 2.4669 Å, Dij ) 8.0 kHz and
d ) 2.6242 Å, Dij ) 6.6 kHz, respectively). In addition, four
contacts of 1-NH to aromatic protons of both PS (d ) 3.1624
Å, Dij ) 3.8 kHz; d ) 3.2184 Å, Dij ) 3.6 kHz) and DAC (d
) 3.3725 Å, Dij ) 3.1 kHz; d ) 3.4594 Å, Dij ) 2.9 kHz),
respectively, are found in the crystal structure, which are
reflected by a rather weak DQ cross peak at 17.6 ppm (10.2
ppm + 7.4 ppm), but no contact to aliphatic protons (also not
observed in the DQ spectrum, Figure 8). In contrast, the two
DAC-NH-protons have shortest contacts to the methyl protons
of DAC (d ) 2.0139 Å, Dij ) 14.7 kHz; d ) 2.0051 Å, Dij )
14.9 kHz), which is reflected by strong DQ cross peaks at 12.8
ppm (11.8 ppm + 1.0 ppm) and 11.6 ppm (9.9 ppm + 1.7 ppm).
After recrystallization from acetone, orange needle-like single-
crystals suitable for X-ray analysis were obtained. It was found
that 1+PS+DAC crystallizes in a monoclinic lattice, space
group P21/n (No. 14), with the lattice parameters a ) 8.9840(5)
Å, b ) 17.4356(7) Å, and c ) 23.5112(8) Å. The asymmetric
unit consists of an enolate 1+DAC complex and one molecule
PS with a chelated proton that populates both N(CH3)2 units of
PS in a 50:50 ratio. The enolate complex 1+DAC is stabilized
by hydrogen bonds between the CdO/N and NH groups of both
DAC and 1.
1
In the solid-state H MAS NMR spectrum of the mixture
1+PS+DAC, four different exchangeable proton sites are
resolved at 19.3 (chelated proton), 11.8, 10.2, and 9.9 ppm,
respectively. The formation of the enolate anion of 1 in the
presence of PS is evidenced by a strong DQ cross peak at 21.7
ppm (19.3 ppm + 2.4 ppm) between the chelated proton (19.3
ppm) and the methyl protons of PS (2.4 ppm) in the corre-
sponding 1H-1H DQ MAS NMR spectrum (Figure 8). Notably,
there is no auto-correlation peak of the NH-protons of 1 which
J. Org. Chem. Vol. 73, No. 13, 2008 4789

Bolz et al.
FIGURE 8. 1H-1H DQ MAS NMR spectrum of 1+PS+DAC at 850 MHz and 59524 Hz MAS, acquired under the following experimental
conditions: τ(exc.) ) 33.6 µs, 256 t1 increments at steps of 16.8 µs, relaxation delay 10 s, 32 transients per increment. Sixteen positive contour levels
between 7% and 95% of the maximum peak intensity were plotted. The F2 projections are given. (Top) Full spectrum. (Bottom) Excerpt highlighting
the important NH/NH cross peaks.
On the other hand, corresponding distances of the DAC-NH-
protons to aromatic protons are much larger (d ) 3.2953 Å, Dij
) 3.3 kHz; d ) 3.4446 Å, Dij ) 2.9 kHz), thus resulting in a
considerably weaker DQ cross peak at 17.4 ppm (9.9 ppm +
7.5 ppm). The second DQ cross peak of aromatic protons
involving the DAC-NH-proton at 11.8 ppm is missing and hence
suggests that the distance between two dipolar coupled protons
at the given DQ excitation period of 33.6 µs is limited to about
3.3 Å. In summary, the DQ spectrum of 1+PS+DAC is in
perfect agreement with the reported crystal structure. While
DAC may act as a weak base in the mixture 1+DAC yielding
a minor fraction of 1-enolate, the presence of the much stronger
base PS clearly allows for complete removal of the 1-OH-proton
and thus, DAC is solely involved in complex formation with
1.
An inspection of Table 2 reveals that the hydrogen bond
lengths within the various assemblies are strongly affected by
the presence of the Proton Sponge. While the barbiturate NH-
resonances in pure 1 as well as in the complex 1+DAC are
(24) (a) Tsiourvas, D.; Sideratou, Z.; Haralabakopoulos, A. A.; Pistolis, G.;
Paleos, C. M. J. Phys. Chem. 1996, 100, 14087–14092. (b) Yang, W.; Chai, X.;
Tian, Y.; Chen, S.; Cao, Y.; Lu, R.; Jiang, Y.; Li, T. Liq. Cryst. 1997, 22, 579–
583. (c) Wu¨rthner, F.; Yao, S.; Heise, B.; Tschierske, C. Chem. Comm. 2001,
2260–2261. (d) Itahara, T.; Uto, T.; Sunose, M.; Ueda, T. J. Mol. Struct. 2002,
616, 213–220. (e) Hao, X.; Liang, C.; Jian-Bin, C. Analyst 2002, 127, 834–837.
(f) Sivakova, S.; Rowan, S. J. Chem. Commun. 2003, 2428–2429.
4790 J. Org. Chem. Vol. 73, No. 13, 2008

Molecular Recognition in the Solid-State
TABLE 2. Experimental or Calculated Intermolecular Distances
of 1 and Its Molecular Assemblies with PS and DAC
temperatures indicate destabilized packing effects of the added
receptor to the molecular structure of the host.24 The DSC traces
of the complex 1+DAC and 1+PS+DAC, respectively, in
comparison with the starting compounds 1 and 1+PS are shown
in Figure 9.
distances
compound
bond type
Da (Å)
db (Å)
1a
N-H---OdC
2.7725
3.032
2.971
1.8263
2.016
1.952
1+DACc
1-CdO---HN-DAC
1-CdO---H′N-DAC
1-NH---N-DAC
The DSC thermogram of 1 shows two negligible endothermic
peaks at 89 and 103 °C hinting at evaporating acetone. The
endothermic transition at 120 °C is attributed to the melting of
barbiturate 1, while the exothermic at 249 °C indicates
decomposition. In contrast, a sample recrystallized from diethyl
ether (see the Supporting Information) shows two intense
endothermic transitions at 107 and 127 °C. There, the first peak
reflects molecular reorientation of the n-butyl chain20 revealing
disorder of the alkyl chains in this sample. Upon addition of
DAC to the barbiturate 1, a lower and broader melting peak
(111 °C) and decomposition temperature (233 °C) of 1+DAC
is observed suggesting that the former hydrogen-bonded dimeric
arrangement of 1 is broken. Notably, no evidence for unbound
1 or DAC was found in this sample (recrystallized from
acetone), which is in contrast to the crude product obtained from
diethyl ether (Et2O).
3.075
2.031
1+PS+DACa
1-CdO---HN-DAC
1-CdO---H′N-DAC
1-NH---N-DAC
2.9405
2.7893
3.0444
1.9903
1.8385
2.2033
a N---O, N---N, and O---O distances are directly obtained from
single-crystal X-ray data. b Hydrogen bond lengths (the hydrogen atoms
were refined with respect to known geometries using SHELXS8630
software). c Data obtained from an ab initio structure assuming
enol2-type 1.
The salt 1+PS shows an endothermic melting peak at 185
°C and an exothermic peak at 243 °C indicating decomposition.
The stabilizing effect of the adenine-mimetic base DAC to the
enolate anion of 1 in the complex 1+PS+DAC is revealed by
a broader and higher endothermic phase transition at 190 °C
(probably due to an eutectic behavior of the enolate anion of 1
with DAC) and a higher exothermic peak at 262 °C (decom-
position).
Taken together, the DSC-investigations prove that all com-
pounds are thermally stable up to 100 °C and thus, any possible
frictional heating effects during fast MAS NMR experiments
(60 kHz spinning) can safely be neglected.
Push-Pull Character of
1 and in Its Molecular
Assemblies Investigated by Solid-State UV/vis Spectro-
scopy. In the previous parts, we have presented the molecular
structure of the enolic barbiturate 1 and its molecular assemblies
with the Proton Sponge PS and 2,6-diacetamidopyridine DAC,
and combination thereof. In this last section, we elucidate the
observed UV/vis response (Scheme 2, Figure 10) of the
chromophoric 1 caused by the molecular recognition, thus
demonstrating the versatile bonding potential of this new type
of compound. The structural details derived from solid-state
NMR spectroscopy are in good agreement with the correspond-
ing UV/vis absorption bands of all assemblies.
FIGURE 9. DSC thermograms of the complex 1+DAC and
1+PS+DAC in comparison with the starting compounds 1 and 1+PS.
Inset: comparison of the observed onset temperature for the melting
(Tmelt) and decomposition (Tdecomp).
almost identical (11.1 vs 11.2 ppm) indicating comparable
hydrogen bond lengths, a removal of the OH-proton and, thus,
formation of an enolate anion due to acid-base reaction with
PS results in a high-field shift of NH-resonances in both dimeric
enolate anion of 1+PS (1-NH: 10.6 ppm) and in the DAC-
complexed enolate anion of 1+PS+DAC (1-NH---N-DAC,
10.2 ppm) possibly reflecting local changes of electron delo-
calization. Indeed, rather strong interaction of the DAC-NH′-
proton with the enolate oxygen (1-C-O----H′N-DAC) is
evidenced by the change in 1H chemical shift of the DAC-NH′-
proton of ∆δ ) +1.1 ppm with respect to pure DAC and a
shorter hydrogen bond length than observed in the complex
1+DAC.
DSC Thermograms of the Barbiturate 1 and of the
Corresponding Structures with PS and DAC. Calorimetric
investigations are very useful tools for the determination of
thermal stability of compounds. Indeed, complex formation may
be concluded from DSC (differential scanning calorimetry)
traces by displacements of corresponding phase transitions.
Well-organized supramolecular structures are observed at higher
transition temperatures, whereas lower or else broader transition
The UV/vis absorption band of the single-crystals of 1 has
its maximum at 414 nm. Due to the presence of acetone in the
crystal structure, the polarity of the environment is increased
which significantly enhances the push-pull character of the
enol1-type 1. Shoulders at approximately 440 and 470 nm are
probably resulting from a charge-transfer excitation. For com-
parison, the crude product of 1 obtained from Et2O absorbs at
334 nm. Furthermore, the solvent used for recrystallization
remarkable influences the position of the complex formation
equilibrium. For example, the complexation of 1 with DAC from
Et2O is incomplete which demonstrates that the hydrogen-
bonded dimer of enol1-type 1 is fairly stable in Et2O (see the
Supporting Information). In contrast, recrystallization of the
complex 1+DAC from acetone results in a clear UV/vis
absorption maximum at 425 nm. In comparison to pristine 1
from acetone, the bathochromic shift (∆λ ) 11 nm, ∆ν˜ ) 625
cm-1) of the UV/vis absorption band is attributed to the
J. Org. Chem. Vol. 73, No. 13, 2008 4791

Bolz et al.
SCHEME 2. Influence of the Hydrogen-Bonded Structures of the Complex 1+DAC and 1+PS+DAC in Comparison with the
Enol1-Type 1 and Its Enolate Anion in 1+PS on the UV/vis Absorption Band of the Chromophor
hydrogen bond between the NH-proton of enol2-type 1 and the
electron-rich ring nitrogen of DAC increasing the electron
density of the barbituric acid moiety. Another support for this
interpretation is the broken stacked arrangements of 1 which
has decreased the (+)M-effect of the barbiturate. This feature
is of importance for our conceptual development of a novel type
of adjustable UV/vis probe for detection of supramolecular
sequences.
III. Conclusions
The novel enolizable chromophor 1-n-butyl-5-(4-nitrophe-
nyl)barbituric acid 1 displays adjustable hydrogen-bonding
properties. In the solid-state, an enol form with a DDA
hydrogen-bonding pattern is preferred that self-aggregates to
hydrogen-bonded dimers. These dimers are involved in stacked
arrangements stabilized by additional hydrogen bonds. In the
presence of strong bases like the so-called Proton Sponge PS,
a simple acid-base reaction occurs where the OH-proton of 1
is stripped. The corresponding enolate anion of 1 retains the
dimeric structure reflecting the stability of this arrangement. It
was found that the enolic dimer of 1 can be broken upon addition
of the adenine-mimetic base 2,6-diacetamidopyridine DAC,
which provides a complementary DAD hydrogen-bonding. The
solvent used for (re)crystallization highly influences the equi-
librium of complex formation. In particular for 1+DAC,
complex formation is strongly preferred using the solvent
acetone, while otherwise self-aggregation of 1 is observed to
compete with complex formation. Furthermore, complexation
with DAC induces the molecular reorientation of 1 to the
complementary ADA sequence. This nicely demonstrates that
both the prototropic tautomerism and the acidity of the enoliz-
able barbituric acid 1 in the solid compounds is strongly
influenced by ordering or packing effects, which are absent in
solution-state. The corresponding solid-state structures were
characterized using both X-ray analysis and solid-state NMR
spectroscopy. Interpretation of the obtained NMR data was
supported by DFT-based ab initio chemical shift calculations.
Depending on the chemical environment, complementary in-
formation on crystallochromic properties of 1 and its derivatives
were revealed by UV/vis spectroscopy measured in diffuse
reflection. It was shown that the electron-donating strength of
the barbituric acid moiety is significantly influenced by interac-
tion with bases. Therefore, this type of enolizable barbituric
acid derivatives is a promising candidate to measure effects of
complementary hydrogen-bonded complexes as well as the
basicity of the environment by means of UV/vis spectroscopy.
Quantitative proton-transfer between 1 and PS is verified by
the observation of a single UV/vis absorption band at 445 nm
representing self-aggregated enolate anion of 1 (cf. Figure 4).
Due to the deprotonation, the electron-donating effect of the
barbituric acid moiety in the enolate anion is increased yielding
a significant bathochromic shift (∆λ ) 34 nm, ∆ν˜ ) 1683 cm-1
)
in the UV/vis spectrum of 1+PS compared to 1from acetone.
In the complex 1+PS+DAC the electron density of the enolate
oxygen is decrease due to the hydrogen bond to the NH proton
of DAC (cf. Scheme 2). So, the decrease of the (+M)-effect of
the enolate oxygen involved in complex formation with DAC
is noticed by a small hypsochromic shift (∆λ ) 4 nm, ∆ν˜ )
204 cm-1) of the UV/vis absorption band in comparison to
1+PS.
FIGURE 10. Solid-state UV/vis spectra of the complex 1+DAC and
1+PS+DAC in comparison to the starting compound 1 and 1+PS.
For structure assignment to the UV/vis response, see Scheme 2.
4792 J. Org. Chem. Vol. 73, No. 13, 2008

Molecular Recognition in the Solid-State
used to excite and reconvert double-quantum coherences,25 applying
the States-TPPI method26 for phase-sensitive detection. Further
details are given in the figure captions of the respective 2D-spectra.
DFT-Based Chemical Shift Calculations. Where necessary,
equilibrium geometries of the investigated compounds were ob-
tained by density functional theory (DFT)17 based quantum
chemical calculations using the BLYP functional27 and 6-311G28
split valence basis set augmented with diffuse and polarization
functions. Subsequently, 13C chemical shifts with respect to
tetramethyl silane (TMS) were computed at B3LYP/6-311++G
(2df, 2pd) level of theory with the GIAO approach as implemented
in Gaussian03 program.29
Single-Crystal Structure Analyses. (a) Crystal parameters of
1 are reported as follows: pale yellow; C17H21N3O6; Mr ) 363.77;
monoclinic P21/c; a ) 11.3856(5) Å, b ) 7.8718(4) Å, c )
19.8518(6) Å; ꢀ ) 91.114(1)°; Z ) 4. (b) Crystal parameters of
1+PS+DAC are reported as follows: orange needles; C29H35N5O4;
Mr ) 570.24; monoclinic P21/n; a ) 8.9840(5) Å, b ) 17.4356(7)
Å, c ) 23.5112(8) Å; ꢀ ) 97.33(0)°; Z ) 5. In both cases, data
collection was carried out at 120 K (Mo KR (λ ) 0.71073 Å))
equipped with a graphite monochromator. Intensity data were
corrected for Lorentz and polarization effects. Structure solution
and refinement was done employing the SHELXS8630 and CRYS-
TALS31 software packages. All non-hydrogen atoms were refined
in the anisotropic approximation against F of all observed reflec-
tions. The hydrogen atoms were refined in the riding mode with
fixed isotropic temperature factors; (1): R ) 0.066; (1+PS+DAC):
R ) 0.1522. The figures were created using the Diamond 3.1b32
program package.
IV. Experimental Section
Synthesis of 1-n-Butyl-5-(4-nitrophenyl)barbituric Acid 1. 4.0
mmol of 1-n-butyl-5-phenylbarbituric acid was dissolved in 3 mL
concentrated sulfuric acid, cooled off 0 °C, and then treated with
5.0 mmol of powdery KNO3 over a time period of 5 min. After
continuously stirring for 30 min at the same temperature, the
reaction mixture was allowed to warm up at 22 °C. To complete
the reaction, the mixture was stirred for 2 h again and then poured
into 5 mL of ice-water. The precipitate was filtered off, washed
with water (4 × 3 mL), and dried in vacuo. The powdery crude
product was washed with a small amount of dichloromethane
(DCM) and recrystallized from diethyl ether (Et2O). After drying
under reduced pressure (40 °C, 40 mbar), 1 was obtained as a pale
yellow precipitate. Yield: 19 %. Mp: 107, 127, 262 °C (decomp.).
MS (ESI): m/z calcd for C14H16N3O5 (M + H+) 306.2860, found
306.1504. IR (cm-1): 3200-3000 (w), 2965, 2934, 2873 (m), 1707
(s), 1617, 1597 (m), 1542 (m), 1518 (s), 1457 (m), 1345 (s), 1109
(w), 857 (m), 781 (m), 598 (m). 1H NMR (DCM-d2): 0.93 (t, 3 H,
CH3), 1.33 (se, 2 H, CH2), 1.58 (quin, 2 H, CH2), 3.89 (t, 2 H,
N-CH2), 4.82 (s, 1 H, 5), 7.46 (d, 2 H, 2′), 8.25 (d, 2 H, 3′), 8.52
(s, 1 H, NH-3). 13C NMR (DCM-d2): 13.5 (CH3), 20.0 (CH2), 29.9
(CH2), 41.8 (N-CH2), 55.0 (5), 124.2 (3′), 130.0 (2′), 139.6 (1′),
148.1 (4′), 149.5 (2), 165.4 (4/6), 166.3 (6/4). Anal. Calcd for
C14H15N3O5: C, 55.08; H, 4.95; N, 13.76. Found: C, 55.28; H, 4.70;
N, 13.71.
DSC Analyses. Calorimetric melting profiles were determined
in the temperature range from 25 to 400 °C (scan rate of 10 °C
min-1) in a stream of nitrogen.
UV/vis Spectroscopy. The UV/vis absorption spectra of the
solid-state compounds were obtained by means of a diode-array
spectrometer in diffuse reflection. The measurements were carried
out in the spectral range of 180-1000 nm using quartz plates and
Spectrolon as the standard white reference.
The crystal structure of 1 discussed in the paper was obtained
by slow recrystallization from acetone. Mp: 89, 103, 120, 249 °C
(decomp.). H NMR (DCM-d2): 0.93 (t, 3 H, CH3), 1.34 (m, 2 H,
1
CH2), 1.59 (m, 2 H, CH2), 2.12 (s, 6 H, acetone), 3.89 (t, 2 H,
Acknowledgment. Financial support from the DFG (Deut-
sche Forschungsgemeinschaft) through the SFB 625 in Mainz
is gratefully acknowledged.
N-CH2), 4.81 (s, 1 H, 5), 7.47 (d, 2 H, 2′), 8.17 (s, 1 H, NH-3),
1
8.25 (d, 2 H, 3′). H NMR (acetone-d6): 0.91 (t, 3 H, CH3), 1.35
(m, 2 H, CH2), 1.58 (m, 2 H, CH2), 3.85 (dt, 2 H, N-CH2), 5.27 (s,
1 H, 5), 7.70 (d, 2 H, 2′), 8.27 (d, 2 H, 3′), 10.47 (s, 1 H, NH-3).
Anal. Calcd for C14H15N3O5 + C3H6O: C, 56.19; H, 5.83; N, 11.56.
Found: C, 55.80; H, 5.90; N, 11.49.
Supporting Information Available: Synthetic procedures,
general experimental methods, optimized geometries, CIF files,
spectral data not shown in the manuscript, as well as a complete
ref 29. This material is available free of charge via the Internet
at http://pubs.acs.org.
Solid-State NMR Methods. Proton solid-state NMR data was
recorded on either a 850 or 700 MHz spectrometer; additional 13
C
CP MAS NMR spectra were recorded at 75.5 MHz using a 500
MHz machine. Most experiments were carried out using a 1.3 mm
double-resonance MAS probe at a spinning frequency of 60 kHz,
typical π/2-pulse lengths of 2 µs, and recycle delays of 5-10 s.
Additional spectra were acquired using 2.5 mm double-resonance
MAS probe at spinning frequencies of 30 kHz. The spectra are
referenced with respect to tetramethyl silane (TMS) using adaman-
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