Four hydrogen bonds - DDAA, DADA, DAAD and ADDA hydrogen bond motifs

Article abstract of DOI:10.1002/1099-0690(200212)2002:23<4063::AID-EJOC4063>3.0.CO;2-L

Receptor molecules containing four hydrogen-bond acceptor or donor sites based on aminopyridines, aminonaphthyridines and urea subunits have been synthesized and their association has been investigated. DDAA (13a-c) and DADA (18a-b) arrays may form homodimers, while DAAD (24a-d) with ADDA (25a-b) may form heterodimers. While most parent heterocycles were only slightly soluble in standard organic solvents, substitution was able to enhance the solubility in most cases. The naphthyridine 24d, bearing a substituent derived from lysine, possesses potential anchor groups for a covalent connection. Binding studies were carried out in chloroform and monitored by ¹H NMR, and the binding constants K_ass for the heterodimers DAAD·ADDA (24·25) were compared to the binding of smaller (ADD, 26) or mismatching (DADD, 27) counterparts, showing that the matching heterodimer is formed with a selectivity of > 50. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2002).

Full text of DOI:10.1002/1099-0690(200212)2002:23<4063::AID-EJOC4063>3.0.CO;2-L

FULL PAPER
Four Hydrogen Bonds ؊ DDAA, DADA, DAAD and ADDA Hydrogen Bond
Motifs[‡]
Ulrich Lüning,*[a] Christine Kühl,[b] and Andreas Uphoff[a]
Keywords: Association constants / Heterocycles / Hydrogen bond / Molecular recognition / Supramolecular chemistry
Receptor molecules containing four hydrogen-bond acceptor
or donor sites based on aminopyridines, aminonaphthyrid-
ent derived from lysine, possesses potential anchor groups
for a covalent connection. Binding studies were carried out
ines and urea subunits have been synthesized and their asso- in chloroform and monitored by 1H NMR, and the binding
ciation has been investigated. DDAA (13a−c) and DADA
(18a−b) arrays may form homodimers, while DAAD (24a−d)
with ADDA (25a−b) may form heterodimers. While most par-
ent heterocycles were only slightly soluble in standard or-
ganic solvents, substitution was able to enhance the solubil-
ity in most cases. The naphthyridine 24d, bearing a substitu-
constants Kass for the heterodimers DAAD·ADDA (24·25)
were compared to the binding of smaller (ADD, 26) or mis-
matching (DADD, 27) counterparts, showing that the match-
ing heterodimer is formed with a selectivity of Ͼ 50.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2002)
Multiple hydrogen bonds can be found in many recogni-
tion processes, both in enzymes and in the genetic code.[1]
Correct binding by two or three parallel[2] or antiparallel
hydrogen bonds is the key feature of the genetic code, which
uses substituted purines and pyrimidines for the recognition
and the storage of genetic information.[3] The number of
hydrogen bonds involved in a recognition event has two im-
portant influences on the quality of this process: (i) the
more hydrogen bonds are involved in a recognition, the
tighter the binding usually becomes,[4Ϫ7] and (ii) more hy-
drogen bonds can convey more information.
Figure 1. There are ten possible ways to arrange hydrogen-bond
donors D and acceptors A for quadruple hydrogen-bond arrays
(1؊10); two of them form homodimers (1·1, 2·2), the other eight
(3Ϫ10) form heterodimers
A hydrogen bond between a hydrogen-bond donor (D)
and a hydrogen-bond acceptor (A) possesses a direction.
Therefore, with two hydrogen bonds, two different pairs,
formed from three different molecules, are possible: a hetero-
dimer in which a DD unit binds AA, and a homodimer
made of two DA molecules. Addition of one more hydrogen
bond results in three possible dimers formed by six different
units: DDD·AAA, DDA·AAD and DAD·ADA. With four
hydrogen bonds, ten different molecules and six different
dimers are possible (see Figure 1).
in each of the ten molecules 1Ϫ10. While two hydrogen
bonds may be oriented in two ways to give two different
dimers originating from three different building blocks,
three hydrogen bonds may give three dimers resulting from
six different building blocks. Four hydrogen-donor and
-acceptor sites give ten possible molecules 1Ϫ10. For each
of these, there is only one matching partner (out of ten) with
which a strong dimer can be formed by the formation of
four hydrogen bonds. However, the stability of the com-
plexes with four hydrogen bonds will vary, depending on the
number of secondary attractive or repulsive interactions.[6]
Two arrays (1 and 2) are self-complementary[8Ϫ11] and
have already been exploited for the construction of ‘‘intelli-
gent’’ polymers.[12,13] In Meijer’s systems, nitrogen and oxy-
gen atoms are the acceptors (A), and NϪH functions are
the donors (D) (Figure 2).[14]
In addition to the stronger binding due to the four hydro-
gen bonds in these dimers, more information can be stored
[‡]
Multiple hydrogen bonds, 3. Part 2 Ref.[33]
Institut für Organische Chemie der Universität Kiel,
[a]
Olshausenstr. 40, 24098 Kiel, Germany
Fax: (internat.) ϩ 49-(0)431/880-1558
E-mail: luening@oc.uni-kiel.de
[b]
New address: Bernina Biosystems GmbH,
In this work we describe the syntheses of receptors 1Ϫ4
and present binding studies for heterodimers consisting of
different DAAD and ADDA molecules 3 and 4.
Am Klopferspitz 19a, 82152 Martinsried, Germany
Fax: (internat.) ϩ 49-(0)89/18930955
E-mail: kuehl@bernina-biosystems.de
Eur. J. Org. Chem. 2002, 4063Ϫ4070  2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1223Ϫ4063 $ 20.00ϩ.50/0
4063

U. Lüning, C. Kühl, A. Uphoff
FULL PAPER
Figure 2. First[12] examples of self-complementary DADA[8] and DDAA[9,11] arrays
From 13a, single crystals have been obtained, and an X-
ray analysis was carried out.[17] In this crystal, a dimer of
13a was found but the hydrogen-bonding pattern was not
as expected. As also known for N-(pyridin-2-yl)ureas[18,19]
an (E,Z) conformer, stabilized by an intramolecular hydro-
gen bond, was found. On rotation of the NHϪCO unit to
form an (E) conformer, a new AD recognition site is
formed, by which the molecules dimerize. The resulting
homodimer also contains four hydrogen bonds but only two
of them are intermolecular hydrogen bonds, while the other
two are intramolecular hydrogen bonds, one within each
urea molecule (Figure 3).
Synthesis of the Self-Complementary Sequences
DDAA (1) and DADA (2)
Schemes 1 and 2 show self-complementary DDAA and
DADA systems based on aminopyridine, aminonaphthyrid-
ine and urea units, which may form homodimers 1·1
and 2·2 connected exclusively by N····HϪN hydrogen
bonds. The syntheses of 13 and 18 are depicted in
Schemes 1 and 2.
Scheme 1
Figure 3. The DDAA molecule 13a does not dimerize in the ex-
pected way, by establishing four parallel and antiparallel hydrogen
bonds, but forms an (AD)2 dimer containing two intramolecular
hydrogen bonds[27]
Although not verified by X-ray analyses, it is very prob-
able that the analogues 13b and 13c form the same AD
homodimers containing these intramolecular hydrogen
bonds.
A DADA receptor based exclusively on N and NH units
will result from an alternating arrangement of pyridine
Scheme 2
A very quick route to DDAA molecules containing two rings and NH units such as, for instance, in 17 or 18. To
nitrogen atoms and two NH groups for hydrogen bonding avoid the rotational problems discussed above, the pyridine
is shown in Scheme 1. The aminonaphthyridine 11[15] was rings have to be connected in the 3-position. If this connec-
synthesized easily in 84Ϫ90% yield by literature procedures. tion is performed through a carbonyl group the resulting
Addition to several isocyanates 12 formed the DDAA re- molecule is an anthyridone 18. Scheme 2 summarizes the
ceptors 13 in 72Ϫ87% yield.[16]
synthesis.
4064
Eur. J. Org. Chem. 2002, 4063Ϫ4070

Four Hydrogen Bonds Ϫ DDAA, DADA, DAAD and ADDA Hydrogen Bond Motifs
FULL PAPER
The 2-bromo-3-pyridinecarboxylic acid 15 was synthe- the naphthyridines 23.[26] The amino acid derived cy-
sized by literature procedures[20] via its ethyl ester (56%) anoacetamide 20 was prepared from lysine as shown in
and subsequent saponification (66%). Compound 15 was Scheme 3.
then coupled with 2,6-diaminopyridine (14) under Ullmann
Many naphthyridines like 23 and related heterocycles
conditions by first mixing the solids 14 and 15 with copper show very low solubility (see also above) in most organic
powder, copper iodide and potassium carbonate and then solvents, especially when the crystalline form is additionally
heating to 170 °C. The resulting (pyridylamino)pyridinecar- stabilized by hydrogen bonds. Aliphatic substituents help to
boxylic acid 16 (24%) was then cyclized with hot concen- solubilize such compounds. The diaminonaphthyridines 23
trated sulfuric acid, giving 79% of the highly insoluble an- were therefore acylated with valeryl or pivaloyl chloride to
thyridone 17, which was only characterizable by IR. Sub- give the chloroform-soluble DAAD compounds 24.[16,26]
sequent treatment with acetic anhydride, however, gave the Only in the case of the amino acid derivative 23d was such
more soluble anthyridone 18a in 50% yield. A valeric acid functionalization was unnecessary, as 23d was already sol-
derivative 18b was synthesized in analogous fashion, but uble in chloroform due to the amino acid component
both compounds were only soluble in very polar solvents, (Scheme 4).
and association constants in chloroform could therefore not
be determined. Attempts to synthesize other more lipo-
philic anthyridones were stopped by very low yields of the
Ullmann coupling.
Syntheses of DAAD Molecules 3
With the syntheses of the systems 13 and 18, containing
four hydrogen bonds, we have already encountered two im-
portant problems in the designing of multiple hydrogen-
bond receptors: insolubility and ‘‘rearrangements’’ that
may result in altered donor-acceptor sequences [e.g., rota-
tions (see above), tautomerism[21]]. Therefore, for a DAAD
receptor of type 3, 2,7-diamino-1,8-naphthyridines in which
all four nitrogen atoms are fixed in one plane were selected.
In one case (23d), an amino acid residue was attached to the
DAAD moiety on its remote side in order to allow covalent
connection to other molecules. One possible reaction could Scheme 4
be the incorporation of this four hydrogen bond forming
unit into PNA.[22Ϫ24]
The naphthyridines 23 and 24 were synthesized by the
Friedländer procedure.[15] The 2,6-diaminopyridine-3-car-
Counterparts ADDA 4
baldehyde (21) starting material was prepared by literature
procedures.[25] Condensation with cyanoacetamides gave
The counterpart for a DAAD system 3 will be an ADDA
unit 4. A very convenient DD system is the urea molecule.
In order to extend the DD system to produce an ADDA
one, hydrogen-bond acceptors such as pyridine nitrogen
atoms have to be attached to a urea moiety. Because ureas
can easily be prepared from carbonic acid derivatives and
amines, the reaction between 2-aminopyridines and car-
bonic acid derivatives was chosen for the construction of
ADDA molecules 4. One-step syntheses starting from phos-
gene are also conceivable, but the less toxic, non-gaseous
ethyl chloroformate can be used as starting material
too.[27Ϫ29] Two dipyridylureas 25 were synthesized in two
steps from chloroformate, giving 25a and its dimethyl deriv-
ative 25b[18] in improved overall yields of 27 and 25%, re-
spectively.
The dipyridylureas 25 are able to form dimers through
two hydrogen bonds, as was determined by X-ray ana-
lysis.[18,19] Rotation about one bond between a pyridine ring
and the urea allows an intramolecular hydrogen bond be-
Scheme 3
tween one NH group and the non-adjacent pyridine nitro-
Eur. J. Org. Chem. 2002, 4063Ϫ4070
4065

U. Lüning, C. Kühl, A. Uphoff
FULL PAPER
gen atom. The other NH group is oriented cis to the car-
bonyl group of the urea, thus forming a DA binding unit.
In the crystal, two of these cis-amides form a dimer.[18,19]
Because of the symmetry of this molecule, two degenerate
conformations exist in rapid equilibrium at room temper-
ature, resulting in broad NMR signals for 3-H in the pyrid-
ine rings (Figure 4).[16]
Figure 6. Heterodimer formation between DAAD naphthyridines
24 and ADDA dipyridylureas 25; the hydrogen bonds are drawn
with horizontally dashed lines (||||), the positive secondary interac-
tions as longitudinally dashed lines (-----), the repulsive secondary
interactions with zig-zag lines (/\/\/\/\) for an estimation of the bind-
ing constants according to the increments listed by Schneider et
al.,[5,6] two positive and four negative secondary interactions have
to be taken into account
From the titration curves (see Figure 5, for example),
binding constants Kass were determined[31] and the corres-
ponding ∆G values calculated. Table 1 lists the results for
the titration of four DAAD receptors 23 and 24 with two
ADDA dipyridylureas 25 and two related compounds 26
(ADD) and 27 (DADD),[32,33] and compares them with
∆Gcalc values obtained from the increments.[5] For the deter-
mination of the ∆Gcalc values in addition to the primary
and secondary interactions[6] of the hydrogen binding, the
energy to cleave the intramolecular hydrogen bond in 25
has also been taken into account.
Figure 4. Rotation about one bond between one NH and the Cϭ
O group allows an intramolecular hydrogen bond between one NH
group and the non-adjacent pyridine nitrogen atom; the other NH
group is oriented cis to the carbonyl group of the urea, allowing
the formation of DA·AD bound dimers as established by X-ray
analysis[18,19] (see also Figure 3)
Binding Studies for DAAD·ADDA
Recognition between the DAAD receptors 23 and 24 and
the complementary ADDA dipyridylureas 25 was investig-
ated by NMR. Small volumes of 25 in CDCl3 were added
to CDCl3 solutions of 23 or 24 and the chemical shifts were
recorded. Figure 5 shows as an example the titration curve
for the amide signals of 24c during titration with 25a. Both
NH signals shift drastically to low field, indicating that
both NH components take part in hydrogen bonds (Fig-
ure 6).[31]
Surprisingly, the free enthalpy of binding (∆G) calculated
from the binding constant Kass for the complex 24c·25a
matches the calculated value exactly.[34] Deviations were
found for the other pairs, and can be explained by addi-
tional steric interactions. Thus, the change in the acyl res-
idue R2 in the DAAD receptors 24 from butyl (24c) to tert-
butyl (24b) resulted in a decrease in the binding constants
Kass for both ADDA counterparts: from Kass ϭ 2000 to
47 (25a) and from Kass ϭ 160 to 16 (25b). However, the
introduction of methyl groups into the dipyridyl urea 25
also diminishes the binding constants: from Kass ϭ 2000 to
160 (24c) and from Kass ϭ 47 to 16 (24b). If the ADDA
counterpart 25a is compared to those not complementary
to the DAAD pattern [26 (ADD) and 27 (DADD)], a de-
crease in Kass of a factor of at least 50 is observed. The
amino acid derivative 23d showed a smaller than expected
Kass association constant. Presumably the less acidic NϪH
atoms of the amino groups in 23d are the reason for the
less tight binding relative to the bis(amido) compound 24c.
This difference shows that the good fit of the calculated and
measured ∆G values for the couple 24c·25a is not a given
and argues for very careful use of empirical estimation of
binding constants by the increment method.
Figure 5. Titration of the DAAD receptor 24c (6.4 m) with the
complementary ADDA moiety 25a; the differences in chemical
shifts ∆δobs of the amide hydrogen atoms of 24c are plotted against
the total concentration [G]o of the dipyridylurea 25
4066
Eur. J. Org. Chem. 2002, 4063Ϫ4070

Four Hydrogen Bonds Ϫ DDAA, DADA, DAAD and ADDA Hydrogen Bond Motifs
FULL PAPER
Table 1. Binding constants Kass and free enthalpies of binding ∆G of heterodimers as determined by titration of the DAAD receptors 23
or 24 with ADDA dipyridylureas 25 and related compounds 26 (ADD) and 27 (DADD)[32,33] at 295 K, and the corresponding calculated
binding free enthalpies ∆Gcalc
Complex
∆δmax
Kass
∆G
∆Gcalc
∆∆Gcalc
NHa
NHb
[Ϫ1
]
[kJ molϪ1
]
[kJ molϪ1
]
[kJ molϪ1
]
DAAD·ADDA
DAAD·ADDA
DAAD·ADD
DAAD·DADD
DAAD·ADDA
DAAD·ADDA
DAAD·ADDA
24c·25a
24c·25b
24c·26
4.4
3.0
2.2
1.7
0.8
0.8
1.7
3.7
2.4
2.5
2.1
1.5
0.2
1.9
2000
160
40
31
47
16
271
Ϫ18.6
Ϫ12.5
Ϫ9.0
Ϫ8.4
Ϫ9.4
Ϫ6.8
Ϫ13.7
Ϫ17.9
Ϫ17.9
Ϫ15.8
Ϫ15.8
Ϫ17.9
Ϫ17.9
Ϫ17.9
Ϫ0.7
5.5
6.8
7.4
8.5
11.1
4.2
24a·27
24b·25a
24b·25b
23d·25a
sium hydroxide was added to the black filtrate, which was allowed
to stand for 15 h at 5 °C. The resulting solid was filtered off and
was dissolved in 20 mL of conc. acetic acid. After dilution with
40 mL of water, the solution was allowed to stand for one week at
5 °C. Brown needles crystallized and were filtered off, dried and
recrystallized twice [first from dimethyl sulfoxide/water (1:1), then
Experimental Section
General: For general information, see ref.[33]
N-Butyl-NЈ-(2,4-dimethyl-1,8-naphthyridin-7-yl)urea (13b): A solu-
tion of 7-amino-2,4-dimethyl-1,8-naphthyridine[15] (11, 1.73 g,
10.0 mmol) in 50 mL of dry toluene was mixed under nitrogen with from water], giving 1.50 g (24%) of colourless needles, m.p.
butyl isocyanate (12b, 990 mg, 10.0 mmol) and heated to reflux for
2 h. At room temp., the solid was filtered off, washed with toluene,
dried and recrystallized first from ethanol and then from toluene,
giving 1.97 g (72%) of a colourless solid, m.p. 204 °C. IR (KBr):
145Ϫ155 °C. IR (KBr): ν
˜ ϭ 3422 cmϪ1 (COOH), 3095 (NϪH),
1604 (CϭO), 1560, 1492 (arom.). 1H NMR (300 MHz,
[D6]DMSO): δ ϭ 2.51 (s, 3 H, CH3), 6.13 (d, J ϭ 8.1 Hz, 1 H,
ArH), 6.34 (br. s, 2 H, NH2), 6.87 (d, J ϭ 5.8 Hz, 1 H, ArH), 7.05
ν˜ ϭ 3330, 3180, 3050 cmϪ1 (NϪH), 2959, 2930, 2874 (aliph. CϪH), (br. s, 1 H, ArH), 7.43 (t, J ϭ 8.0 Hz, 1 H, ArH), 8.13 (d, J ϭ
1684 (CϭO), 1604, 1522 (arom.), 1560 (NϪH), 1458 (CϪH). 1H 5.6 Hz, 1 H, ArH) ppm. MS (EI, 70 eV): m/z (%) ϭ 199 (100). MS
NMR (500 MHz, CDCl3): δ ϭ 0.85 (t, J ϭ 7.3 Hz, 3 H, CH3), 1.32
(CI, isobutane): m/z (%) ϭ 245 (100). HR-MS: C12H12N4O2: calcd.
(mc, 2 H, CH2), 1.54 (mc, 2 H, CH2), 2.55 (s, 3 H, CH3), 2.62 (s, 3 244.0960, found 244.0960 (diff.: 0.1 ppm); C1113CH12N4O2: calcd.
H, CH3), 3.36 (q, J ϭ 6.4 Hz, 2 H, CH2), 6.99 (s, 1 H, ArH), 7.51 245.0994 found 245.0993 (diff.: 0.3 ppm).
(br. s, 1 H, ArH), 8.11 (d, J ϭ 9.2 Hz, 1 H, ArH), 9.52 (br. s, 1 H,
NH), 10.51 (br. s, 1 H, NH) ppm. MS (EI, 70 eV): m/z (%) ϭ 272
(20), 229 (42), 200 (70), 173 (85), 71 (100). MS (CI/isobutane):
m/z (%) ϭ 273 (100). C17H22N4O (272.4): calcd. C 66.15, H 7.40,
N 20.57, found C 65.99, H 7.38, N 20.48.
2-Amino-6-methylpyrido[2,3-b]-1,8-naphthyridin-5(10H)-one (17):
Conc. sulfuric acid (15 mL) was heated to 200 °C and 2-[(6-amino-
pyridin-2-yl)amino]-4-methyl-3-pyridinecarboxylic acid (16, 1.30 g,
5.33 mmol) was added in portions. After 10 min at 200 °C and
subsequent cooling to room temp., the mixture was hydrolysed
(100 mL of ice/water, 1:1) and, while cooling with ice, ca. 60 mL of
conc. ammonia was added carefully until pH ϭ 10 was reached.
After 1.5 h, the solid was filtered off, washed with water and dried,
resulting in 946 mg (79%) of a black solid, m.p. (dec.) Ͼ 260 °C.
IR (KBr): ν˜ ϭ 3373, 3125 cmϪ1 (NϪH), 1606 (CϭO), 1560, 1490
(arom.).
N-Cyclohexyl-NЈ-(2,4-dimethyl-1,8-naphthyridin-7-yl)urea (13c): A
solution of 7-amino-2,4-dimethyl-1,8-naphthyridine[15] (11,
1.73 mg, 10.0 mmol) and cyclohexyl isocyanate (12c, 2.48 g,
20.0 mmol) in 30 mL of dry toluene was heated to reflux under
nitrogen for 2 h. After cooling to room temp., the colourless solid
was filtered off, dried and recrystallized first from ethanol/toluene
(1:1) and then from toluene, giving 2.46 g (83%) of a colourless
solid, m.p. Ͼ 300 °C. IR (KBr): ν˜ ϭ 3446, 3181, 3034 cmϪ1 (NϪH),
2933, 2851 (aliph. CϪH), 1680 (CϭO), 1600, 1523 (arom.), 1554
N-(6-Methyl-5-oxo-5,10-dihydropyrido[2,3-b]-1,8-naphthyridin-2-
yl)acetamide (18a): Dry acetic anhydride (5 mL) was added under
1
(NϪH). H NMR (200 MHz, [D6]DMSO): δ ϭ 1.3Ϫ1.9 (m, 10 H,
nitrogen
to
2-amino-6-methylpyrido[2,3-b]-1,8-naphthyridin-
CH2), 2.57 (s, 6 H, CH3), 3.66 (mc, 1 H, CH), 7.18 (s, 1 H, ArH),
7.28 (d, J ϭ 9.0 Hz, 1 H, ArH), 8.35 (d, J ϭ 9.0 Hz, 1 H, ArH),
9.61 (br. d, J ϭ 7.2 Hz, 1 H, NH), 9.72 (s, 1 H, NH) ppm. MS (EI,
70 eV): m/z (%) ϭ 298 (21), 200 (42), 173 (100). MS (CI/isobutane):
m/z (%) ϭ 299 (100). C17H22N4O (298.4): calcd. C 68.43, H 7.43,
N 18.78, found C 68.20, H 7.34, N 18.56.
5(10H)-one (17, 100 mg, 442 µmol). After having been heated at
reflux for 5 h, the mixture was cooled to room temp. and was hy-
drolysed by addition of 20 mL of water and 2  sodium hydroxide
until pH ϭ 10 was reached. The resulting solid was filtered off,
dried and recrystallized from dimethyl sulfoxide, yielding 59.0 mg
(50%) of a yellow solid, m.p. Ͼ 300 °C. IR (KBr): ν˜ ϭ 3414, 3244
cmϪ1 (NH), 2920 (aliph. CϪH), 1696, 1620 (CϭO), 1582 (arom.).
1H NMR (300 MHz, [D6]DMSO): δ ϭ 2.20 (s, 3 H, CH3), 7.12 (d,
J ϭ 4.8 Hz, 1 H, ArH), 8.00 (d, J ϭ 8.7 Hz, 1 H, ArH), 8.46 (d,
2-[(6-Aminopyridin-2-yl)amino]-4-methyl-3-pyridinecarboxylic Acid
(16): 2,6-diaminopyridine (14, 10.6 g, 97.2 mmol), 2-bromo-4-
methyl-3-pyridinecarboxylic acid (15, 5.42 g, 25.1 mmol), dry pot-
assium carbonate (5.84 g, 42.3 mmol), potassium iodide (ca. J ϭ 8.8 Hz, 1 H, ArH), 8.55 (d, J ϭ 4.7 Hz, 1 H, ArH), 10.72 (br.
100 mg) and powdered copper (ca. 100 mg) were ground and s, 1 H, NH), 12.20 (br. s, 1 H, NH) ppm. MS (EI, 70 eV): m/z
heated to 170 °C under nitrogen for 4 h. After cooling, the black
(%) ϭ 268 (61), 253 (8), 226 (100), 198 (13). MS (CI, isobutane):
m/z (%) ϭ 269 (100). HR-MS: C14H12N4O2: calcd. 268.0960, found
solid was extracted with 70 mL of boiling ethyl acetate. After filtra-
tion of the hot solution, the solid residue was extracted with 70 mL 268.0959 (diff.: 0.5 ppm); C1313CH12N4O2: calcd. 269.0994, found
of boiling water. After filtration of the hot solution, 15 g of potas-
269.0993 (diff.: 0.4 ppm).
Eur. J. Org. Chem. 2002, 4063Ϫ4070
4067

U. Lüning, C. Kühl, A. Uphoff
N-(6-Methyl-5-oxo-5,10-dihydropyrido[2,3-b]-1,8-naphthyridin-2- uct was mixed with triethylamine (460 mg, 4.6 mmol) and ethyl cy-
FULL PAPER
yl)pentanamide (18b): Valeryl chloride (1.28 g, 10.6 mmol) was
slowly added under nitrogen to a mixture of 2-amino-6-methylpyr-
anoacetate (880 mg, 7.8 mmol). The mixture was stirred, under ni-
trogen and protected from light, for 2 d at room temp. After addi-
ido[2,3-b]-1,8-naphthyridin-5(10H)-one (17, 800 mg, 3.34 mmol) in tion of diethyl ether, some solid was filtered off and the solution
40 mL of dry pyridine and triethylamine (1.07 g, 10.6 mmol). After
having been heated at reflux for 2 h, the solvents were removed in
vacuo and the residue was dissolved in 400 mL of dichloromethane
and 160 mL of 0.5  sodium carbonate solution. The layers were
separated, and the aqueous layer was extracted three times with
100 mL of dichloromethane. The organic layer was filtered and the
resulting solid was washed with ethanol and dried (crude yield:
687 mg). The dichloromethane and the ethanol layers were com-
bined and the solvents were evaporated. Recrystallization from
was washed first with hydrochloric acid (pH ϭ 2) until the aqueous
layer remained acidic (three times), and then with water. After dry-
ing with MgSO4, the solvent was removed and the remaining yel-
lowish oil was purified by chromatography [150 mL of silica gel,
0.04Ϫ0.063 mm, first CH2Cl2 until all ethyl cyanoacetate had been
removed, then CH2Cl2/EtOH (10:1), detection with anisaldehyde:
red], giving 151 mg (0.46 mmol, 18% for 2 steps) of a brown oil.
IR (film): ν˜ ϭ 3326 cmϪ1 (NϪH), 2933 (aliph.), 2259 (CN), 1682
(several CϭO), ca. 1538 (amide, arom.), 1367 (CϪH). 1H NMR
DMSO/H2O (ca. 2:1) gave 531 mg (51%) of 18b, m.p. Ͼ 260 °C. (200 MHz, CDCl3): δ ϭ 1.2Ϫ2.0, 1.45 (br. m, CH2, CH, s, tBu, 16
IR (KBr): ν˜ ϭ 3320 cmϪ1 (NϪH), 2925 (aliphat. C-H), 1675, 1621 H), 3.3 (br. m, ca. 2 H, CH2N), 3.38 (s, ca. 2 H, CH2CN), 3.75 (s,
1
(CϭO), 1516 (arom.). H NMR (300 MHz, [D6]DMSO): δ ϭ 0.91
3 H, CH3), 4.3 (br. s, 1 H, NH), 6.4 (br. s, 1 H, NH) ppm. MS (EI,
(t, J ϭ 7.2 Hz, 3 H, CH3), 1.2Ϫ1.4 (m, 2 H, CH2), 1.60 (mc, 2 H, 70 eV): m/z (%) ϭ 271 (3), 239 (2), 212 (16), 168 (13), 152 (9), 151
CH2), 2.90 (s, 3 H, CH3), 7.12 (d, J ϭ 4.8 Hz, 1 H, ArH), 8.04 (d,
J ϭ 8.8 Hz, 1 H, ArH), 8.46 (d, J ϭ 9.0 Hz, 1 H, ArH), 8.55 (d,
J ϭ 4.8 Hz, 1 H, ArH), 10.66 (s, 1 H, NH), 12.17 (s, 1 H, NH)
ppm. MS (EI, 70 eV): m/z (%) ϭ 310 (41), 226 (100). MS (CI,
isobutane): m/z (%) ϭ 311 (100). HR-MS: C17H18N4O2: calcd.
310.1430, found 310.1430 (diff.: Ϫ0.1 ppm); C1613CH18N4O2: calcd.
311.1463, found 311.1464 (diff.: Ϫ0.2 ppm). C17H18N4O2 (310.4):
calcd. C 65.79 H 5.85 N 18.05, found C 65.22 H 5.64 N 17.71.
(100), 84 (11). MS (CI/isobutane): m/z (%) ϭ 328 (4), 272 (24), 229
(11), 228 (100), 151 (11).
2,7-Diamino-1,8-naphthyridine-3-carboxamide (23a): 2,6-Diamino-
pyridine-3-carbaldehyde[25] (21, 1.57 g, 11.5 mmol), cyanoacetam-
ide (22a, 19.3 g, 230 mmol) and piperidine (5 mL) were dissolved
under nitrogen in dry ethanol (150 mL) and heated to reflux for
3.5 h. After removal of the solvent, the residue was partitioned be-
tween 150 mL of water and 150 mL of dichloromethane. The layers
were separated and the yellow solid at the interface between the
layers was filtered off. The aqueous layer was extracted three times
with 50 mL of dichloromethane. The solid which formed at the
interface was filtered off each time. After thorough washing with
water and dichloromethane the residue was dried, giving 1.45 g
(62%) of a yellow solid, m.p. 203Ϫ206 °C. IR (KBr): ν˜ ϭ 3399,
3350, 3197, 3076 cmϪ1 (NϪH), 1651 (CϭO), 1616, 1566, 1496
Nε-Benzyloxycarbonyl-Nα-tert-butoxycarbonyllysine Methyl Ester
(19b): A solution of diazomethane in diethyl ether was added to
the doubly N-protected lysine 19a (1.00 g, 2.63 mmol) in 25 mL of
dry methanol until the mixture remained yellow. Gas was evolved,
the mixture was stirred for an additional 1 h, and the degree of
conversion was checked by TLC [CH2Cl2/EtOH (20:1): Rf(acid,
19a) ϭ 0.16; Rf(ester, 19b) ϭ 0.53]. Ca. 200 mg of silica gel was
added to decompose excess diazomethane. After filtration, the solv-
ent was evaporated in vacuo, giving 1.09 g of a colourless oil. IR
(film): ν˜ ϭ 3337 cmϪ1 (NϪH), 2950 (aliphat.), 1704 (CϭO), 1530
(amide, arom.), 1455, 1366 (CϪH), 1252 (CϪO). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.2Ϫ1.9, 1.44 (m, CH, CH2, s, tBu, 16 H),
3.19 (mc, 2 H, CH2NH), 3.73 (s, 3 H, OCH3), 4.28 (br. m, 1 H,
NH), 4.82 (br. s, 1 H, NH), 5.09 (s, ca. 2 H, ArCH2, traces of H2O),
7.74 (m, 5 H, ArH) ppm. MS (EI, 70 eV): m/z (%) ϭ 394 (Ͻ 1),
338 (6), 294 (12), 235 (8), 218 (21), 91 (100). MS (CI/isobutane):
m/z (%) ϭ 395 (7), 339 (19), 295 (100), 231 (17), 91 (32).
1
(arom.), 1547 (NϪH). H NMR (200 MHz, [D6]DMSO): δ ϭ 6.44
(d, J ϭ 8.6 Hz, 1 H, ArH), 6.69 (br. s, 2 H, NH2), 7.32 (br. s, 4 H,
NH2), 7.59 (d, J ϭ 8.6 Hz, 1 H, ArH), 8.21 (s, 1 H, ArH) ppm.
MS (EI, 70 eV): m/z (%) ϭ 203 (100), 186 (14), 159 (41), 131 (24),
105 (20). MS (CI/isobutane): m/z (%) ϭ 204 (100). HR-MS:
C9H9N5O: calcd. 203.0807, found 203.0799; C813CH9N5O: calcd.
204.0841, found 204.0840.
Nα-tert-Butoxycarbonyl-Nε-[(2,7-diamino-1,8-naphthyridin-3-
yl)carbonyl]lysine Methyl Ester (23d): Nα-tert-Butoxycarbonyl-Nε-
(2-cyanoacetyl)lysine methyl ester (20, 320 mg, 1.0 mmol) and 2,6-
diaminopyridine-3-carbaldehyde[25] (21, 140 mg, 1.0 mmol) in 8 mL
of dry methanol were mixed with piperidine (0.5 mL, ca. 5 mmol).
The solution was heated at reflux under nitrogen for 18 h. After
filtration, the organic layer was concentrated in vacuo to ca. 1 mL
and was purified by chromatography [150 mL of silica gel,
0.06Ϫ0.04 mm, CH2Cl2/MeOH (10:3)] giving 260 mg (59%) of a
yellow solid, which crystallized only slowly, m.p. 98Ϫ105 °C. IR
(KBr): ν˜ ϭ 3346 cmϪ1 (NH), 2932 (aliph.), 1737, 1700 (CϭO),
1551, 1493 (amid, arom.), 804 (arom.). 1H NMR (500 MHz,
CDCl3): 1.2Ϫ2.0, 1.39 (br. m, CH2, CH, s, tBu, 16 H), 3.44 (br. t,
J ϭ 5.4 Hz, 2 H, CH2N), 3.74 (s, 3 H, CH3), 4.32 (br. s, 1 H, NH),
4.99 (br. s, 1.5 H, NH), 5.13 (br. s, 1 H, NH), 6.37 (br. s, 0.5 H,
NH), 6.45 (br. d, J ϭ 7.7 Hz, 1 H, ArH), 6.55 (br. s, 1 H, NH),
7.63 (br. d, J ϭ 7 Hz, 1 H, ArH), 7.90 (br. s, 1 H, ArH) ppm. MS
(EI, 70 eV): m/z (%) ϭ 446 (16), 389 (7), 387 (8), 373 (7), 346 (6),
331 (9), 281 (6), 270 (11), 258 (13), 230 (8), 216 (27) 187 (100) 160
(51) 132 (29). MS (CI/isobutane): m/z (%) ϭ 447 (84), 347 (29), 264
(34), 163 (84), 69 (100). HR-MS: C21H30N6O5 calcd. 446.22778,
found 446.22770; C2013CH30N6O: calcd. 447.23111, found
447.23111.
Nα-tert-Butoxycarbonyllysine Methyl Ester (19c): The doubly pro-
tected ester 19b (1.075 g, 2.73 mmol) was placed under nitrogen in
a
round-bottomed flask, and methanol (5 mL), acetic acid
(0.45 mL) and Pd/C (10% Pd, 200 mg) were then added. The flask
was flushed with hydrogen and shaken for 4 h. After flushing with
nitrogen, the catalyst was filtered off and washed with methanol.
The combined methanol layers were concentrated in vacuo and
purified by chromatography on silica gel [CH2Cl2/MeOH (10:3)].
Yield: 423 mg (62%) of a slightly yellow oil. IR (film): ν˜ ϭ 3303
cmϪ1 (NϪH), 2932 (aliph.), 1710 (CϭO), 1525 (amide, arom.),
1366 (CϪH), 1250 (CϪO). 1H NMR (200 MHz, CDCl3): δ ϭ
1.9Ϫ1.3, 1.34 (br. m, CH2, CH, s, tBu, 16 H), 2.9 (m, 2 H, CH2N),
3.74 (s, 3 H, CH3), 4.25 (br. s, 1 H, NH), 5.6 (br. m, 1 H, NH)
ppm. MS (EI, 70 eV): m/z (%) ϭ 260 (5), 204 (18), 187 (21), 160
(10), 143 (27), 142 (34), 116 (16), 87 (12), 84 (100), 82 (10), 72 (20).
MS (CI/isobutane): m/z (%) ϭ 261 (100), 205 (100), 61 (95).
Nα-tert-Butoxycarbonyl-Nε-(2-cyanoacetyl)lysine Methyl Ester (20):
Boc-protected lysine methyl ester 19c was synthesized from the
doubly protected ester 19b (2.6 mmol) as described above, but no
purification by chromatography was undertaken. The crude prod-
4068
Eur. J. Org. Chem. 2002, 4063Ϫ4070

Four Hydrogen Bonds Ϫ DDAA, DADA, DAAD and ADDA Hydrogen Bond Motifs
2,7-Bis(2,2-dimethylpropanoylamino)-1,8-naphthyridine-3-carb- methane/water mixture (1:1). The layers were separated and the
FULL PAPER
oxamide (24a): A suspension of 2,7-diamino-1,8-naphthyridine-3-
carboxamide (23a, 100 mg, 493 µmol) in 5 mL of dry pyridine was
treated under nitrogen with triethylamine (174 mg, 1.72 mmol). 2,2-
Dimethylpropanoyl chloride (178 mg, 1.48 mmol) was then added
carefully at 0 °C, and the mixture was heated at reflux for 1 h.
After removal of the solvents, the residue was dissolved in 50 mL
of dichloromethane. The organic layer was washed with 20 mL of
1  sodium carbonate solution and extracted five times with 20 mL
of dichloromethane. The combined organic layers were dried with
sodium sulfate and the solvent was removed in vacuo. The re-
aqueous layer was extracted five times with 100 mL of dichlorome-
thane. The aqueous layer was then continuously extracted with
dichloromethane for 50 h. The combined organic layers were dried
with sodium sulfate and the solvent was evaporated in vacuo. The
remaining yellow solid (4.88 g) was purified by double chromato-
graphy on silica gel: (i) (90 g), dichloromethane/ethanol (10:1),
Rf ϭ 0.75, (1.79 g); (ii) (90 g), dichloromethane/ethanol (10:1). The
resulting solid was recrystallized from toluene, giving 1.57 g (62%)
of a colourless solid, m.p. 211 °C. IR (KBr): ν˜ ϭ 3368, 3331, 3256
cmϪ1 (NϪH), 2957, 2929, 2871 (aliph. CϪH), 2228 (CϵN), 1687
maining oil was purified by triple chromatography on silica gel: (i) (CϭO), 1605, 1570, 1504 (arom.), 1535 (NϪH). 1H NMR
1 ϫ 5 cm, acetone, Rf ϭ 0.90; (ii) 2 g, dichloromethane/ethanol
(10:1), Rf ϭ 0.72 (nitrile 24b), Rf ϭ 0.65 (amide 24a); (iii) 1 g,
(500 MHz, CDCl3): δ ϭ 0.96 (t, J ϭ 7.4 Hz, 3 H, CH3), 0.97 (t,
J ϭ 7.4 Hz, 3 H, CH3), 1.45 (sext, J ϭ 7.5 Hz, 2 H, CH2), 1.46
dichloromethane/ethanol (10:1). Nitrile 24b was first recrystallized (sext, J ϭ 7.5 Hz, 2 H, CH2), 1.75 (quint, J ϭ 7.4 Hz, 2 H, CH2),
from toluene/ethanol (10:1) and then from toluene, giving 61.0 mg
(35%) of a yellowish solid, m.p. 183Ϫ185 °C (analytical data see
below). The amide 24a was recrystallized from toluene/ethanol
1.78 (quint, J ϭ 7.4 Hz, 2 H, CH2), 2.49 (t, J ϭ 7.5 Hz, 2 H, CH2),
2.69 (t, J ϭ 7.5 Hz, 2 H, CH2), 8.15 (br. s, 1 H, NH), 8.18 (d, J ϭ
8.9 Hz, 1 H, ArH), 8.35 (br. s, 1 H, NH), 8.49 (s, 1 H, ArH), 8.59
(20:1), giving 25 mg (14%) of colourless needles, m.p. 204 °C. IR (d, J ϭ 8.9 Hz, 1 H, ArH) ppm. MS (EI, 70 eV): m/z (%) ϭ 353
(KBr): ν˜ ϭ 3382, 3183 cmϪ1 (NϪH), 2970 (aliph. CϪH), 1704,
1676 (CϭO), 1607, 1582 (arom.), 1531 (NϪH), 1383 (tert-butyl,
(9), 324 (28), 296 (4), 269 (24), 240 (20), 212 (10), 185 (100). MS
(CI/isobutane): m/z (%) ϭ 354 (100). HR-MS: C19H23N5O2: calcd.
CϪH). 1H NMR (300 MHz, [D6]DMSO): δ ϭ 1.26 [s, 9 H, 353.1852, found 353.1852; C1813CH23N5O2: calcd. 354.1885, found
C(CH3)3], 1.29 [s, 9 H, C(CH3)3], 7.96 (br. s, 1 H, NH), 8.31 (mc,
354.1885. C19H23N5O2 (353.4): calcd. C 64.57, H 6.56, N 19.82,
2 H, ArH), 8.52 (br. s, 1 H, NH), 10.56 (br. s, 1 H, NH), 11.95 (br. found C 63.89 H 6.43 N 19.37.
s, 1 H, NH) ppm. MS (EI, 70 eV): m/z (%) ϭ 371 (4), 353 (6), 314
N,NЈ-Dipyridin-2-ylurea
(25a):
2-Aminopyridine
(50.0 g,
(100), 296 (9), 269 (12), 213 (14), 187 (6). MS (CI/isobutane): m/z
(%) ϭ 372 (100). C19H23N5O2 (371.5): calcd. C 61.44, H 6.78, N
18.85, found C 61.21, H 6.71, N 18.69.
532 mmol) was dissolved under nitrogen in dry pyridine (150 mL),
and ethyl chloroformate (75.0 g, 691 mmol) was added at 0 °C.
After the mixture had been kept for 15 h at 5 °C, ice-cold water
(250 mL) was added, and the solid was filtered off, washed thor-
oughly with water and dried. The yellow solid was recrystallized
N-{3-Cyano-7-[(2,2-dimethylpropanoyl)amino]-1,8-naphthyridin-2-
yl}-2,2-dimethylpropanamide (24b): Triethylamine (435 mg,
4.31 mmol) and 2,2-dimethylpropanoyl chloride (830 mg, from ethanol, giving colourless crystals of ethyl pyridin-2-ylcarba-
6.88 mmol) were added dropwise under nitrogen to a suspension
of 2,7-diamino-1,8-naphthyridine-3-carboxamide (23a, 350 mg,
1.72 mmol) in 20 mL of dry pyridine. After the mixture had been
heated at reflux for 2 h, the solvents were removed in vacuo and
the residue was dissolved in 50 mL of dichloromethane. The or-
ganic layer was washed with 20 mL of 2  sodium carbonate solu-
tion and with 20 mL of water. The aqueous layer was extracted
twice with 20 mL of dichloromethane. The combined organic layers
were dried with sodium sulfate and the solvent was removed in
vacuo, giving 541 mg of crude product which was purified by triple
chromatography on silica gel: (i) 5 g, dichloromethane/ethanol
(10:1), Rf ϭ 0.72, (ii) 3 g, dichloromethane/ethanol (10:1), (iii) 1 g,
dichloromethane/ethanol (10:1). The resulting solid was first
mate (104.9 g, 67%, 70%[27]), m.p. 95 °C. IR (KBr): ν˜ ϭ 3183 cmϪ1
(NϪH), 2987 (aliph. CϪH), 1725 (CϭO), 1586 (arom.), 1538
(NϪH), 1440 (CϪH), 1223, 1070 (CϪO). 1H NMR (90 MHz,
CDCl3): δ ϭ 1.35 (t, J ϭ 7.5 Hz, 3 H, CH3), 4.27 (q, J ϭ 7.5 Hz,
2 H, CH2), 6.97 (mc, 1 H, py-H), 7.68 (mc, 1 H, py-H), 8.07 (d,
J ϭ 8.4 Hz, 1 H, py-H), 8.38 (mc, 1 H, py-H), 10.33 (br. s, 1 H,
NH) ppm. MS (EI, 70 eV): m/z (%) ϭ 166 (74), 121 (23), 107 (27),
94 (100). MS (CI/isobutane): m/z (%) ϭ 167 (100). The ethyl pyri-
din-2-ylcarbamate (16.6 g, 100 mmol) and 2-aminopyridine (14.1 g,
150 mmol) were dissolved under nitrogen in pyridine (200 mL) and
heated at reflux for 6 d. After evaporation of the solvent, dichloro-
methane (500 mL) was added and the organic layer was washed
with water (5 times 100 mL). After drying with magnesium sulfate,
recrystallized from toluene/ethanol (10:1) and then from toluene, the solvent was evaporated and the residue was recrystallized first
giving 258 mg (43%) of a yellowish solid, m.p. 181Ϫ183 °C. IR from ethanol/cyclohexane (1:2) and then from toluene, giving
(KBr): ν˜ ϭ 3438, 3221 cmϪ1 (NϪH), 2969 (aliph. CϪH), 2231 8.62 g (40%) of 25a (33%[28]), m.p. 169Ϫ170 °C. IR (KBr): ν˜ ϭ
(CϵN), 1702, 1683 (CϭO), 1608, 1515 (arom.), 1566 (NϪH), 1478
3436, 3221, 3064 cmϪ1 (NϪH), 2999 (aliph. CϪH), 1700 (CϭO),
(CϪH). 1H NMR (500 MHz, CDCl3): δ ϭ 1.36 (s, 9 H, CH3), 1.40 1603, 1574, 1510 (arom.), 1554 (NϪH). 1H NMR (500 MHz,
(s, 9 H, CH3), 8.16 (br. s, 1 H, NH), 8.22 (d, J ϭ 8.9 Hz, 1 H, CDCl3): δ ϭ 6.99 (dd, J ϭ 7.9, J ϭ 5.1 Hz, 2 H, py-H), 6.9Ϫ8.4
ArH), 8.47 (br. s, 1 H, NH), 8.52 (s, 1 H, ArH), 8.62 (d, J ϭ 9.0 Hz,
1 H, ArH) ppm. MS (EI, 70 eV): m/z (%) ϭ 353 (32), 296 (100), (d, J ϭ 5.0 Hz, 2 H, py-H), 9.5Ϫ12.0 (br. s, 2 H, NH) ppm. MS
269 (85), 212 (32), 185 (78). MS (CI/isobutane): m/z (%) ϭ 354 (EI, 70 eV): m/z (%) ϭ 214 (10), 121 (28), 94 (100), 78 (20). MS
(br. s, 2 H, py-H), 7.70 (dd, J ϭ 7.8, J ϭ 7.7 Hz, 2 H, py-H), 8.37
(100). C19H23N5O2 (353.4): calcd. C 64.57, H 6.56, N 19.82, found (CI/isobutane): m/z (%) ϭ 215 (100).
C 64.48, H 6.66, N 19.78.
NMR Titrations: 1H NMR titrations were performed in CDCl3
N-{3-Cyano-7-(pentanoylamino)-1,8-naphthyridin-2-yl}pentanamide
(24c): 2,7-Diamino-1,8-naphthyridine-3-carboxamide (23a, 1.45 g,
7.14 mmol) was suspended under nitrogen in 30 mL of dry pyrid-
ine. First triethylamine (2.16 g, 21.4 mmol), and then valeryl chlor-
ide (3.46 g, 28.6 mmol), were added dropwise, and the suspension
was heated to reflux for 2 h. After removal of the solvents in vacuo,
the dark residue was dried and dissolved in 200 mL of a dichloro-
with the aid of a Bruker DRX 500, starting with ca. 5·10Ϫ3  of
one component. For Kass ϭ 400, the choice of this concentration
gives 50% complexation at 1:1 stoichiometry. The partner was ad-
ded in small aliquots in such a way that several data points could
be measured in the vicinity of 1:1 stoichiometry. Data points with
very high or low ratios of the two components are of lower signific-
ance because at 1:1 stoichiometry the difference between an ob-
Eur. J. Org. Chem. 2002, 4063Ϫ4070
4069

U. Lüning, C. Kühl, A. Uphoff
FULL PAPER
[17]
[18]
[19]
[20]
[21]
[22]
[23]
[24]
U. Lüning, C. Kühl, M. Bolte, Acta Crystallogr., Sect. C 2001,
57, 989Ϫ990.
M. Bolte, C. Kühl, U. Lüning, Acta Crystallogr., Sect. E 2001,
57, 502Ϫ504.
S. C. Zimmerman, P. S. Corbin, J. Am. Chem. Soc. 2000, 122,
3779Ϫ3780.
served complexation-induced chemical shift and the theoretical
values for maximum complexation is largest.
Acknowledgments
J. J. Baldwin, A. W. Raab, G. S. Ponticello, J. Am. Chem. Soc.
1978, 100, 2529Ϫ2535.
We thank Dr. M. Bolte for his interest in our work and for the X-
ray analyses[17,18] he carried out.
Meijer’s DDAA unit may equilibrate to a tautomeric DADA
unit, see ref.[9]
P. E. Nielsen, M. Egholm, R. H. Berg, O. Buchardt, Science
1991, 254, 1497Ϫ1500.
Peptide Nucleic Acids: Protocols and Applications (Eds.: P. E.
Nielsen, M. Egholm), Horizon Scientific Press, Oxford, 1999
U. Diederichsen, H. W. Schmitt, Angew. Chem. 1998, 110,
312Ϫ315; Angew. Chem. Int. Ed. 1998, 37, 302Ϫ305 and refs.
cited.
[1]
See for example: L. Stryer, Biochemistry, W. H. Freeman and
Company, New York, 1995.
When several hydrogen bonds are positioned next to each
[2]
other, the hydrogen bond donor and acceptor sites may be loc-
ated on the same or on opposite sides (e.g., DD·AA versus
DA·DA). We use the expressions parallel and anti-parallel, re-
spectively. In a parallel orientation, additional attractive sec-
ondary interactions exist, while the secondary interactions in
an anti-parallel orientation are repulsive; see also ref.[4]
[25]
E. E. Fenlon, T. J. Murray, M. H. Baloga, S. C. Zimmerman,
J. Org. Chem. 1993, 58, 6625Ϫ6628.
[26]
[27]
U. Lüning, C. Kühl, Tetrahedron Lett. 1998, 39, 5735Ϫ5738.
Ethyl pyridin-2-ylcarbamate and ethyl 6-methylpyridin-2-ylcar-
bamate: A. R. Katritzky, J. Chem. Soc. 1956, 2063Ϫ2064.
Beilsteins Handbuch der Organischen Chemie, 4th ed., 3rd and
4th Ergänzungswerk, vol. 22, Springer Verlag, Berlin, 1979, p.
3896.
N,NЈ-Bis(6-methyl-2-pyridyl)urea: G. R. Clemo, B. W. Fox, R.
Raper, J. Chem. Soc. 1954, 2693Ϫ2701.
Corbin, Zimmerman et al. have carried out more detailed ex-
periments for closely related systems, to prove the four hydro-
gen bonds; see ref.[27]
Binding constants Kass for complex formation between a host
H and a guest G can be calculated as follows: the total concen-
tration of the host [H]0 is the sum of the free concentration of
the host [H] and the concentration of the complex [HG]: [H]0 ϭ
[H] ϩ [HG] (1). If the kinetics are fast on the NMR timescale,
the observed chemical shift δobs is the weighted average of the
shifts of the host δfree and the complex δmax: δobs ϭ δfree[H]/
[H]0 ϩ δmax[HG]/[H]0 (2). The differences in chemical shifts
See ref.[1], part V.
[3]
[4]
This rule has exceptions. According to investigations by Schnei-
[28]
der et al.,[5] each hydrogen bond contributes approx. 8 kJ/mol
to the binding enthalpy. However, when hydrogen bonds are
oriented next to each other, secondary Coulomb interac-
tions[6,7] either favour or disfavour binding. Two parallel bonds
additionally contribute approx. 3 kJ/mol while anti-parallel hy-
drogen bonds reduce the binding enthalpy by approx. 3 kJ/mol,
due to electrostatic repulsions.
[29]
[30]
[5]
J. Sartorius, H.-J. Schneider, Chem. Eur. J. 1996, 2, 1446Ϫ1452.
[6]
[31]
W. L. Jorgensen, J. Pranata, J. Am. Chem. Soc. 1990, 112,
2008Ϫ2010.
[7]
S. C. Zimmerman, P. S. Corbin, Struct. Bonding 2000, 96,
63Ϫ94.
F. H. Beijer, H. Kooijman, A. L. Spek, R. P. Sijbesma, E. W.
[8]
Meijer, Angew. Chem. 1998, 110, 79Ϫ82; Angew. Chem. Int. Ed.
1998, 37, 75Ϫ78.
F. H. Beijer, R. P. Sijbesma, H. Kooijman, A. L. Spek, E. W.
[9]
Meijer, J. Am. Chem. Soc. 1998, 120, 6761Ϫ6769.
∆δobs (∆δobs ϭ δobs Ϫ δfree) and ∆δmax (∆δmax ϭ δmax Ϫ δfree)
[10]
B. J. B. Folmer, R. P. Sijbesma, E. W. Meijer, J. Am. Chem.
are related by: ∆δobs ϭ ∆δmax[HG]/[H]0 (3). The same consid-
erations can be made for the guest concentration and chemical
shifts, respectively. Host, guest and complex are in equilibrium:
Kass ϭ [HG]/[H][G] (4). Combination of these equations gives:
Soc. 2001, 123, 2093Ϫ2094, and refs. cited.
Further DDAA systems have been described, but tautomeriz-
ation may occur, altering the DDAA sequence into a DADA:
P. S. Corbin, S. C. Zimmerman, J. Am. Chem. Soc. 1998, 120,
9710Ϫ9711.
[11]
Kass ϭ ∆δobs/∆δmax·(1 Ϫ ∆δobs/∆δmax) /
Ϫ1·([G]0 Ϫ [H]0·∆δobs
Ϫ1
∆δmax
)
(5). Thus, Kass can be calculated from the chemical
[12]
R. P. Sijbesma, F. H. Beijer, L. Brunsveld, B. J. B. Folmer, J.
shift differences ∆δobs if ∆δmax is known or fitted. Mathemat-
H. K. K. Hirschberg, R. F. M. Lange, J. K. L. Lowe, E. W.
Meijer, Science 1997, 278, 1601Ϫ1604.
L. Brunsveld, B. J. B. Folmer, E. W. Meijer, R. P. Sijbesma,
Chem. Rev. 2001, 101, 4071Ϫ4097.
DDAA and DADA arrays with a larger distance between the
four hydrogen bonds have also been reported: B. Gong, Y. Yan,
H. Zeng, E. Skrzypczak-Jankunn, Y. W. Kim, J. Zhu, H. Ickes,
J. Am. Chem. Soc. 1999, 121, 5607Ϫ5608.
D. K. J. Gorecki, E. M. Hawes, J. Med. Chem. 1977, 20,
838Ϫ841.
Related DDAA and DAAD sequences have been investigated
recently by: P. S. Corbin, S. C. Zimmerman, P. A. Thiessen, N.
A. Hawryluk, T. J. Murray, J. Am. Chem. Soc. 2001, 123,
10475Ϫ10488.
ical treatment of this equation gives: ∆δobs
∆δmax·[H]0Ϫ1·([H]0 ϩ [G]0 ϩ KassϪ1)·0.5 Ϫ [([H]0 Ϫ [G]0
ϭ
ϩ
KassϪ1)2·0.25 ϩ [G]0/Kass)]0·5 (6). This correlates the parameters
∆δobs and [G]0 of the titration curves (see Figure 5), with Kass
and ∆δmax being the parameters to be fitted.
The related compounds 26 (ADD) and 27 (DADD) have been
synthesized by addition of 2-aminopyridine or 2,6-diaminopyr-
idine, respectively, to butyl isocyanate. For 26 see: G. Crosby,
F. Niemann, J. Am. Chem. Soc. 1954, 76, 4458Ϫ4462.
S. Brammer, U. Lüning, C. Kühl, Eur. J. Org. Chem. 2002,
4054Ϫ4062 .
[13]
[14]
[32]
[15]
[33]
[34]
[16]
In this case, the estimation of ref.[5] fits well, but see ref.[7]
Received May 3, 2002
[O02240]
4070
Eur. J. Org. Chem. 2002, 4063Ϫ4070