CH???O hydrogen bonds in "clicked" diketopiperazine-based amide rotaxanes

Article abstract of DOI:10.1021/ol201915j

Two amide [2]rotaxanes were synthesized in high yields using a novel N,N′-dipropargyl diketopiperazine axle centerpiece as the template to which the stoppers are attached through "click chemistry". ¹H and 2D NMR spectra provide evidence for two different H-bonding motifs, in one of which the triazole CH groups form C-H???O=C bonds with the wheel carbonyl O atoms. This motif can be controlled and switched reversibly by competitive anion binding.

Full text of DOI:10.1021/ol201915j

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4838–4841
CH O Hydrogen Bonds in “Clicked”
3 3 3
Diketopiperazine-Based Amide Rotaxanes
†
†
†
†
€
Egor V. Dzyuba, Lena Kaufmann, Nora L. Low, Annika K. Meyer,
Henrik D. F. Winkler,† Kari Rissanen,‡ and Christoph A. Schalley*,†
€
Institut fu€r Chemie und Biochemie, Freie Universitat Berlin, Takustrasse 3, D-14195
Berlin, Germany, and Department of Chemistry, Nanoscience Center, University of
€
€
€
€
Jyvaskyla, P.O. Box 35, 40014 Jyvaskyla, Finland
christoph@schalley-lab.de
Received July 15, 2011
ABSTRACT
Two amide [2]rotaxanes were synthesized in high yields using a novel N,N0-dipropargyl diketopiperazine axle centerpiece as the template to which the
stoppers are attached through “click chemistry”. 1H and 2D NMR spectra provide evidence for two different H-bonding motifs, in one of which the triazole
CH groups form CꢀH OdC bonds with the wheel carbonyl O atoms. This motif can be controlled and switched reversibly by competitive anion binding.
3 3 3
1
€
Hunter/Vogtle-type tetralactam macrocycles (TLMs)
host and guest. Even though these forces do not contribute
as much after substitution of the amide N-atoms with
groups suitable for stopper attachment, diketopiperazines
should be useful templates for the synthesis of interlocked
amide rotaxanes. Here, we report the N,N0-dipropargyl
diketopiperazine-templated synthesis of [2]rotaxanes
through “click” reactions, their structural characterization,
and their responsiveness to anions as external stimuli.
According to NMR experiments performed at 233 K, the
two pseudorotaxanes PS1 and PS2 (Figure 1) form with
similar free binding enthalpies of ΔG ≈ 18 kJ molꢀ1. Both
axles are functionalized at the diketopiperazine N-atoms
and bear solubilizing C11H21 side chains. The triazole rings
in PS2 do not appear to cause large differences in ΔG.
bind guest molecules, e.g. dicarbonyl compounds,2 inside
their cavities by H-bonding and have thus been used for
anion-3 or amide-templated4 rotaxane syntheses. Hunter
et al. reported diketopiperazine to form very stable hostꢀ
guest complexes with TLMs (Ka = 106 Mꢀ1 in CDCl3 and,
depending on substitution, Ka = 100ꢀ760 Mꢀ1 in H2O).5
Such high binding constants were explained by NꢀH
π
3 3 3
and CꢀH π interactions that add to the H-bonds between
3 3 3
†
€
Freie Universitat Berlin.
University of Jyvaskyla.
‡
€
€
€
(1) (a) Hunter, C. A. J. Am. Chem. Soc. 1992, 114, 5305. (b) Vogtle,
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Spickermann, C.; Reckien, W.; Schalley, C. A. J. Am. Chem. Soc. 2010,
132, 484. (e) Spickermann, C.; Felder, T.; Schalley, C. A.; Kirchner, B.
Chem.;Eur. J. 2008, 14, 1216. (f) Sokolowski, M.; Kossev, I.; Reckien,
W.; Felder, T.; Kishan, M. R.; Schalley, C. A. J. Phys. Chem. C 2009,
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r
10.1021/ol201915j
Published on Web 08/16/2011
2011 American Chemical Society

The major difference between the two [2]rotaxanes R1 and
R2 (Figure 3) is that the tritylphenyl stopper groups are
directly attached to the triazole in R1, with one of the phenyl
groups in conjugation with the triazole, while it is connected to
the triazole through a flexible chain in R2 and thus is not
conjugated to it. N,N0-Dipropargyl diketopiperazine served
as the axle centerpiece and was synthesized by alkylation of
diketopiperazine with propargyl bromide after deprotonation
with sodium hydride (Supporting Information).8 The two
rotaxanes were prepared by “clicking”9,10 the corresponding
stopper azide to the N,N0-dipropargyl diketopiperazine axle
centerpiece in the presence of the tetralactam macrocycle.
Figure 1. [2]pseudorotaxanes PS1 and PS2 and binding data
obtained by 1H NMR experiments at 233 K.
The crystal structure6 of a related pseudorotaxane with a
pyridine-bearing TLM and an N,N0-dipropargyl diketopi-
perazine axle confirms the expected formation of four
NꢀH OdC hydrogen bonds between the four converging
3 3 3
TLM amide NH groups and the two axle carbonyl groups
(Figure 2). The H-bond N O distances of 2.94 to 3.10 A,
3 3 3
and NꢀH O angles between 146° and 156° are compar-
3 3 3
able to other amide rotaxanes and catenanes.3h,i,7 The two
acetylene protons interact one with a diethylether and one
with a chloroform molecule incorporated in the crystal.
Figure 3. [2]rotaxanes R1 and R2 and the corresponding free
axles A1 and A2 (side products of the rotaxane syntheses).
(Ph3P)3Cu(I)Br11 was used as the catalyst for this template-
directed click reaction which gave the two desired rotaxanes
R1 and R2 in good yields of 67% and 75%, respectively. Since
the diketopiperazine centerpiece and the stoppers were used in
excess,3d this reaction also provided the two free axles A1 and
A2 as side products that can be used for comparison with the
rotaxanes.
Evidence for the threaded topology of R1 comes from
the 1H NMR spectra in Figure 4 (see Supporting Informa-
tion for 1H,1H COSY peak assignments). Low-field shifts
of the signals for wheel protons a, b, and c in R1 relative to
those of the free wheel indicate the presence of the axle
Figure 2. ORTEP plot (50% probability level) of the solid-state
structure of the pseudorotaxane shown at the bottom. Left: Top
view; right: side view.
(6) CCDC-833461. M = 1584.67, colorless prisms, 0.15 ꢁ 0.20 ꢁ 0.25
mm3, triclinic, space group P1, a = 12.3795(8) A, b = 16.3654(10) A, c
= 21.5944(14) A, R = 91.210(3)°, β = 94.228(3)°, γ = 112.025(3)°, V =
4039.0(4) A3, Z = 2, Dc = 1.303 g/cm3, T = 173(2) K, 923 parameters, R
= 0.0947 [Io > 2σ(Io)], wR = 0.3956 (all reflections). See Supporting
Information for more details.
These results clearly show the diketopiperazine to be a
suitable axle centerpiece for the synthesis of rotaxanes, even
though the binding energy is significantly lower than that of
unsubstituted diketopiperazine itself due to the absence of
NꢀH π and CꢀH π interactions that are likely dimin-
€
(7) (a) Reuter, C.; Seel, C.; Nieger, M.; Vogtle, F. Helv. Chim. Acta
€
2000, 83, 630. (b) Mohry, A.; Vogtle, F.; Nieger, M.; Hupfer, H.
Chirality 2000, 12, 76.
3 3 3
3 3 3
(8) Du, Y.; Wiemer, D. F. J. Org. Chem. 2002, 67, 5709.
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Matthys, S.; Lee, J.-J.; Wojcik, A.; Kamat, P. V.; Smith, B. D.
Chem.;Eur. J. 2010, 16, 2916.
(10) For the use of the “click” reaction for rotaxane synthesis, see: (a)
Miljanic, O. S.; Dichtel, W. R.; Aprahamian, I.; Rohde, R. D.; Agnew,
H. D.; Heath, J. R.; Stoddart, J. F. QSAR Comb. Sci. 2007, 26, 1165 and
literature cited therein.
ished by the more upright orientation of the diketopiperazine.
€
(4) (a) Ottens-Hildebrandt, S.; Meier, S.; Schmidt, W.; Vogtle, F.
€
€
Angew. Chem., Int. Ed. Engl. 1994, 33, 1767. (b) Vogtle, F.; Dunnwald,
T.; Schmidt, T. Acc. Chem. Res. 1996, 29, 451. (c) Schalley, C. A.;
€
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Commun 1996, 2529. (b) Allot, C.; Adams, H.; Bernad, P. L., Jr.; Hunter,
C. A.; Rotger, C.; Thomas, J. A. Chem. Commun. 1998, 2449.
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Org. Lett., Vol. 13, No. 18, 2011
4839

1
Figure 4. Aromatic region of the H NMR spectra (500 MHz,
CDCl3, 298 K) of (A) the wheel, (B) axle A1, and (C) [2]rotaxane R1.
in the wheel cavity.12 The largest complexation-induced
shift (Δδ = 1.3 ppm) is found for the amide NH proton c
indicating H-bond formation to the axle. In analogy to
earlier findings,3f,h signal shifts to higher field are observed
for axle protons e, h, and i which experience the anisotropy
of the wheel’s aromatic rings.
1
Figure 5. Aromatic region of the H NMR spectra (500 MHz,
CDCl3, 298 K) of (A) the wheel, (B) axle A2, (C) [2]rotaxane R2,
(D) R2 after adding 1 equiv of nBu4OAc, (E) R2 after adding 1
equiv of nBu4Cl, and (F) the chloride adduct of R2 after adding
NaBPh4 (*: NaBPh4 phenyl groups).
Similar signal shifts are observed for R2 (Figure 5), with
two notable exceptions: (i) The signal for the amide proton
c splits into two with different low-field shifts of Δδ = 1.0
and 1.4 ppm. (ii) The signal for the triazole protons e shifts
to lower field. Since the other signal shifts as well as ESI
MS strongly support rotaxane formation for both, two
different binding motifs are clearly realized in R1 and R2.
R1 is characterized by one set of signals for both axle and
wheel indicating high symmetry. Instead, the signal split-
ting of the amide protons c in R2 agrees with a reduced
symmetry with two wheel NH pairs. Since the axle protons
appear as a single set of signals, both axle halves reside in
equivalent environments. Furthermore, the reversal of the
shift of proton e points to a significant change in the
environment of the triazole proton.
to reside in the proximity of the isophthaloyl diamide
moieties. These observations are consistent with triazoleꢀ
CꢀH OdC hydrogen bonding13 and exclude NꢀH
N
3 3 3
3 3 3
hydrogen bonds between a wheel NH and any of the triazole
N-atoms. This interpretation relies on the assumption that
the wheel can adopt different conformations, among them
an all-in as well as a 2-in-2-out conformation. Indeed, earlier
experimental and theoretical studies14 revealed both con-
formations to be within ca. 5 kJ molꢀ1 in energy with barriers
for the rotation of a whole amide group of ca. 10 kJ molꢀ1
.
The TLM can thus easily adapt its conformation to the
binding requirements of the axles.
1
The H,1H ROESY NMR spectrum of R2 (Figure 6)
exhibits cross peaks between the amide protons c and both
wheel protons b and a in agreement with a wheel con-
formation in which two amide NH groups point inward
and two outward. Inaddition, cross peaks between triazole
proton e and wheel proton b indicate the triazole protons
(12) Hunter, C. A.; Packer, M. J. Chem.;Eur. J. 1999, 5, 1891.
(13) For selected references on triazole CꢀH X hydrogen bond-
3 3 3
ing, see: (a) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor
Chemistry; RSC Publishing: Cambridge, U.K., 2006. (b) Li, Y.; Flood, A. H.
J. Am. Chem. Soc. 2008, 130, 12111. (c) Juwarker, H.; Lenhardt, J. M.;
Pham, D. M.; Craig, S. L. Angew. Chem., Int. Ed. 2008, 47, 3740. (d)
Hecht, S.; Meudtner, R. M. Angew. Chem., Int. Ed. 2008, 47, 4926. (e)
Wang, Y.; Li, F.; Han, Y. M.; Wang, F. Y.; Jiang, H. Chem.;Eur. J.
2009, 15, 9424. (f) Juwarker, H.; Lenhardt, J. M.; Castillo, J. C.; Zhao,
E.; Krishnamurthy, S.; Jamiolkowski, R.; Kim, K.-H.; Craig, S. L. J.
Org. Chem. 2009, 74, 8924. (g) Fisher, M. G.; Gale, P. A.; Hiscock, J. R.;
Hursthouse, M. B.; Light, M. E.; Schmidtchen, F. P.; Tong, C. C. Chem.
Commun 2009, 3017. (h) Zheng, H.; Zhou, W.; Lv, J.; Yin, X.; Li, Y.;
Liu, H.; Li, Y. Chem.;Eur. J. 2009, 15, 13253. (i) Romero, T.;
1
Figure 6. Partial H,1H ROESY spectrum (500 MHz, CDCl3,
298 K) of R2. Relevant cross peaks are highlighted in green.
ꢀ
Caballero, A.; Tarraga, A.; Molina, P. Org. Lett. 2009, 11, 3466. (j)
€
Mullen, K. M.; Mercurio, J.; Serpell, C. J.; Beer, P. D. Angew. Chem.,
(14) (a) Schalley, C. A.; Reckien, W.; Peyerimhoff, S.; Baytekin, B.;
€
Int. Ed. 2009, 48, 4781. (k) Gassensmith, J. J.; Matthys, S.; Lee, J.-J.;
Wojcik, A.; Kamat, P. V.; Smith, B. D. Chem.;Eur. J. 2010, 16, 2916.
(l) Lee, S.; Hua, Y.; Park, H.; Flood, A. H. Org. Lett. 2010, 12, 2100. (m)
Vogtle, F. Chem.;Eur. J. 2004, 10, 4777. (b) Kossev, I.; Reckien, W.;
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Kirchner, B.; Felder, T.; Nieger, M.; Schalley, C. A.; Vogtle, F.;
Sokolowski, M. Adv. Funct. Mater. 2007, 17, 513. (c) Zhu, S. S.; Nieger,
M.; Daniels, J.; Felder, T.; Kossev, I.; Schmidt, T.; Sokolowski, M.;
For a recent review, see: Jurı
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4840
Org. Lett., Vol. 13, No. 18, 2011

In rotaxanes R1 and R2, the axles and wheels are thus
connected by different H-bonding patterns: In R1, four wheel
amide NH groups converge to bind the two diketopiperazine
carbonyl oxygens (motif A). In R2, two wheel amides con-
verge toward the axle’s CdO groups, while the carbonyl
remarkable that the anion exchange is slow on the NMR time
scale at room temperature as indicated by the splitting of
the wheel signals into two sets. Chloride binding to R2 can
be reversed by addition of NaBPh4 which precipitates the
chloride from the chloroform solution as sodium chloridꢀe
(Figure 5F). With the exception of the signals for the BPh4
anion, the spectra in Figure 5C and 5F are identical confirm-
ing the hydrogen bonding pattern in rotaxane R2 to be
reversibly switchable with a chemical signal.
In conclusion, a new disubstituted diketopiperazine axle
centerpiece was used for the synthesis of amide rotaxanes. A
variant of the click reaction which applies (Ph3P)3Cu(I)Bras
the catalyst and operates in nonpolar organic solvents was
used for the stoppering reaction. The compatibility of this
reaction with noncompetitive solvents is important, because
the hydrogen-bond-mediated template effect is quite sensi-
tive to competitive solvents. Depending on the nature of the
stoppers, two binding motifs were observed that connect the
axle and wheel through hydrogen bonding. One of them
O-atoms of the other two wheel amides form CꢀH OdC
3 3 3
bonds with triazole CꢀH groups (motif B). Both binding
motifs were calculated with semiempirical AM1 MOZYME
calculations (Figure 7),13a,15 in order to obtain an impression
of whether motif B is geometrically feasible. These calcula-
tions not only result in reasonable structures for both binding
motifs but also predict motif Ato be less favorable by ca. 20 kJ
molꢀ1. One factor in why motif B is not realized in R1 may be
the flat, extended, and conjugated triazole-phenyl moiety
which can favorably interact with the less electron-rich iso-
phthaloyl units when motif A is realized. According to our
calculations, this arrangement brings the trityl groups into a
favorable position, in which they maximize their van der
Waals contacts with the TLM’s tBu groups. The long and
flexible chains in R2 instead do not support this interaction
and motif B is then formed.
involves CꢀH OdC hydrogen bonds between the tria-
3 3 3
zole rings and the carbonyl groups of inverted TLM amide
groups. Their formation is supported by ROESY NMR
contacts between the triazole protons e and the inner
isophthaloyl protons b. The rotaxane formation mechanism
is supported by studies of related pseudorotaxanes, which
exhibit free binding enthalpies substantially higher than
those found for other amide template effects.2a For a related
pseudorotaxane, a crystal structure confirmed a binding
motif in which four converging wheel amide NH groups
form hydrogen bonds to the diketopiperazine carbonyl
oxygen atoms. Finally, the hydrogen bonding patterns in
rotaxane R2 can be switched by the addition of anions that
block one side of the wheel and thus cause large changes in
the relative orientations of axle and wheel. The anion
binding and binding mode switching are fully reversible.
Anion binding desymmetrizes the wheel, and the observa-
tion of two distinct sets of signals for the two sides provides
evidence that the chloride exchange is slow on the NMR
time scale at room temperature.
Figure 7. Two AM1MOZYME-optimized structures of R2. The
structure with four NH O hydrogen bonds (left) is calculated
3 3 3
to be less stable than that with two NH O and two CH
3 3 3
O
3 3 3
hydrogen bonds (right). Glycol chains, cyclohexanes, stoppers,
and H-atoms are omitted for clarity.
The addition of 1 equiv of either nBu4NOAc or nBu4NCl
(Figure 5D,E) to the NMR solution of R2 gives rise to two
sets of signals for the wheel protons a, b, and d and an
additional low-field shift of the NH protons c. Most strik-
ingly, the signal of the triazole proton e shifts to higher field
(ca. 7.5 ppm). This is almost the same position that is
observed for the triazole proton e in rotaxane R1. All these
findings are in agreement with the conjecture that the anion
binds to one isophthaloyl diamine side of the TLM and
changes the axle orientation relative to the wheel. The
Acknowledgment. This research has been funded
by the Deutsche Forschungsgemeinschaft (SFB 765
“multivalency”), the German Academic Exchange
Service (DAAD), and the Academy of Finland (proj.
212588 and 218325). E.V.D. and L.K. thank the
Studienstiftung des deutschen Volkes for a PhD scho-
€
larship. We thank Dr. Andreas Schafer (FU Berlin),
Sebastian Richter, M. Sc. (FU Berlin) and Dipl.-Ing.
Fabian Klautzsch (FU Berlin) for help with NMR and
ESI MS experiments.
cleavage of the CꢀH OdC hydrogen bonds is then
3 3 3
responsible for the signal shift of proton e. The second
isophthaloyl diamide binds to one of the diketopiperazine
carbonyl oxygen atoms as indicated by the very small changes
observed for one of the a and one of the b signals. It is further
Supporting Information Available. General experimen-
tal methods, synthetic procedures, original spectra of new
compounds, and binding constant determination. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) CAChe 5.0 for Windows; Fujitsu Ltd., Krakow, Poland, 2001.
For a validation of the AM1MOZYME approach with DFT calculations,
see ref 13a.
Org. Lett., Vol. 13, No. 18, 2011
4841