Enhancing the reactivity of 1,2,3-triazoles in "click" macrocycles by face-to-face dibenzylammonium ion binding

Article abstract of DOI:10.1039/b711505a

A face-to-face binding motif between dibenzylammonium ions and macrocycles containing 1,2,3-triazoles was established, which operates cooperatively to enhance the reactivity of 1,2,3-triazoles in an Arbuzov-type dealkylation reaction. The Royal Society of

Full text of DOI:10.1039/b711505a

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Enhancing the reactivity of 1,2,3-triazoles in ‘‘click’’ macrocycles by
face-to-face dibenzylammonium ion binding{
Yi Liu,*a Xiyun Zhang,b Liana M. Klivanskya and Gayane Koshkakaryanac
Received (in Austin, TX, USA) 30th July 2007, Accepted 15th October 2007
First published as an Advance Article on the web 23rd October 2007
DOI: 10.1039/b711505a
field. On the other hand, contrasting to the usual crown ether/
ammonium complexes,3a very small shifts were observed for the
ethylene glycol protons, implying that the ammonium center
interacted weakly with the OCH2CH2 unit. The host–guest
complexation underwent fast exchange on the 1H NMR time
scale as only one set of signals was observed. A binding constant
(Ka) was measured to be 290 ¡ 20 M21 in a mixed solvent system
(CD2Cl2–CD3CN 4 : 1) using a 1H NMR titration method.12 The
host–guest complexation was highly solvent dependent. When
CD3CN was used as the solvent, no interaction could be seen
between MC3 and 4-H?PF6. The host–guest pair also existed in the
gas phase as detected by electrospray ionization mass spectroscopy
(ESI-MS). A peak at m/z 698 could be assigned to the molecular
ion of the complex [MC3?4-H]+. The same binding constant
(290 ¡ 20 M21) was obtained for the MC1/4-H?PF6 complexa-
tion, suggesting that increasing the p-surface from catechol to
naphthanol did not affect the binding strength. In addition,
increasing the ring size by including one extra CH2CH2O unit
decreased the binding strength, as indicated by a smaller Ka
(140 ¡ 30 M21) for the MC2/4-H+ complexation, thus implying a
diminished macrocyclic effect.6b
A face-to-face binding motif between dibenzylammonium ions
and macrocycles containing 1,2,3-triazoles was established,
which operates cooperatively to enhance the reactivity of 1,2,3-
triazoles in an Arbuzov-type dealkylation reaction.
Crown ethers have been recognized1 for their exceptional binding
ability towards various types of cationic guests, including
ammonium ions and primary alkylammonium ions (RNH3+).2
+
Most RNH3 ions complex with crown ethers in a face-to-face
manner.2 Recent studies on secondary dialkylammonium ions
(R2NH2+) and dibenzo[24]crown-8 (DB24C8) revealed3 a threaded
+
motif where the R2NH2 interpenetrates through the cavity of
DB24C8 to give a [2]pseudorotaxane. Such discovery opens up the
window for the construction of both discrete interlocked
molecules4 and more diverse functional interlocked molecular
5
+
…
structures. In the [2]pseudorotaxanes, collective [N –H O] and
+
…
[N C–H O] hydrogen bondings are the major stabilizing
noncovalent interactions, assisted by electrostatic interactions
and macrocyclic effects.6 Many variants of the macrocyclic hosts
were synthesized and tested in terms of fine tuning the non-
covalent binding interactions. It is shown that subtle structural
changes to the crown structure can affect the binding ability
significantly.6b,7 Recently we have tested the Cu(I) catalyzed [3 + 2]
cycloaddition — one of the supreme ‘‘click’’ reactions,8 — in
macrocycle synthesis. An appealing feature of such macrocycles is
that the cycloaddition product, 1,2,3-triazole, can serve as ligands9
to enhance host–guest interactions. Here we describe that ‘‘click’’
macrocycles MC1–3{ (Scheme 1) can bind dibenzylammonium
ions in a face-to-face manner rather than a threaded one.10
Moreover, such noncovalent interaction acts cooperatively to
enhance the receptor’s reactivity in an Arbuzov-type11 dealkylation
reaction by placing the 1,2,3-triazole unit close to the reactive site.
The complexation between MC3 and 4-H?PF6 was established
by the 1H NMR spectra (Fig. 1) of their equimolar mixture
(5.0 mM) in CD2Cl2–CD3CN (4 : 1). Both the NH2+ protons from
4-H?PF6 and the amide protons from MC3 displayed noticeable
downfield shifts, suggesting their involvement in hydrogen
bondings. The benzyl protons in 4-H?PF6, originally resonating
as a triplet at 4.35 ppm, now appeared as a singlet at slightly lower
It is difficult to conclude from the 1H NMR spectra whether the
ammonium center threads through the macrocycles to form a
[2]pseudorotaxane or binds the macrocycles face-to-face. To
identify if [2]pseudorotaxane complexes formed in solution, we
attempted the stoppering reaction by installing bulky groups to the
ammonium salt in the presence of MC3. A mild ‘‘click’’ reaction
condition was employed where MC3, azide-functionalized ammo-
nium salt 5-H?PF6, 4-tert-butylphenylacetylene, CuPF6?4MeCN
aThe Molecular Foundry, Lawrence Berkeley National Laboratory, One
Cyclotron Road, MS 67R6110, Berkeley, CA, 94720, USA.
E-mail: yliu@lbl.gov; Fax: 01 510 4867413; Tel: 01 510 4866287
bCodexis Inc., 200 Penobsco, Redwood City, CA, 94063, USA
cUniversity of California, Berkeley, CA, 94720, USA
{ Electronic supplementary information (ESI) available: Experimental
procedures for the syntheses of all the new compounds and their
characterization data. Details on binding constant measurements using 1H
NMR spectroscopic method. See DOI: 10.1039/b711505a
Scheme 1 The molecular structures of 1,2,3-triazole-containing macro-
cycles MC1–3 and the dibenzylammonium salts 4-H?PF6, 5-H?PF6 and
6-H?PF6, and the azide 7.
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Fig. 1 Partial 1H NMR spectra (500 MHz, CD2Cl2–CD3CN 4 : 1,
298 K) of (a) MC3, (b) an equimolar mixture of MC3 and 4-H?PF6, and
(c) 4-H?PF6.
(cat.) and diisopropylethylamine (cat.) were mixed in a CH2Cl2–
MeCN (4 : 1) solution under N2 atmosphere. From the reaction
mixture only the stoppered ammonium salt 6-H?PF6 was isolated
in 92% yield and no rotaxane could be identified. The lack of
[2]rotaxane formation is a good indication of the absence of
[2]pseudorotaxane in solution.
Fig. 2 The aromatic region of 1H NMR spectra (500 MHz, CDCl3,
298 K) of (a) an equimolar mixture of MC3 and the azide-containing
ammonium salt 5-H?PF6, (b) MC3, (c) an equimolar mixture of MC3 and
the stoppered ammonium salt 6-H?PF6, and (d) 6-H?PF6.
We then mixed the stoppered ammonium ion 6-H?PF6 with
1
MC3 in CDCl3 and followed the chemical shifts using H NMR
spectroscopy. The formation of [2]pseudorotaxane should be
excluded on account of the sterically demanding threading
process.6b As indicated in Fig. 2(b), the resonances of the mixture
of MC3 and 6-H?PF6 displayed chemical shifts that were similar to
those observed in the mixture of MC3 and the azido ammonium
salt 5-H?PF6 (Fig. 2(a)). Such results confirmed that the
complexation between the macrocycle and the dibenzylammonium
ion, although weaker,13 was still present in the solution, and it had
to be a face-to-face one.
The origin of face-to-face binding might be understood from the
relatively rigid nature of the macrocycles on account of the
1,4-disubstituted triazole units. The arrangement of oxygen atoms
ontheoligo-ethyleneglycolunitisdisruptedtotheextentwhere[N+–
…
…
H
O] and [C–H O] interactions, the major driving forces for the
formation of [2]pseudorotaxanes,6 are significantly weakened.
Another stoppering reaction under mild conditions was tested
by reacting the azide containing 5-H?PF6 with triethyl phosphite to
give a phosphoramidate.14 P(OEt)3 was added to a solution of
MC1 and 5-H?PF6 in CH2Cl2 (Scheme 2). No rotaxane product
was detected, again supported the absence of [2]pseudorotaxane.
Interestingly, a macrocyclic triazolium 9?PF6 was obtained in 45%
yield with one of the 1,2,3-triazoles in MC1 being alkylated,
Scheme 2 The reaction pathway illustrating the participation of 1,2,3-
1
triazole in the Arbuzov-type dealkylation process.
resulting a low-symmetry H NMR spectrum compared to the
parent macrocycle MC1. The protons of the newly introduced
ethyl group could be identified at around d 4.9 ppm and 1.7 ppm.
The formation of 9?PF6 indicated that one of the 1,2,3-triazoles
participated in the dealkylation step during the formation of
phosphoramidate 10-H?PF6.15 Similar monoalkylated product was
obtained when the catechol-based MC3 was used.16 To understand
4774 | Chem. Commun., 2007, 4773–4775
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click reaction in many areas, such as the design of novel
supramolecular and biomimetic systems.
This work was performed at the Molecular Foundry, Lawrence
Berkeley National Laboratory, and was supported by the Office of
Science, Office of Basic Energy Sciences, of the U.S. Department
of Energy under contract No. DE-AC02-05 CH11231. We thank
Prof. K. Barry Sharpless and Prof. Valery V. Fokin for their
support of the early work.
Notes and references
{ For the synthetic details of MC1–3, please see the Electronic
Supplementary Information (ESI{).
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2723–2750.
Fig. 3 Optimized structure of the intermediate 8-H?PF6. The reaction
center is highlighted with green ball-and-stick model. The blue arrow
indicates the bond to be formed between triazole N atom and ethoxy C
atom. All the hydrogen atoms were omitted for clarity except for those
involved in hydrogen bonding.
2 (a) C. J. Pedersen, J. Am. Chem. Soc., 1967, 89, 7017–2036; (b)
R. C. Helgeson, J. M. Timko and D. J. Cram, J. Am. Chem. Soc., 1973,
95, 3023–3025; (c) Crown Ethers and Analogous Compounds, ed.
M. Hiraoka, Elsevier, Amsterdam, The Netherlands, 1992.
3 (a) P. R. Ashton, P. J. Campbell, E. J. T. Chrystal, P. T. Glink,
S. Menzer, D. Philp, N. Spencer, J. F. Stoddart, P. A. Tasker and
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A. G. Kolchinski, D. H. Busch and N. W. Alcock, J. Chem. Soc., Chem.
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4 (a) P. R. Ashton, P. T. Glink, J. F. Stoddart, P. A. Tasker, A. J. P. White
and D. J. Williams, Chem.–Eur. J., 1996, 2, 729–736; (b) S. J. Cantrill,
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S.-H. Chiu, S. J. Rowan, S. J. Cantrill, J. F. Stoddart, A. J. P. White and
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5 (a) J.-P. Collin, C. Dietrich-Buchecker, P. Gavina, M. C. Jimenez-
Molero and J.-P. Sauvage, Acc. Chem. Res., 2001, 34, 477–487; (b)
J. D. Badjic, V. Balzani, A. Credi and J. F. Stoddart, Science, 2004, 303,
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H. W. Gibson, J. Org. Chem., 1998, 63, 7634–7639; (b) P.-N. Cheng,
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2372–2383.
better the role of hydrogen bonding in such reactions, a couple of
control experiments were conducted. When the N-Boc protected
azide 7 was used instead of 5-H?PF6 and subjected to the same
reaction conditions, no alkylated product was detected. In another
experiment where MeCN was used to suppress hydrogen bonding
interactions, no triazolium 9?PF6 was formed either. These results
clearly indicated that the 1,2,3-triazole was not reactive when
hydrogen bonding was unavailable, thus proving the key role of
hydrogen bonding in order for the triazole alkylation to happen.
Based on these results, a proposed reaction pathway was
depicted in Scheme 2. The face-to-face hydrogen bonding
interactions between MC1 and the ammonium salt 5-H?PF6
brings the triazole and the ethoxy unit in phosphorimidate to close
proximity. Such spatial arrangement facilitates a nucleophilic
attack of the long pair of the triazole N atom towards the ethyl
group to furnish an alkylated product while generating a
phosphoramidate as the leaving group.
7 S. J. Cantrill, D. A. Fulton, A. M. Heiss, A. R. Pease, J. F. Stoddart,
A. J. P. White and D. J. Williams, Chem.–Eur. J., 2000, 6, 2274–2287.
8 (a) H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int.
Ed., 2001, 40, 2004–2021; (b) V. V. Rostovtsev, L. G. Green, V. V. Fokin
and K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596–2599.
9 (a) T. R. Chan, R. Hilgraf, K. B. Sharpless and V. V. Folkin, Org. Lett.,
2004, 6, 2853–2587; (b) Y. Li, J. C. Huffman and A. H. Flood, Chem.
Commun., 2007, 2692–2694.
The proposed reaction pathway of the triazolium formation was
also supported by molecular modeling results (Fig. 3). The
intermediate 8-H?PF6 was constructed using MOE200617 and
optimized with MMFF94x force field implemented in MOE. The
+
…
resulting structure suggested that intermolecular [N –H N]
10 Crown ethers having less than 24 atoms in their macrorings were
reported to form complexes with secondary dialkylammonium ions in a
face-to-face manner. See: (a) J. C. Metcalfe, J. F. Stoddart and G. Jones,
J. Am. Chem. Soc., 1977, 99, 8317–8319; (b) S. S. Abed-Ali, B. J. Brisdon
and R. England, J. Chem. Soc., Chem. Commun., 1987, 1565–1566.
11 B. A. Arbuzov, Pure Appl. Chem., 1964, 9, 307–335.
12 The binding constant was determined using WinEQNMR program. For
a discussion of its application in determining binding constant, see:
M. J. Hayes, J. Chem. Soc., Dalton Trans., 1993, 311–312.
13 The binding constants were measured to be 50 ¡ 20 M21 and 120 ¡
80 M21 for MC3/6-H?PF6 and MC3/5-H?PF6, respectively.
14 W.-C. Huang, K.-S. Liao, Y.-H. Liu, S.-M. Peng and S.-H. Chiu,
Org. Lett., 2004, 6, 4183–4186.
hydrogen bondings could be formed between one of the triazole
+
…
units and the ammonium center. [N –H O] interaction was also
seen between the ammonium center and one of the amide carbonyl
groups on the macrocycle.18 Meanwhile, N3 of another triazole
unit could be placed in an appropriate position where SN2 attack
of the electron deficient ethoxy carbon atom on the phosphor-
imidate was ready to occur.
In summary, macrocycles containing 1,2,3-triazoles were shown
to recognize secondary dibenzylammonium ions in a face-to-face
manner rather than a threaded one. Moreover, such supramole-
cular interactions were shown to be responsible for the enhanced
reactivity of one of the 1,2,3-triazole units in the macrocyclic host.
To the best of our knowledge, covalent modification of the host
modulated by noncovalent interactions was not seen before in the
related classical crown ether/ammonium host–guest systems, and is
reminiscent of the enzymatic action in biological processes. Such
findings may have an impact on the application of the popular
15 10-H?PF6 could not be isolated from the reaction mixture although
its presence was clearly confirmed by a prominent m/z peak at 419.2
in electrospray ionization mass spectrometry, corresponding to
[M 2 PF6]+. The spectrum was included in ESI{.
16 See ESI{ for the synthetic details and characterization data.
17 MOE2006 is a product of Chemical Computing Group, Montreal,
Canada.
…
18 Intramolecular [N–H O] interaction was also seen between one of the
amide NH groups and a naphthanolic oxygen in the macrocycle.
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