Enhanced reactivity of twisted amides inside a molecular cage

Article abstract of DOI:10.1038/s41557-020-0455-y

When an amide group is distorted from its planar conformation, the conjugation between the nitrogen lone pair and the π* orbital of the carbonyl is disrupted and the reactivity towards nucleophiles is enhanced. Although there are several reports on the synthesis of activated twisted amides, amide activation through mechanical twisting is much less common. Here, we report twisted amides that are stabilized through their inclusion in a self-assembled coordination cage. When secondary aromatic amides are included in a T_d-symmetric cage, the cis-twisted conformation is favoured over the trans-planar one—as evidenced by single-crystal X-ray diffraction analysis—revealing that the amide can twist by up to 34°. As a consequence of this distortion, the hydrolysis of amides is significantly accelerated upon inclusion. [Figure not available: see fulltext.]

Full text of DOI:10.1038/s41557-020-0455-y

Articles
https://doi.org/10.1038/s41557-020-0455-y
Enhanced reactivity of twisted amides inside a
molecular cage
1
ꢀ✉
1
1,2
ꢀ✉
Hiroki Takezawaꢀ ꢀ , Kosuke Shitozawa and Makoto Fujitaꢀ ꢀ
When an amide group is distorted from its planar conformation, the conjugation between the nitrogen lone pair and the π*
orbital of the carbonyl is disrupted and the reactivity towards nucleophiles is enhanced. Although there are several reports on
the synthesis of activated twisted amides, amide activation through mechanical twisting is much less common. Here, we report
twisted amides that are stabilized through their inclusion in a self-assembled coordination cage. When secondary aromatic
amides are included in a T -symmetric cage, the cis-twisted conformation is favoured over the trans-planar one—as evidenced
by single-crystal X-ray difdfraction analysis—revealing that the amide can twist by up to 34°. As a consequence of this distor-
tion, the hydrolysis of amides is significantly accelerated upon inclusion.
he high rotation barrier and the chemical inertness of Results and discussion
amide functional groups are explained by the conjugation Formation of amide inclusion complexes and their structures. In
T
of the nitrogen lone pair with the carbonyl π* orbital1,2. a D2O solution of cage 1a (20mM, 1.0ml), amide 2a (5equiv. to 1a)
When this conjugation is disrupted by distorting the planar con- was suspended and the mixture was stirred at 100°C for 1h (Fig. 2).
1
formation of amides, their chemical and physical properties After removal of the residual 2a by filtration, H NMR analysis
are varied. The reactivity control of amides by varying the showed the formation of inclusion complex 1a•(2a)2 in 25% yield.
dihedral angles around amide bonds has therefore been of great The faint yellow colour of a solution of 1a turned reddish-orange,
interest both in synthetic chemistry and biochemistry1–18. Highly indicating host–guest charge transfer in 1a•(2a)2 (ref. 29). Two sets
twisted amides have been synthesized and their enhanced reac- of guest signals are observed and the host signals split into a com-
tivities have been unveiled3–11. However, the switching of stable plex pattern, suggesting the reduction of the cage symmetry from
planar amides to reactive non-planar ones through mechanical T to C1 (Fig. 2b). Presumably, amide 2a formed a dimer with C1
d
twisting manipulation, without any chemical processes, has seldom symmetry in the cavity, by analogy with the bent and twisted con-
been achieved.
formation of an asymmetric 1,2-diketone we previously observed in
Amide activation by mechanical twisting is still a challenging the cavity18. Other electron-rich amides 2b–2e also gave inclusion
task19–21. Kumagai and Shibasaki reported coordination-driven complexes with broad 1H NMR signals. The signal broadening indi-
amide twisting to enhance solvolytic cleavages, although coordi- cates that the tumbling of the guest amides occurs with rates com-
nating substituents are necessary on the amide nitrogen12. Amide parable to the NMR timescale and thus the amides are moderately
twisting by protein folding is hypothesized to play crucial roles in fixed in the cavity. Non-electron-rich amides were hardly encapsu-
autoproteolysis and protein splicing to cleave a particular amide lated (Supplementary Fig. 25), suggesting that interactions between
bond under mild conditions13–17. Here, we report non-covalent the amides and the electron-deficient cage walls are crucial.
trapping of a reactive conformer with a twisted amide bond by
The cis-twisted conformations of amide 2a in the cavity were
accommodating amides in the restricted cavity of a self-assem- revealed by single-crystal X-ray diffraction analysis (Fig. 2d–f).
bled cage. When aromatic secondary amides are included in the Single crystals suitable for the analysis were obtained from an aque-
cavity of coordination cage 1, the cis-twisted conformation is ous solution of 1b•(2a)2. In the structure, two crystallographi-
favoured over their latent trans-planar one, as clearly revealed cally inequivalent amides were observed around a crystallographic
by NMR spectroscopy and single-crystal X-ray studies. The cis- C2 axis. These two amides formed a C1 symmetric dimer, consistent
twisted amides are activated and smoothly hydrolysed under mild with the NMR observations. Most importantly, the amides adopted
conditions (Fig. 1).
a cis-twisted conformation with dihedral angles (ω) around C–N–
Coordination cage 1 possesses a large hydrophobic cavity with C(O)–C of 34° and 30°. There is π–π stacking (<3.5Å) between the
Td symmetry (Fig. 1b)22–29. This unique symmetry induces specific four triazine ligands and the aromatic rings of amide 2a, explain-
arrangements of included guests: for example, orthogonal pack- ing the charge transfer (reddish-orange colour). Thus, the twisted
ing of two linear molecules23–25, a metastable twisted conforma- conformer of amide 2a was non-covalently trapped by inclusion
tion of an overcrowded alkene26 and an open/closed equilibrium in the cage.
shift of chromic dyes27. Any two panel ligands on the cage provide
The inclusion complex 1a•(2b)2 was also crystallographically
a V-shaped region sandwiched between the electron-accepting analysed. Interestingly, guest 2b formed a cis–trans 1:1 dimer
π planes of the triazine-cored ligand. Therefore, aromatic amides (ω=26° and 164° in major disordered conformers, Fig. 3f). The
in a trans-planar conformation should adopt a cis-twisted confor- cis dimer of 2b is presumably too compact to be compatible with
mation to form a pseudo-S4 symmetric dimer fitting within the the cavity, while the cis–trans 1:1 dimer seems to fill the void more
1
Td symmetric cavity.
efficiently. In the H NMR spectrum, two sets of signals from 2b
1Department of Applied Chemistry, School of Engineering, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. 2Division of Advanced Molecular Science,
✉
Institute for Molecular Science (IMS), Okazaki, Aichi, Japan. e-mail: takezawa@appchem.t.u-tokyo.ac.jp; mfujita@appchem.t.u-tokyo.ac.jp
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a
12+
N
b
Pd
1a: M =
N
–
•12 NO3
N
Pd
1b: M =
Cage
N
2
N
N
Pt
Amide
1c: M =
Twisted amides in a cage
OMe
c
OMe
OMe
O
OMe
O
O
O
O
OMe
N
O
S
N
N
N
N
H
H
H
H
OMe
OMe
MeO
OMe
OMe
MeO
OMe
2e
2a
2d
2c
2b
Fig. 1 | Trapping of twisted amides by inclusion in a molecular cage. a, Cartoon representation of trapping of twisted amides by confinement in a
coordination cage. b, The octahedral coordination cages used in this work are self-assembled from four electron-deficient panel ligands (2,4,6-tris(4-
pyridyl)-1,3,5-triazine) and six metal corners (cis-endcapped Pd(ii) or Pt(ii) complexes). c, Electron-rich diaryl amides were selected as candidates for
amide twisting by inclusion.
f
a
d
e
OMe
1a
34°
D2O
100 °C, 1 h
25%
cis
+
OMe
OMe
OMe
O
H
N
O
MeO
H
N
OMe
H
N
OMe
O
30°
MeO
2a
1a•(2a)2
MeO
cis
b
d
OMe
–OMe
a
O
b
CHCl3
e
c
N
H
g
h
OMe
MeO
2a
cis
e
b
c
a
(NH)
d
trans
c
DOH
1a
1a
1a
d
c
c
e e
a
CHCl
3 b
b
a
trans
b
cc
b
d
10
8
6
4
2 (ppm)
Fig. 2 | amide inclusion in a coordination cage. a, Schematic of inclusion of diaryl amide 2a within cage 1a. Amide 2a formed 1:2 host–guest complex
1a•(2a)2 in 25% yield. b, 1H NMR spectrum of a CDCl3 solution of 2a (500ꢀMHz, 300ꢀK). c, 1H NMR spectrum of 1a•(2a)2 (500ꢀMHz, 300ꢀK). Two sets of
signals from amide 2a and splitting of pyridine protons of cage 1a indicate C1-symmetric dimer formation of 2a in the cavity and that molecular motion of
2a is restricted on the NMR timescale. d, Crystal structure of 1b•(2a)2 reveals the twisted conformation of amide 2a in the cage. e, The two inequivalent
twisted amides form a C1 symmetric dimer and are tightly packed in the cavity. f, The amides are twisted by 34° and 30° around their C–N–C(O)–C bonds.
g,h, Crystal structures of 1a•(2c)2 and 1a•2d show that cis and trans conformers of amide 2c are included in one cavity (g) and amide 2d adopts trans-planar
conformation in the cavity (h).
are observed (Fig. 3c). Because of efficient π–π stacking with the they stick out from portals of the cage. Similarly, guest 2c formed a
panel ligands, the aromatic protons of the cis conformer are shifted cis–trans 1:1 dimer to give 1a•(2c)2 (Fig. 2g). For guest 2d, only
upfield at 5.4–3.5ppm. The trans conformer shows almost stan- the 1:1 complex 1a•2d was formed, in which 2d adopted its latent
dard chemical shifts for aromatic protons (8.2–5.6ppm), because trans-planar conformation (ω=174°, Fig. 2h).
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a
b
H
O
1a
1a 1a
DOH
N
S
3
3b
cis-2b
MeO
OMe
1a
*
1•(2b•3)
*
c
H
O
N
1a
MeO
trans-2b
cis-2b
S
(2 equiv. of 2b)
+
MeO
N
OMe
OMe
OMe
O
O
H
S
N
S
H
OMe
1•(2b)2
2b
*
4
d
O
S
N
H
OMe
trans-2b
MeO
4
1•(2b•4)
*
10
8
6
4
2
0
(ppm)
e
f
g
cis
cis
trans
trans
Fig. 3 | Conformation control of an amide by co-inclusion. a, Schematic of conformation control of amide 2b by co-inclusion. Inclusion of 2b as a sole guest
resulted in the formation of the ternary complex with cis and trans conformers in the same cavity 1•(2b)2, while co-inclusion of amide 2b and biphenyl (3a)
or phenanthrene (3b) into cage 1 provided ternary complexes 1•(2b•3). Co-inclusion with p-(1-adamantyl)toluene (4) gave ternary complex 1•(2b•4). b, In
the 1H NMR spectrum of 1a•(2b•3b) (500ꢀMHz, D2O, 300ꢀK), aromatic protons of 2b appeared relatively upfield (5.5–3.4ꢀppm). c, Two sets of signals from
amide 2b were observed and aromatic protons on each guest appeared in relatively downfield (mainly in 8.2–5.6ꢀppm) and upfield regions (5.4–3.5ꢀppm).
d, In contrast to the case of 1a•(2b•3b), the aromatic protons of 2d in 1a•(2b•4) appeared in the downfield region (mainly in 8.1–6.1ꢀppm). Asterisks denote
signals from the internal standards. e–g, Crystal structures of 1a•(2b•3a) (e), 1a•(2b)2 (f) and 1a•(2b•4) (g) show that the conformation of amide 2b is
controlled by co-guests 3 and 4. The cis conformers in 1a•(2b•3a) and 1a•(2b)2 show efficient π–π stacking between the aromatic rings of 2b and panel
ligands of the cage, which are consistent with the 1H NMR chemical shifts.
The 1:1 cis–trans dimer formation from 2b and 2c inspired Hydrolysis of the confined amides. Expecting the enhanced
us to tune the magnitude of guest twisting by co-inclusion with reactivities of the twisted amides in the cavity, we investigated the
appropriate modulator guests (Fig. 3). From amide 2b and biphe- kinetics of the hydrolysis of the included amides in a basic solu-
nyl 3a, for example, ternary complex 1a•(2b•3a) was obtained. tion (Fig. 4 and Supplementary Table 1). Cage 1c, a platinum ana-
Crystallographic analysis showed the cis conformation of 2b with logue of 1a, was employed for the study because of its stability
twisting angle (ω) of 19° (Fig. 3e). With phenanthrene 3b, a ternary under basic conditions28. An aqueous solution of inclusion complex
complex 1a•(2b•3b) was also formed (Fig. 3b). With p-(1-adaman- 1c•(2b•3b) (2.4mM) was treated with a base (100mM of NaOH)
1
tyl)toluene 4, in contrast, 2b showed trans-planar geometry with at 60°C and the conversion was monitored by H NMR measure-
a ω value of 169° in ternary complex 1a•(2b•4) (Fig. 3g). These ments by extracting the reaction mixture with CDCl3 (Fig. 4; see
observations are consistent with the interpretation of NMR spectra Supplementary Information for details). The rate constants with
discussed above.
and without cage 1c (kcage and kbulk, respectively) were determined
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a
b
OMe
H
O
N
O
100
80
60
40
20
0
NaOH (100 mM)
S
O–
S
D2N
OMe
MeO
OMe
D2O, 60 °C
kobs = 1.8 × 10–2 h–1
5b
6
+
k
cage/kbulk = 14
∙
∙
1c (2b 3b)
1c•(2b•3b)
H
O
N
NaOH (100 mM)
MeO
S
5b + 6
MeO
N
OMe
OMe
D2O, 60 °C
kobs = 8.2 × 10–3 h–1
∙
1c (2b)2
O
H
S
kcage/kbulk = 6.1
1c•(2b)2
∙
∙
1c (2b 4)
O
NaOH (100 mM)
D2O, 60 °C
S
5b + 6
2b
N
H
MeO
OMe
k
obs = 4.3 × 10–3 h–1
k
cage/kbulk = 3.2
0
20
40
60
80
1c•(2b•4)
Time (h)
d
c
OMe
O
OMe
O–
O
MeO
MeO
O
N
N
OMe
HN
OMe
H
N
5a
OMe
OMe
NaOH (100 mM)
O
O
MeO
MeO
+
OMe
H
N
D2O, 60 °C
cage = 3.9 × 10–3 h–1
O
OMe
k
OMe
MeO
1c•(2e)2
kcage/kbulk = 5.1
D2N
1c•2d
OMe
MeO
kcage = 1.3 × 10–4 h–1
kcage/kbulk = 1.7
k
cage = 9.4 × 10–1 h–1
6
1c•(2a)2
kcage/kbulk = 0.11
(with 10 mM K2CO3)
Fig. 4 | Hydrolysis of twisted amides in a cavity. a, Amide 2b in cage 1c showed enhanced hydrolysis under basic conditions (kcage/kbulk up to 14).
Modulation of the magnitude of guest twisting by co-inclusion enabled reactivity control of amide 2b. b, Averaged conversions of three trials were plotted
(error bars indicate the standard deviations calculated from the conversions of three trials). c, Twisted amide 2a in cage 1c also showed rate enhancement
in hydrolysis under basic conditions (kcage/kbulkꢀ=ꢀ5.1). d, Effect of cage inclusion in the hydrolysis of related compounds 2d and 2e supports an activation
mechanism by trapping of the twisted conformers. Amide 2d adopts a planar conformation in the cavity and shows almost negligible acceleration of
hydrolysis. Hydrolysis of N-acylindole 2e is suppressed by the cage, despite the similar conformation to 2a in the cavity of 1a.
by curve fitting with pseudo-first-order kinetics (due to the low Interestingly, cage 1c suppressed the hydrolysis of 2e in 1c•(2e)2
solubility of amides 2 in water, the reactions without cage 1c were (kcage/kbulk =0.11) despite the similarity to 1c•(2a)2 in the inclusion
performed in a D2O/CD3OD=1:1 solution; see Supplementary geometry (Supplementary Fig. 43). This is explained by the delo-
Information for details). Surprisingly, we observed a remarkable calization of the amide nitrogen lone pair to the indole aromatic
rate enhancement with kcage/kbulk =14. When an inclusion com- ring in 2e. Namely, the amide conjugation (nN–π*CO interaction) in
plex 1c•(2b)2 was examined, we again observed significant rate 2e is relatively weak and the twisting of the amide bond does not
enhancement, but kcage/kbulk was reduced to 6.1. The decreased cage significantly enhance the amide reactivity. The observed negative
effect is due to the contribution of the inert (almost planar) trans cage effect for 2e is presumably due to steric shielding by the cage
conformer. The rate enhancement was also observed for 1c•(2b•4) that dominates over the twisting activation. Therefore, the obser-
(kcage/kbulk =3.2). Although 2b adopts the trans conformation, it is vation of large rate enhancement for 2a and 2b (kcage/kbulk ≈5–14),
slightly twisted from the planar conformation (ω=169°). Overall, despite the steric shielding effect, is remarkable. These results also
we observed the enhanced amide reactivity by deviating the amide exclude the possibility of anionic intermediate stabilization by
bonds from their planar conformation.
the cationic cage.
The kinetic studies with the other substrates are in good
agreement with the above discussion. A rate enhancement of Conclusion
k
cage/kbulk =5.1 was observed for 1c•(2a)2. On the other hand, the In conclusion, we have achieved the non-covalent trapping of reac-
cage effect was almost negligible for 1c•2d, where only one mol- tive cis-twisted conformers of secondary aryl amides by inclusion
ecule of 2d was included with its latent trans-planar conformation. in the T -symmetric coordination cage. The twisted amides within
d
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Articles
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Methods
Formation of inclusion complex 1a•(2a)2. Amide 2a (29.3mg, 102μmol) was
suspended in an aqueous solution of cage 1a (20.0mM, 1.0ml) and stirred at
100°C for 1h. Afer removal of residual solid by fltration, the formation of
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1a•(2a)2 was determined as 25% from the integral ratio between 1a and 2a.
Formation of ternary complex 1a•(2b•3b). Amide 2b (15.5mg, 58.9μmol) and
phenanthrene (3b, 11.0mg, 61.7μmol) were suspended in an aqueous solution of
cage 1a (20.0mM, 1.0ml) and stirred at 100°C for 1h. After removal of residual
solid by filtration, the formation of ternary complex 1a•(2b•3b) in 85% yield was
confirmed by 1H NMR spectroscopy.
Hydrolysis of amide 2b from ternary complex 1c•(2b•3b). To an aqueous
solution of 1c•(2b•3b) ([1c]=3.0mM, 1.0ml) was added a 500mM aqueous
solution of NaOH (0.25mM) to prepare an aqueous solution of 1c•(2b•3b)
([1c]=2.4mM) with 100mM NaOH. The mixture was stirred at 60°C and the
crude product was extracted with CDCl3 to estimate conversion by 1H NMR
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by slow evaporation of solvent water from an aqueous solution of 1b•(2a)2
([1b]=5.0mM). Crystal data: tetragonal, space group P41212, a=b=30.657(6)Å,
c=29.219(5)Å, α=β=γ=90°, V=27,461(11)Å3, T=90(2)K, Z=4,
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ρ
calcd =1.246Mgm–3, R1 =0.0656, wR2 =0.1960. CCDC reference no. 1949143.
Online content
Any Nature Research reporting summaries, source data, extended data,
supplementary information, acknowledgements, peer review information; details
of author contributions and competing interests; and statements of data and code
availability are available at https://doi.org/10.1038/s41557-020-0455-y.
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Received: 27 August 2019; Accepted: 9 March 2020;
Published: xx xx xxxx
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Data availability
author contributions
The data supporting the findings of this study are available within this article and
its Supplementary Information. Crystallographic data for inclusion complexes
1b•(2a)2, 1a•(2b)2, 1a•(2b•3a), 1a•(2b•4), 1a•(2c)2, 1a•2d and 1a•(2e)2 are free of
charge from the Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk)
under reference nos. 1949143, 1949144, 1949145, 1949146, 1949149, 1949150 and
1949151, respectively.
H.T. and K.S. performed the described experiments and analysed the data. H.T. and M.F.
conceived and designed the experiments and co-wrote the manuscript.
Competing interests
The authors declare no competing interests.
additional information
Supplementary information is available for this paper at https://doi.org/10.1038/
s41557-020-0455-y.
acknowledgements
This research was supported by Grants-in-Aid for Specially Promoted Research
(19H05461 to M.F.), for Young Scientists (19K15581 to H.T.) and the Noguchi Institute
(to H.T.).
Correspondence and requests for materials should be addressed to H.T. or M.F.
Reprints and permissions information is available at www.nature.com/reprints.
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