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ISSN 2041-6539rsc.li/chemical-science

ChemicalScience

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Naoya Kumagai, Masakatsu Shibasaki et al.

Pyramidalization/twisting of the amide functional group via remote steric congestion triggered by metal coordination

Volume 8 Number 1 January 2017 Pages 1-810

Pyramidalization/twisting of the amide functional

groupviaremote steric congestion triggered by metal coordination†Shinya Adachi, Naoya Kumagai*and Masakatsu Shibasaki* For decades, the planarity of the amide functional group has garnered sustained interest in organic

chemistry, enticing chemists to deform its usually characteristic high-fidelity plane. As opposed to the

construction of amides that are distorted by imposing rigid covalent bond assemblies, we demonstrate

herein the deformation of the amide plane through increased steric bulk in the periphery of the amide

moiety, which is induced by coordination to metal cations. A crystallographic analysis revealed that the

thus obtained amides exhibit significant pyramidalization and twisting upon coordination to the metals,

while the amide functional group remained intact. The observed deformation, which should be

attributed to through-space interactions, substantially enhanced the solvolytic cleavage of the amide,

providing compelling evidence that temporary crowding in the periphery of the amide functional group may be used to control the reactivity of amides.

Introduction

The amide bond is characterized by its thermodynamic stability and kinetic tolerance toward hydrolytic cleavage, which arises from conjugationviathe planar O-C-N array. 1

Under neutral

conditions in aqueous solution at ambient temperature, non- activated amide bonds have a half-life ofca.100 years.2 This high stability is usually attributed to the resonance interaction between the n N andp* C]O orbitals, which occurs most effi- ciently in a planar geometry with a shortened and stronger C-N bond. Therefore, amide bonds are commonly used as a robust structural motif (e.g.in synthetic polymers), and the hydrolysis of the amide bond in a practical timescale requires general harsh conditions (e.g.high or low pH at elevated temperatures). The deformation of the co-planarity of the amide bond repre- sents an intuitive strategy to lower its robustness, which was initially proposed by Luke

ˇs in 1938, who presented a model of

strained"twisted amides"with a nitrogen atom at the bridge- head position. 3

The longstanding pursuit toward twisted

amides led to the identication of extreme examples of fully- characterized and highly distorted amides (A-C), 4,5 which exhibited twistangles (s) and pyramidalization (c N ) valuesat the nitrogen, dened by Winkler and Dunitz,6 ofca.90 and 60 respectively (Fig. 1a). The prime importance of the resonance

interaction for stabilizing the amide bond manifests in the caseofB, which lacks an amide resonance, and exhibits a remark-

ably short half-life of <15 s in water. 5d

Besides these extreme

examples, a number of amides that exhibit unusualsandc N values have been reported, typically using covalently distorted bridged lactam architectures. 1,7,8

These structurally intriguing

bonds may not only be of fundamental academic interest, but also of signicant applied importance in life science, consid- ering that amides constitute the primary backbone of proteins. Fig. 1(a) Extreme examples of highly distorted amides in a covalent framework, (b) deformation/activation of amidesviathe coordination of the amide nitrogen to metals, and (c) the distortion of the amide induced by peripheral steric constraints upon the coordination to metal cations.Institute of Microbial Chemistry (BIKAKEN), 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo

141-0021, Japan. E-mail: nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp

†Electronic supplementary information (ESI) available. CCDC 1494998-1495005. For ESI and crystallographic data in CIF or other electronic format see DOI:

10.1039/c6sc03669d

Cite this:Chem. Sci.,2017,8,85

Received 16th August 2016

Accepted 21st September 2016

DOI: 10.1039/c6sc03669d

www.rsc.org/chemicalscience This journal is © The Royal Society of Chemistry 2017Chem. Sci.,2017,8,85-90 |85

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Open Access Article. Published on 23 September 2016. Downloaded on 7/18/2023 8:02:17 AM.

This article is licensed under a

Creative Commons Attribution 3.0 Unported Licence.View Article OnlineView Journal | View Issue Indeed, the involvement of distorted amides has been invoked for enzymatic transformations. 1,9

In this context, we were inter-

ested in distorting the amide planarity using an external trigger; more specically, instead of constructing covalently assembled distorted amides, we aimed at inducing the amide deformation viatemporary non-covalent interactions. Although several reports link the deformation and activation (e.g.hydrolysis and E/Zisomerization) of amides to the coordination of the amide nitrogen to metal cations (Fig. 1b), 10,11 substantial amide defor- mation without direct coordination of the amide nitrogen or oxygen has, to the best of our knowledge, not yet been reported. Herein, we show that it is possible to induce signicant pyr- amidalization and twisting of the amide functional group by remote steric congestion upon the coordination of the substit- crystallographic analysis revealed that the substantial deforma- tion of the amide planarity occurs without direct coordination of the amide. Peripheral crowding being a viable strategy to weaken the amide linkage is supported by the observed rapid solvolysis of the thus obtained distorted amides. 12

Results and discussion

We began our study by designing a suitable amide with metal- coordination sites that may be able to create a steric bias upon the addition of appropriate metal cations. As the metal coor- dination should be orthogonal to the amide functional group, we selected a combination of azophilic metals and nitrogen- based bidentate coordination sites. Fig. 2a shows the generic structure of amide1with a 3-substituted-2-hydrazonopyridine moiety, which contains an amide (N Am ) and an adjacent imine (hydrazone of benzophenone; N Im ) functional group. It should be noted that1prefers a planar amide structure, which is achieved by tilting the pyridine ring and the imine along the

C(pyridine)-N

Am and N Am -N Im single bonds, respectively (Fig. 2a,I). Conversely, we anticipated that the addition of azophilic cations (M) should induce a bidentate chelation through N Im and N Py , thus affording a rigid and planar

5-membered cycle. This conformational change should provokeboth the bulky benzophenone imine and the R

2 group on the pyridine ring to swing close to the amide, thus compromising the amide planarityviathrough-space steric bias (Fig. 2a,II). With this blueprint in hand, we set out to synthesize three derivatives, which contain R 2 groups of varying steric bulk: H (1a), Me (1b), and 2,6-dimethylphenyl (1c) (Fig. 2b). 13

While1b

and1cwere synthesized as (E)-crotonyl amides,1awas based on ap-uorocinnamoyl amide in order to increase its crystallinity.

The coordination of1ato azophilic Pd

2+ cations, which favor a square-planar coordination mode, afforded in aprotic solvents the corresponding complexes. The formation of these complexes, which are thermodynamically stable under anhy- drous conditions at ambient temperature, was monitored using 1 H and 13 C NMR spectroscopy. The NMR analysis revealed that

1a/Pd (1a:Pd¼1 : 1) and (1a)

2 /Pd (1a:Pd¼2 : 1) complexes were formed depending on the ratio of1aand [Pd(CH 3 CN) 4 (BF 4 2 (Fig. 3). In CD 3

CN, a 1 : 1 mixture of1aand [Pd(CH

3 CN) 4 (BF 4 2 favored the formation of1a/Pd. The observed NOE signals between H e and H d are consistent with the anticipated coordination modeviaN py and N Im , in which the amide nitrogen N Am is leuncoordinated (Fig. 3a and b). 14

The char-

acteristic downeld shiof theb-olenic proton H f upon complexation implied an increased polarization of the C]O bondviadistortion of the amide moiety. The formation of the homoleptic complex (1a) 2 /Pd from bidentate coordinationvia N py and N Im induced similar spectral changes in the 1 H and 13 C NMR spectra, together with diagnostic NOE signals between the two1afragments (H a and H i ; Fig. 3c). For (1a) 2 /Pd, the observed downeld shiof H f was even more pronounced, which was tentatively ascribed to the deshielding effect of the phenyl group on the opposite1a/Pd fragment (Fig. 3b and c and 4d;vide infra). Unfortunately, the chemical shis in the 13 C NMR spectra were not straightforward to interpret (Fig. 3d-f); in contrast to the rather subtle changes to the resonances for the amide carbonyl (C Am ) moiety, the signal for the imino carbonyl (C Im ) fragment experienced a substantial downeld shi. In the Ph group-rich environment of these complexes, the downeld shiof the amide carbonylviadistortion and the imino carbonylviadirect coordination might be increased and decreased, respectively, by shielding and deshielding effects from nearby multiple bonds (vide infra). The distortion of the amide plane in1aby peripheral crowding was further examinedviasingle-crystal X-ray diffrac- tion analysis (Fig. 4a and d). Single crystals of amide1aand its

Pd complex (1a)

2 /Pd were obtained from acetone/hexane, and their solid-state structures are shown in Fig. 4a and d, while selected bond lengths and distortion parameters are summa- rized in Table 1. In1a, the pyridyl and the hydrazine group occupy the far side of the amide group in order to minimize steric repulsion. The amide group exhibited a negligible twist angle (s¼3.0 ), whereas partial pyramidalization was observed for the amide nitrogen (c N

¼19.6

). In stark contrast, the complex (1a) 2 /Pd exhibited a signicant pyramidalization (c N 54.1
) of the amide nitrogen, and the expected bidentate coor- dinationviaNquotesdbs_dbs20.pdfusesText_26

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