Arene Substitution Design for Controlled Conformational Changes of Dibenzocycloocta-1,5-dienes

Article abstract of DOI:10.1021/jacs.0c06579

We report that an agile eight-membered cycloalkane can be stabilized by fusing a benzene ring on each side, substituted with proper functional groups. The conformational change of dibenzocycloocta-1,5-diene (DBCOD), a rigid?flexible?rigid organic moiety,

Full text of DOI:10.1021/jacs.0c06579

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Article
Arene Substitution Design for Controlled Conformational
Changes of Dibenzocycloocta-1,5-dienes
Wenxin Fu, Todd M. Alam, Jiachen Li, Jacqueline Bustamante, Thanh Lien, Ralph W.
Adams, Simon J. Teat, Benjamin J. Stokes, Weitao Yang, Yi Liu, and Jennifer Q. Lu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06579 • Publication Date (Web): 03 Sep 2020
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Arene Substitution Design for Controlled Conformational Changes
of Dibenzocycloocta-1,5-dienes
Wenxin Fu,1 Todd M. Alam,2 Jiachen Li,3 Jacqueline Bustamante,1 Thanh Lien,4 Ralph W. Adams,5
Simon J. Teat,6 Benjamin J. Stokes,4 Weitao Yang,3 Yi Liu,7 Jennifer Q. Lu1,*
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1Materials Science and Engineering, School of Engineering, University of California, Merced, 5200 North Lake Road,
Merced, California 95343, USA. *Email: jlu5@ucmerced.edu
2Department of Organic Material Sciences, Sandia National Laboratories, Albuquerque, NM 87185
3Department of Chemistry and Department of Physics, Duke University, Durham, North Carolina 27708, USA
4Department of Chemistry and Chemical Biology, University of California, Merced, 5200 North Lake Road, Merced, Cali-
fornia 95343, USA
5Department of Chemistry, The University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom
6Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
7The Molecular Foundry, Lawrence Berkeley National Laboratory, One Cyclotron Road, Berkeley, California 94720, United
States
KEYWORDS: Dibenzocycloocta-1,5-diene, Conformational change, Thermal response, Submolecular shape-changing
ABSTRACT: We report that the agile eight-membered cycloalkane can be stabilized by fusing two rigid benzene rings, substi-
tuted with proper functional groups. The conformational change of dibenzocycloocta-1,5-diene (DBCOD), a rigid-flexible-rigid
organic moiety, from Boat to Chair conformation requires an activation energy of 42 kJ/mol that is substantially lower than
that of existing submolecular shape-changing unit. Experimental data corroborated by theory calculations demonstrate that
intramolecular hydrogen bonding can stabilize Boat whereas electron repulsive interaction from opposing ester substituents
favors Chair. Intramolecular hydrogen bonding, formed by 1,10-diamide substitution stabilizes Boat, spiking the temperature
at which Boat and Chair can readily interchange from –60 °C to 60 °C. Concomitantly this intramolecular attraction raises the
energy barrier from 42 kJ/mol of unsubstituted DBCOD to 68 kJ/mol of diamide-substituted DBCOD. Remarkably, this value
falls within the range of the activation energy of highly efficient enzyme catalyzed biological reactions. With shape changes
once considered only possible with high-energy, our work reveals a potential pathway exemplified by a specific submolecular
structure to achieve low-energy driven shape changes for the first time. Together with intrinsic cycle stability and high energy
output systems that would have incurred damage under high-energy stimuli, could particularly benefit from this new kind of
low-energy driven shape-changing mechanism. This work has laid the basis to construct systems for low-energy driven stim-
uli-responsive applications, hitherto a challenge to overcome.
offers advantages, such as high speed and spatiotemporal
resolution using remote optical stimuli.29 However, conven-
tional photon-enabled submolecular shape-changing struc-
tures intrinsically require a high-energy stimulus, i.e., ultra-
violet light for the conversion from the ground state to an
excited state. These high-energy stimuli are responsible for
photobleaching and harmful to biological species. Several
decades of research have developed molecular structures
that respond to longer irradiation wavelengths including
visible and infrared light.30-34 However, limitations include
strong medium dependence, spontaneous reversal, and in-
adequate cycle stability. Intrinsically, molecules below one
micron from a surface can’t be stimulated due to limited
penetration of light stimulus.35 This limits the maximum en-
ergy output. Numerous real-world applications require new
types of submolecular shape-changing structures that can
be addressed by low-energy stimuli.
INTRODUCTION
Molecular- and submolecular-level shape changes in re-
sponse to an external stimulus serves as a foundation to en-
able low-energy driven actuations, such as biomanipulators
(e.g., tweezers and gear,1 and ion channel regulation2), con-
trolled drug release,3 regenerative medicine (e.g., dynamic
scaffolds,4 and artificial muscle5), adaptive architectural
systems (e.g., “heliophilic” optics6), soft robotics,7-8 deploy-
able structures (such as erectable trusses and inflatable so-
lar concentrators),9-11 and memory and logic devices.12-13
Typically stimulus is based on chemical (phenanthro-
line/copper redox combination,14 hydrazine,15-16 and bi-
phenyl motor17), or electrochemical reaction (thiophenyli-
dene derivative18 and π-donor/π-acceptor systems19), as
well as photoinduced isomerization (azobenzene,20 stil-
bene-containing,21 dicyanoethene22 and hydrazone23) or cy-
clization (diarylethene,24-25 spiropyran,26 and fulgide27-28).
The major limitation of chemically or electrochemically ac-
tivated systems is medium dependence. Photon stimulus
Nature provides an endless repertoire of low-energy
driven conformational changes in response to chemical
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investigation, we discovered that intramolecular interac-
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tions can substantially regulate DBCOD conformational dy-
namics. Trans to cis isomerization of azobenzene requires
an activation energy of at least 150 kJ/mol and very often in
excess of 250 kJ/mol.41-42 In stark contrast, 2,3,8,9-tetrame-
thyl substituted DBCOD (TM-DBCOD) requires 3 times less
energy, approximately 40 kJ/mol, which is similar to the re-
ported value of unsubstituted DBCOD.43 Aldehyde-function-
alized TM-DBCOD on carbons at 1 and 10 positions can raise
the activation energy (ΔGǂ) to 55 kJ/mol. Boat stabilization
stems from two hydrogen bonds between the oxygen from
a water molecule and the two hydrogens located on the al-
dehyde groups. On the other hand, for 2,9-dialdehyde sub-
stituted DBCOD, two CHO groups sit too far from each other
to form a water bridge via two hydrogen bonds, thus requir-
ing only 44 kJ/mol for the Boat to Chair conversion.
9
Scheme 1. (a) Chemical structure of a DBCOD unit (in
black) and possible substitution positions on the phenyl
rings (1-10 in blue). (b) Schematic drawing to illustrate
how intramolecular interaction stabilizes Boat and in-
terconversion between Boat and Chair induced by heat.
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stimuli to drive conformation in order to readily bind car-
bon dioxide for disposal.36 The conformational change of a
G protein‐coupled receptor (GPCR) activates a nearby G
protein, leading to the production of secondary messengers.
Through a sequence of events, GPCRs regulate an incredible
range of bodily functions, from sensation to hormone re-
sponses.37 Displaying power-efficiency, reliability and re-
producibility, these molecular-level conformational transi-
tions serve as an inspirational model and control diverse
cellular processes. For instance, hemoglobin delivers oxy-
gen throughout the body, and then changes its .
The strong intramolecular hydrogen bond imposed by
1,10-diamide substituents resulted in an activation energy
of about 68 kJ/mol, equivalent to the photon energy of near
infrared light of 1500 to 1600 nm.44 The value falls within
the range of activation energy of 50 – 80 kJ/mol of enzyme
catalyzed biological reactions, such as decarboxylation by
orotidine-5′-monophosphate decarboxylase,45 methyl
transfer reaction by catechol O-methyltransferase46 and ox-
idative deamination by D-amino acid oxidase.47
Comparing 1, 10 diethyl ester with 1,10 diethyl amide, in-
tramolecular hydrogen bonding favors Boat while electron
repulsive force yields more Chair. Indeed, at room temper-
ature, 1,10-di-Et-ester revealed 86 % Chair whereas 14 %
Chair was found in 1,10-di-Et-amide. The temperature at
which Boat and Chair can be interchanged readily for 1, 10
diethyl ester is -35 °C whereas 50 °C for 1,10 diethyl amide.
Dibenzocycloocta-1,5-diene, DBCOD, features a flexible
central eight-membered cycloalkane with rigid phenyl rings
fused onto each end (Scheme 1a). We have revealed
DBCOD-containing polymers exhibiting significant thermal
contraction38-40 despite containing only a small amount of
tetraphenylamide substituted DBCOD. Theoretical calcula-
tions implied that this substantial thermal contraction
might be the result of the DBCOD conformational change
from Boat (global minimum) to Chair conformation (local
minimum) upon heating (Scheme 1b).39
Our study demonstrates, for the first time, that judicious
molecular design and tailored substitution open a way for
harnessing low-energy conformational changes of medium-
sized hydrocarbon rings.The molecular chassis and substit-
uent design principles described herein could herald a new
category of submolecular shape-changing structures that
do not require high-energy stimuli, unlike conventional
ones. This new low-energy driven mechanism pushes the
application frontier -- introducing this unit into molecular-,
To examine this hypothesis, we have synthesized a li-
brary of DBCODs bearing various substituents (Scheme 2).
Through variable temperature NMR (VT-NMR) spectro-
scopic characterization and density functional theory (DFT)
Scheme 2. Synthetic route of 2,3,8,9-tetramethyl DBCOD (TM-DBCOD) derivatives.
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nano- and macro-scale systems, allows low energy stimuli
such as near infrared and magnetic induced local tempera-
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ture elevations, to regulate systems’ property or function.
For example, incorporating this structure into liquid crystal,
actuation/switch can occur using low-energy sources. Due
to the high penetration depth of low-energy stimuli, we ex-
pect that actuation based on this conformational change
mechanism possesses significantly higher energy density
than conventional systems.
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RESULTS AND DISCUSSION
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Synthesis of Functional Group Substituted DBCOD De-
rivatives. TM-DBCOD and its 1,10-disubstituted deriva-
tives, including dialdehyde (1,10-di-CHO), diphenylester
(1,10-di-Ph-ester), diethylester (1,10-di-Et-ester), diphe-
nylamide (1,10-di-Ph-amide) and diethylamide (1,10-di-Et-
amide) substituted TM-DBCOD, were synthesized according
to the synthetic route shown in Scheme 2. 2,9-dialdehyde
substituted DBCOD (2,9-di-CHO) was prepared based on
our previous published paper48 and used as a control to
study the effect of substitution positions on the DBCOD con-
formational dynamics.
Specifically, TM-DBCOD was synthesized from (4,5-
dimethyl-1,2-phenylene)dimethanol (di-OH) on a large
scale, sequentially through bromination49 using phospho-
rous tribromide and dimerization50-51 in the presence of
lithium sands. 1,10-di-CHO was formed via Rieche formyla-
tion.52-53 One-step column purification of 1,10-di-CHO was
adequate instead of multi-step column purification re-
quired for the preparation of 2,9-di-CHO (Scheme S1 and
Figure S1-2).54 Because there are only four possible posi-
tions for the formylation of TM-DBCOD, fewer than those of
1,2:5,6-dibenzocyclooctadiene (DBCOD). Therefore, the
1,10-di-CHO can be easily distinguished and separated from
its 1,7-diformylated isomer by flash column purification.52
Finally, 1,10-di-Et-ester, 1,10-di-Ph-ester, 1,10-di-Et-amide
and 1,10-di-Ph-amide were successfully prepared through
oxidation with hydrogen peroxide and sodium chlorite,55
followed by acyl chlorination using thionyl chloride and es-
terification/amidation using respective alcohol or amine.
The chemical structures of this series of DBCOD derivatives
1
were confirmed by H and 13C NMR spectroscopy (Figure
S3-S18).
Variable Temperature 1H-NMR Studies of DBCOD
Conformational Dynamics. Variable temperature 1H-NMR
spectroscopy (VT 1H-NMR) has been used to study the con-
formational changes of medium-sized rings.56-57 Through
1
the analysis of VT H-NMR, activation energy (ΔGǂ) corre-
Figure 1. VT 1H-NMR spectra of (a) TM-DBCOD, (b) 1,10-
di-CHO, (c) 2,9-di-CHO in CD2Cl2/CS2 = 4/1 with the con-
centration of 2 mg/mL. B and C denote the Boat and
Chair conformations, respectively.
sponding to the energy difference between the global mini-
mum and transition state, as well as the Gibbs free energy
(ΔGo) between Boat and Chair can be obtained. The coales-
cence temperature (Tc) is defined as the temperature at
which the rate of exchange between Boat and Chair ap-
proaches to the NMR experiment time scale. Below Tc, the
distinct peaks from Boat and Chair conformations show up
and their respective populations can be calculated based on
the ratio of integrations. At and above Tc, a single broadened
signal, observed due to fast exchange, is a result of the pop-
ulation-weighted average of two conformers. Therefore, we
can use the distance between the observed chemical shift at
each given temperature above Tc in relation to the individ-
ual Boat or Chair position to estimate Boat and Chair
1
population as a function of temperature. VT H-NMR anal-
yses were conducted using low polarity CD2Cl2 and non-po-
lar CS2 with the volume ratio of 4/1 for TM-DBCOD, 1,10-di-
CHO, 2,9-di-CHO and 1,10-diesters. High polarity solvent
DMSO-d6 was adopted for 1,10-diamides. A series of mix-
tures of DMSO-d6 and CD2Cl2 at different ratios was used to
understand the effect of solvent polarity on the conforma-
tional properties of 1,10-di-Ph-amide.
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Figure 2. VT 1H-NMR spectra of (a) 1,10-di-Et-amide, (b) 1,10-di-Ph-amide and (c) the region of methylene protons
for both in DMSO-d6 with the concentration of 2 mg/mL. (d) 1H-NMR spectra of 2 mg/mL 1,10-di-Ph-amide in different
deuterated solvents at 23 °C. B and C denote the Boat and Chair conformations, respectively.
Density functional theory (DFT) predicted 1H-NMR chem-
ical shifts for the Boat and Chair conformers of TM-DBCOD
and its derivatives were summarized in Table S1. The calcu-
lated chemical shifts were used to aid the assignment of pro-
ton signals in either Boat or Chair conformation (Figure 1-
3). Molecular symmetry differences caused by substitution
along with different spatial arrangements for Boat and
Chair conformations afford multiple inequivalent meth-
ylene and methyl protons. Experimentally, with increasing
temperature the ring dynamics simplified the 1H-NMR spec-
tra, reducing the number of signals through the averaging of
multiple chemical shifts.
conformer59 whereas two doublets (δ = 2.96 and 2.47) were
assigned to the Chair conformer. DFT calculated H chemi-
cal shifts (Table S1) indicated that methylene (-CH2-) chem-
ical shifts between 2.9 and 2.6 ppm belonged to Chair,
whereas chemical shifts occurring between 3.43 and 2.77
ppm were assigned to Boat.
1
Using the integrals of two sets of methyl protons, relative
populations of Chair and Boat can be calculated as 13 % and
87 %, respectively. At – 60 °C, the NMR resonances, includ-
ing both aromatic protons (δ = 6.77) and methylene protons
on the eight-membered ring (δ = 3.04), appeared as broad‐
ened singlets due to intermediate exchange. It can be as-
sumed that the population of Chair and Boat influenced the
observed NMR chemical shift. The fact that the NMR reso-
nance belonging to aromatic proton moved towards the
predicted chemical shift of Chair was indicative of rising
Chair population with increasing temperature.
(i) 2,3,8,9-tetramethyl substituted DBCOD (TM-DBCOD)
Taking TM-DBCOD at – 80 °C as an example (Figure 1a),
the aromatic protons gave two signals (δ = 6.95 and 6.69)
and the methylene protons gave one broad signal along with
two doublets (δ = 3.05 and δ = 2.96, 2.47). Previous re-
ports58-59 stated that two nonequivalent methylene protons
in the Chair conformer should generate an AB quartet (four
lines), whereas the Boat conformer should exhibit two AB
quartet patterns (eight lines). If the temperature was suffi-
ciently low to slow down the conversion of Boat conform-
(ii) 1,10- and 2,9-dialdehyde substituted DBCOD deriva-
tives
For 1,10-di-CHO at low temperatures (– 80 and – 60 °C)
(Figure 1b), both the deshielded aldehyde and aromatic
protons split into two singlets (δ = 10.66, 10.47, and δ =
7.24, 6.92). The tetramethyl protons gave two sets of two
singlets (δ = 2.40, 2.30, and δ = 2.21, 2.15), while the meth‐
ylene protons appeared as a series of multiplets. The more
intense set (δ = 3.49, 3.39, 3.10, 2.90) corresponded to the
different chemical environments of -CH2- on the eight-
o
ers, two quartet peaks should appear. Even at – 80 C, the
broaden methylene resonances for Boat configuration were
not well resolved, demonstrating rapid conformational av-
eraging existed at this low temperature. The high-intensity
and broad peak (δ = 3.05) was assigned to the Boat
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member ring in the Boat conformer as predicted by DFT cal- integration of methyl protons yielded the relative popula-
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culations (Table S1). Another downfield-shifted minor set
of resonances observed at – 80 °C was the tiny singlet from
aldehyde proton (δ = 10.66) and aromatic proton (δ = 7.24),
together with the doublets from methylene protons (δ =
3.54 and 2.64), indicating the presence of a small portion of
Chair. The relative populations of Boat and Chair can be cal-
culated using methyl proton, yielding 94 % Boat and 6 %
Chair at – 80 °C. Comparing with 87 % Boat and 13 % Chair
for TM-DBCOD at the same temperature, we concluded that
1,10-dialdehyde substitution stabilized the Boat confor-
mation. This was corroborated by the coalescence temper-
ature (Tc) of – 35 °C for 1,10-di-CHO, as opposed to – 60 °C
for TM-DBCOD.
We also studied the VT 1H-NMR spectra of 2,9-dialdehyde
substituted DBCOD (2,9-di-CHO) (Figure 1c) with each alde-
hyde functional group one atomic position away from the
eight-membered ring in contrast to 1,10-di-CHO. The calcu-
lated relative populations of Boat and Chair for 2,9-di-CHO
at – 80 °C were 91 % and 9 %, using the aldehyde proton
signals (δ = 9.76 for Boat and δ = 9.96 for Chair). The ob‐
served Tc for 2,9-di-CHO was similar to that for the unsub-
stituted TM-DBCOD.
tion of Chair and Boat as 28 % and 72 %, respectively, at 23
°C. The reason that the Chair population of 1,10-di-Ph-am-
ide of 28 % at 23 °C was twice as that of 1,10-di-Et-amide of
14 % at the same temperature was most likely caused by the
steric hindrance effect imposed by phenyl rings on 1,10 sub-
stitutions of DBCOD to retard the formation of Boat. Mean-
while, Tc was observed at 60 °C.
The chemical shift changes of methylene protons with in-
creasing temperatures (Figure 2c) also confirmed that the
coalescence of two conformations for both diamide substi-
tuted DBCODs in DMSO occurred above room temperature.
The averaged two singlets of methylene proton at 90 °C for
1,10-di-Ph-amide (δ = 2.96, 3.0) and for 1,10-di-Et-amide (δ
= 2.97, 2.88) changed into two broadened resonances with
shoulder peaks at 40 °C and below, indicating the slow ex-
change of Boat and Chair conformation.
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It is known that solvent polarity impacts the energy bar-
rier of isomerization.60-62 To examine this effect, we per-
1
formed H-NMR studies using different volume ratios of
high polarity solvent DMSO-d6 and the low polarity solvent
CD2Cl2 (Figure 2d). The Boat population increased with a
higher percentage of CD2Cl2 in the solvent mixture, i.e., re-
ducing polarity. This result implied that DMSO can effec-
tively break the DBCOD intramolecular hydrogen bond and
destabilize Boat.
DFT calculations of 1,10-di-CHO molecule indicated (Fig-
ure S19a) that a water molecule can form hydrogen bonds
with the aldehyde group at 1 and 10 positions respectively
and thus stabilizing Boat conformation. This was verified by
differential scanning calorimetry (DSC) (Figure S20). An en-
dothermic peak at around – 30 °C was observed during the
first two runs but disappeared after repeated heating cycles
under dry N2 without taking the pan out. After leaving the
pierced DSC pan exposed to air for an extended period time,
the endothermic peak reappeared, suggesting that this is
water-related. Therefore, this endothermic peak at around
– 30 °C was a result of the release of water molecules. Ac-
cording to VT-1H NMR spectra of 1,10-di-CHO (Figure S21),
water is present.
(iv) 1,10-diester substituted TM-DBCODs
1
The VT H-NMR results of 1,10-di-Et-ester and 1,10-di-
Ph-ester at – 60 °C clearly indicated the presence of two con-
formers (Figure 3a and 3b). DFT calculations (Table S1) also
indicated that both the chemical shifts of aromatic and me-
thyl protons produced by Chair should be more downfield
than those produced by Boat.
Moreover, for 1,10-di-Et-ester, four sets of methylene
doublets (δ = 2.38, 2.55, 2.77 and 3.02) were assigned to
Chair, while two broad peaks (δ = 2.98 and 3.10) belonged
On the contrary, the 2,9-di-CHO did not produce a detect-
able DSC peak. This is due to the greater geographic separa-
tion between two aldehydes preventing water from bridg-
ing two aldehydes via hydrogen bonding interaction, pre-
dicted by DFT (Figure S19b).
Table 1. Relative molar ratio of Boat/Chair for different
DBCOD derivatives at different temperatures and the
corresponding Tc
Relative molar
Coalescence
ratio of
Boat/Chair at
different T
(iii) 1,10-diamide substituted TM-DBCODs
Compound
Temperature
1
(Tc) (°C)
Figure 2a is VT H-NMR spectra of 1,10-di-Et-amide. Ac-
cording to DFT predictions (Table S1), the chemical shifts of
both methyl and aromatic protons in Chair should be more
downfield shifted than those of Boat. One could rationally
deduce that the minor peak of aromatic proton (δ = 6.95)
belonged to Chair and the major one (δ = 6.77) corre‐
sponded to Boat. Similar results can be found for the methyl
protons (δ = 2.15 for Chair and δ = 2.06, 1.94 for Boat).
Based on integration of methyl peaks, relative populations
were 14 % Chair and 86 % Boat at 23 °C. Tc was about 50 °C.
The result reinforced the postulation that intramolecular
hydrogen bonding could raise the activation energy for the
dynamic conversion.
TM-DBCOD
1,10-di-CHO
87/13a
94/6a
-60
-35
90/10b
91/9a
2,9-di-CHO
-60
-35
-35
50
1,10-di-Et-ester
1,10-di-Ph-ester
1,10-di-Et-amide
1,10-di-Ph-amide
59/41b
66/34b
86/14c
72/28c
1
The VT H-NMR spectra of 1,10-di-Ph-amide also dis-
60
played both sets of peaks associated with aromatic and me-
thyl protons (Figure 2b). Similarly, we assigned the smaller
peaks of methyl protons (δ = 2.20 and 2.12) as Chair, and
the more significant ones (δ = 2.15 and 2.06) as Boat. Peak
a: -80 °C. b: -60 °C. c: 23 °C.
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Figure 3. VT 1H-NMR spectra of (a) 1,10-di-Et-ester and (b) 1,10-di-Ph-ester in CD2Cl2/CS2 = 4/1 with the concen-
tration of 2 mg/mL. B and C denote the Boat and Chair conformations, respectively. (c) Noncovalent interaction plots
of DBCOD derivatives in the Boat and Chair conformations for 1,10-di-CHO with one water molecule encased (left),
1,10-di-Ph-ester (middle) and 1,10-di-Et-ester (right). (black: carbon; white: hydrogen; red: oxygen).
to Boat. Analogously, the assignments of Chair and Boat for
1,10-di-Ph-ester can be found in Figure 3b. Based on the in-
tegrals of two sets of methyl protons on DBCOD, relative
populations were 41 % Chair and 59 % Boat for 1,10-di-Et-
ester and 34 % Chair and 66 % Boat for 1,10-di-Ph-ester at
– 60 °C.
the DCBOD conformational dynamics can be modulated by
substitution.
Since the conformational changes of DBCOD derivatives
between Boat and Chair doesn’t involve any covalent bond
disruption/formation, it is intrinsically reversible. This con-
tention is exemplified by the VT-1H NMR analysis of 1,10-di-
Ph-amide in DMSO-d6 upon heating and cooling (Figure
S22).
The remarkable difference of Boat and Chair populations
between 1,10-dialdehyde and 1,10-diester substituted
DBCODs at – 60 °C was originated from their distinct intra-
molecular interactions. In comparison with 1,10-di-Et-es-
ter, π-π stacking interaction of two appended phenyl rings
as parts of two opposing phenyl ester groups can be spa-
tially arranged to stabilize Boat (Figure 3c). At – 60 °C, the
1,10-di-Ph-ester therefore yielded a higher Boat population,
66 %, as opposed to 59 % of 1,10-di-Et-ester. Due to hydro-
gen bonds formed between an encased water molecule and
1,10-dialdehyde groups, 90 % Boat was present in 1,10-di-
CHO at – 60 °C. The electrostatic repulsive interaction be-
tween two adjacent ester groups of 1,10-diesters destabi-
lized Boat, resulting in a 2 – 3 times higher Chair population
for 1,10-diesters than that for 1,10-di-CHO at – 60 °C.
Kinetic and Thermodynamic Study of DBCOD Confor-
mational Conversion
(i) Theoretical and experimental investigation of confor-
mational kinetics
1
The VT H-NMR analysis yielded DBCOD conformational
exchange rates, entropy of activation (ΔSǂ), and enthalpy of
activation (ΔHǂ) (Table S2). We observed negative values of
entropy of activation which varied significantly. Increasing
intramolecular forces formed by the neighboring substitu-
ents produced greater negative ΔSǂ values. These values im-
plied that intramolecular interactions reduce the degrees of
molecular freedom leading to a higher entropic penalty for
a conformational change. This result demonstrated that the
conformation kinetics can be readily tailored through en-
tropy of activation which itself can be modulated by substi-
tution (Figure 4a). Related studies of azobenzene isomeri-
zation also revealed the negative entropy,60, 62-64 more or-
dered activated complex during isomerization.
Displacing ethyl groups with phenyl groups mitigated re-
pulsive interaction and together with the additional π-π in‐
teraction generated by two adjacent phenyl rings shifted
the equilibrium towards Boat. Table 1 demonstrated pre-
ferred conformations and coalescence temperatures of
DBCOD derivatives. Boat population and activation energy
increased with introducing intramolecular hydrogen bond.
The electric repulsive interaction favored Chair. Therefore,
The activation energies (ΔGǂ) of DBCOD derivatives ob-
tained from VT 1H-NMR analysis and DFT calculations were
compared side-by-side in Table S3. 2, 9 substitution
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Journal of the American Chemical Society
inconsiderably impacted on activation energy. Because two Without intramolecular interactions, Chair conformers of
TM-DBCOD were thermodynamically favored at 25 °C. Elec-
trostatic repulsive interaction of 1,10-diester groups af-
forded more Chair than that of TM-DBCOD. This led to more
negative values of Gibbs free energy (ΔGo) of 1,10-diester
substituted DBCODs compared with TM-DBCOD.
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aldehyde groups at 2, 9 positions were too far apart to in-
teract with each other, 2,9-di-CHO had similar activation en-
ergy to that of TM-DBCOD. On the contrary, the two neigh-
boring amide groups at the 1, 10 positions formed a strong
intramolecular hydrogen bond (HNC=O···HNC=O), raising
the activation energy to 68 kJ/mol, a 60 % increase over
that of unsubstituted TM-DBCOD. The two weak hydrogen
bonds between water and the 1,10-substituted aldehyde
pair resulted in an activation energy of 55 kJ/mol for 1,10-
di-CHO. Electron density map of 1,10-diester derivatives in-
dicated that ester groups offered appreciable electrostatic
repulsive interaction (Figure S23), rendering activation en-
ergies around 50 kJ/mol. DFT calculations closely matched
with experimental results throughout (Figure 4a).
For 1,10-diamide substitution, the intramolecular hydro-
gen bond formed by two adjacent diamides rendered Boat
o
as the global minimum at 25 C. Preference of Boat over
o
Chair yielded a positive value of ΔGo at 25 C. For example,
9
DFT calculations predicted ΔGo values of 6.4 and 2.6 kJ/mol
at 25 oC for 1,10-di-Et-amide and 1,10-di-Ph-amide, respec-
tively. Experimentally, we observed the similar trend, ΔGo
values are positive at 25 oC.
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According to VT 1H-NMR analysis, the populations of Boat
and Chair for each DBCOD derivative at different tempera-
tures were estimated as shown in Table S5 and Figure S25a-
g. Indeed, at 23 °C, 1,10-di-Et-amide presented as 86 % Boat
as opposed to 72 % Boat in 1,10-di-Ph-amide. In stark con-
trast, unsubstituted TM-DBCOD could sustain 87% Boat
only at –80 °C. This over 100 °C difference further sup-
ported the contention that intramolecular hydrogen bond-
ing can effectively stabilize Boat. 1,10-di-Ph-amide at 23 oC
adopted 72 % of Boat but the Boat population dropped to
Furthermore, ΔHǂ varied linearly with ΔSǂ as a function of
ΔHǂ=45.68+0.11ΔSǂ (Figure S24). The DBCOD conforma-
tional change showed a typical enthalpy-entropy compen-
sation effect.65 This result indicated that substitution al-
tered neither the conformational change pathway nor
mechanism. Analogously to the cis-trans isomerization of
azobenzene-based molecules with different substitutions,
enthalpies of activations are not sensitive to substitution
properties.63
(ii) Theoretical and experimental investigation of confor-
mational energetics
o
27 % at 90 C. Comparing 1,10-di-Et-ester with 1,10-di-Et-
amide, intramolecular hydrogen bonding favored Boat
while electron repulsive force yielded more Chair. Indeed,
at room temperature, 1,10-di-Et-ester had 86 % of Chair
whereas 14 % of Chair was found in 1,10-di-Et-amide. The
change of population with temperature forms the founda-
tion of thermally driven shape-changing submolecular
structures.
DFT study (Table S4) revealed that intramolecular forces
significantly affected the conformation equilibrium position
between Boat and Chair. Intramolecular interactions gener-
ated by hydrogen bonding and π-π stacking steered the
equilibrium position towards Boat. This trend foreseen by
computation agreed with experimental results (Figure 4b).
While theory calculations and experiment data revealed
the same trend, the discrepancy in magnitude between the-
ory and experimental results of diesters might be due to the
fact that theory calculations do not consider the effect of sol-
vent on electrostatic interaction.
Small-molecule X-ray Crystallography. DFT calcula-
tions of two units of TM-DBCOD and 1,10-di-Et-amide mol-
ecules respectively were used to study molecular packing
configuration in crystal. Adding one more TM-DBCOD mol-
ecule favored Chair, reducing ΔGo from – 3.6 kJ/mol to – 7.9
kJ/mol (Table S4). Due to intermolecular π-π stacking
formed between phenyl rings from neighboring TM-
DBCOD, Chair became more favorable for TM-DBCOD which
was absent of intramolecular interactions. The X-ray crys-
tallography of TM-DBCOD (Figure 5a) confirmed the theo-
retical prediction, showing two stacked TM-DBCODs in the
Chair conformation, agreeing well with prior published data
of unsubstituted DBCOD.66
Based on DFT, the intramolecular hydrogen bonding was
sufficiently large to favor Boat conformation. According to
X-ray crystallography, 1,10-di-Et-amide adopted the Boat
conformation, π-π stacking along the opposite sides of two
Boats and oriented upside down relative to each other in
crystal (Figure 5b). This finding highlights the importance
of intra- and inter-molecular interactions on the DBCOD
conformation state. In solid, the interplay of these two joint
forces dictate the DBCOD conformation dynamics.
Figure 4. (a) Kinetic and (b) energetic Gibbs free energy
changes of DBCOD derivatives at 25 oC.
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event can potentially act as an actuator in an analog device
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and as a switch in a logic device. For example, it can be teth-
ered onto biomolecules and incorporated into a polymer
chain to achieve stimuli-induced desired functionalities.
The geometrical change can also be exploited for pore size
modulation of polymer membranes for applications in en-
ergy and health. DBCOD embedded polymeric electronic
packaging materials could reduce polymer thermal expan-
sion and thus improve reliability of high-density memory
devices and possibly realize higher speed logical devices.
Furthermore, this work provides insight on how to tailor
the energy landscape of medium-sized cyclic structures
which frequently act as subunits in natural products.
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Figure 5. Molecular structure and spatial configuration
based on small-molecule X-ray crystallography of (a)
TM-DBCOD and (b) 1,10-di-Et-amide. Dark gray: Carbon,
white: Hydrogen, red: Oxygen, purple: Nitrogen and
green: Chlorine (solvent).
ASSOCIATED CONTENT
Supporting Information. Detailed information about the syn-
thesis and characterization of DBCOD derivatives, DFT pre-
dicted NMR chemical shifts and kinetic and energetic results,
rate constants, entropy of activation (ΔSǂ) and enthalpy of acti-
vation (ΔHǂ) for conformational change can be found in Sup-
porting Information. This material is available free of charge
via the Internet at http://pubs.acs.org.”
Both inter- and intra-molecular hydrogen bonds are pre-
sent in 1,10-di-Et-amide crystal. Therefore, 1,10-di-Et-am-
ide molecules in polymer form would be oriented so that the
two amide groups are connected via intramolecular hydro-
gen bonds, (position_1 of molecule A) O=C-NH···O=C-NH
(position_10 of molecule A). The amide groups of adjacent
DBCODs are linked by intermolecular hydrogen bonds, (po-
sition_10 of molecule A) O=C-NH···O=C-NH... (position 1 of
molecule B). We will synthesize a series of co-polymers with
short and long 1,10-di-Et-amide-containing segments to
study the interplay of inter- and intra-molecular forces on
the DBCOD conformational preference and activation en-
ergy.
AUTHOR INFORMATION
Corresponding Author
*Jennifer Q. Lu, Email: jlu5@ucmerced.edu
Author Contributions
J.Q.L. conceived the project through closely working with W.F.
J.Q.L and W.F wrote the manuscript. W.F., J.B. and T.L. per-
formed the synthesis and characterizations of all DBCOD deriv-
atives. W.F. and Y.L. conducted the VT 1H-NMR measurements.
J.L., W.T. and T.M.A. performed the DFT calculations to reveal
kinetics and thermodynamic energies at different states. T.M.A.
performed the predicted 1H-NMR chemical shifts of DBCOD de-
rivatives. R.W.A. evaluated the energy barrier for conforma-
CONCLUSION
A low-energy driven shape-changing unit has been highly
sought after for years but eluded attainment. Now, for the
first time, we demonstrate that two rigid benzene rings
fused by a flexible eight-membered cycloalkane with de-
sired substitution property can potentially transform the
DBCOD conformational change into a controlled low-energy
driven shape-changing event. Experimental investigations,
confirmed by theoretical predictions, show that TM-DBCOD
requires only 42 kJ/mol to trigger the conformational
change from Boat to Chair. Intramolecular hydrogen bond-
ing formed by 1,10-diamide stabilizes Boat over Chair, rais-
ing the activation barrier from Boat to Chair up to 68 kJ/mol.
This value is much lower than those required by conven-
tional shape-changing molecular structures. Shape-chang-
ing will no longer be only reliant on high-energy stimuli.
This work could lay the foundation for scientific explora-
tion of this new low-energy driven shape-changing mecha-
nism that responds to a broad range of low-energy stimulus
such as infrared- or magnetically induced heat. Other salient
features include (a) innate reversibility arising from the ab-
sence of disruption and reformation of covalent bonds dur-
ing the conformational change, (b) the options of operating
in a wide range of solid and liquid media, and (c) high en-
ergy throughput as low-energy stimuli are able to penetrate
into the entire material.
1
tional exchange based on the VT H -NMR. S.J.T. conducted the
X-ray single-crystal diffraction measurements. W.F., R.W.A.,
S.J.T., B.J.S., T.M.A., W.Y., Y.L. and J.Q.L discussed the data pro-
cessing, analysis and interpretation.
Notes
The authors declare no competing interests.
ACKNOWLEDGMENT
We appreciate the financial support from NSF CHE-1900647
and CHE-1900338, R01 GM061870-17, and National Aero-
nautics and Space Administration (NASA) grant no.
NNX15AQ01. The NMR shielding calculation were performed
at Sandia National Laboratories, a multi-mission laboratory
managed and operated by National Technology and Engineer-
ing Solutions of Sandia, LLC., a wholly owned subsidiary of Hon-
eywell International, Inc., for the U.S. Department of Energy’s
National Nuclear Security Administration under contract DE-
NA0003525. This paper describes objective technical results
and analysis. Any subjective views or opinions that might be
expressed in the paper do not necessarily represent the views
of the U.S. Department of Energy or the United States Govern-
ment. The Work at the Molecular Foundry was supported by
the Office of Science, Office of Basic Energy Sciences, of the U.S.
Department of Energy under Contract No. DE-AC02-
05CH11231. We thank Liana M. Klivansky for her help on sam-
ple preparations and trainings in Molecular Foundry. This
The creation of low-energy driven shape-changing struc-
tures broadens applications especially those that are prone
to high-energy damage. This submolecular shape-changing
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