Role of Ring Ortho Substituents on the Configuration of Carotenoid Polyene Chains

Article abstract of DOI:10.1021/acs.orglett.7b03930

The 9-(Z)-configuration was exclusively obtained in the carotenoid polyene chain irrespective of olefination and disconnection methods for terminal ortho-unsubstituted benzene rings. The 2,6-dimethyl substituents in the terminal rings secure an all-(E)-po

Full text of DOI:10.1021/acs.orglett.7b03930

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Role of Ring Ortho Substituents on the Configuration of Carotenoid
Polyene Chains
Minsoo Kim,† Hyunuk Jung,† Albert C. Aragones,‡ Ismael Díez-Perez,*,‡ Kwang-Hyun Ahn,§
̀
́
Wook-Jin Chung,† Dahye Kim,† and Sangho Koo*,†
†Department of Energy Science and Technology and Department of Chemistry, Myongji University, Myongji-Ro 116, Cheoin-Gu,
Yongin, Gyeonggi-Do 17058, Korea
‡Department of Chemistry, Faculty of Natural & Mathematical Sciences, King’s College London, Britannia House, 7 Trinity Street,
London SE1 1DB, United Kingdom
§Department of Applied Chemistry, Kyung Hee University, Yongin, Gyeonggi-Do 17104, Korea
S
* Supporting Information
ABSTRACT: The 9-(Z)-configuration was exclusively obtained in the
carotenoid polyene chain irrespective of olefination and disconnection
methods for terminal ortho-unsubstituted benzene rings. The 2,6-dimethyl
substituents in the terminal rings secure an all-(E)-polyene structure. The
single molecular conductance of the pure 9-(Z)-carotene was measured for
the first time to be 1.53 × 10−4 6.37 × 10−5G0, whose value was 47% that
of the all-(E)-carotene ((3.23 × 10−4) (1.23 × 10−4) G0).
arotenoids are structurally characterized by the conjugated
polyene chain, which endows the red pigments with light-
Scheme 1. Disconnection Approaches to 9,9′,13,13′-
C
Tetramethylcarotene Wire 1
harvesting and energy transferring abilities1 as well as strong
antioxidant activity.2 Even though 256 stereoisomers are
theoretically obtainable by the palindromic structure containing
nine CC bonds, only a dozen stereoisomers were reported.3
All-(E)-carotenes are generally the most stable form and can be
prepared by chemical synthesis.4 (Z)-Carotenes are also
widespread in nature (e.g., bixin, phytofluene, prolycopene,
etc.), 9-(Z)-isomers being prevalent.5 Since the geometry of
carotenoids determines their physicochemical characteristics as
well as their biological activities,6 it is desirable to develop a
stereoselective synthetic method for each isomer.
In our research directed to the utilization of carotenoids as
molecular wires, a series of phenyl-substituted all-(E)-carote-
noids was designed7 in which the phenyl groups not only stabilize
the polyene chain8 but also impart diverse electron-conducting
abilities to the chain.9 We were interested in the conductance
behavior of carotene 1 containing the natural form of 9,9′,13,13′-
tetramethyl substituents (Scheme 1).10 Efforts to synthesize all-
(E)-carotene 1 were unsuccessful, and on the contrary, it was
found that the 9-(Z)-isomer was obtained exclusively. Since there
have been controversial reports on the molecular conductance
behaviors of E/Z isomers of azobenzene and diphenyl-
ethylene,11,12 and since only the theoretical calculation for the
conductance of (Z)-carotene was available,13 it was a good
opportunity to experimentally investigate the conductance of the
(Z)-isomer. It was still necessary to synthesize the corresponding
all-(E)-carotene in order to complete the conductance study on
the E/Z isomerism of carotenoids. We devised a method to
construct all-(E)-9,9′,13,13′-tetramethyl carotene based on the
fact that β-carotene and isorenieratene14 can be easily prepared in
all-(E) form, in which the ring o-methyl substituents were
conceived to play an important role in controlling the
configuration of the polyene chain. We herein report the
syntheses and conductance measurements of 9-(Z)- and all-(E)-
9,9′,13,13′-tetramethylcarotenes.
Typical disconnection approach to 9,9′,13,13′-tetramethylcar-
otene 1 was either using C10 dihalide 315 or C10 dialdehyde 416
(Scheme 1). The functional group X of the coupling partner 2
may be selected among benzenesulfonyl (−SO2Ph), benzothia-
zolesulfonyl (−SO2BT), and triphenylphosphonium bromide
(−PPh3Br) according to the olefination methods of Julia,17
Julia−Kocienski,18 and Wittig,19 respectively (Scheme 1). The
terminal methylthio group was designed as a linker to allow the
carotene wire for reliable contact with gold electrodes for
Received: December 18, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03930
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Organic Letters
Letter
conductance measurement.20 Other disconnection utilizing C20
crocetindial 5 and Wittig salt 6 was also tested.
The synthesis began with the preparation of the key building
blocks 2 with methylthio linker (Scheme 2). Dienyl sulfones 2a
complicated due to the formation of the regioisomer at the
benzylic position. In situ generated triphenylphosphonium
bromide from PPh3 and NBS successfully activated the tertiary
carbinol by forming triphenylphosphonium oxide, which was
replaced by PPh3 at the less hindered terminal vinyl carbon to
provide the Wittig salt 2c quantitatively.
Sulfone-mediated 2:1 coupling between dienyl sulfone 2a and
C10 dihalide 3 was carried out with t-BuOK in DMF at −20 °C to
produce C40 trisulfone 12 (92% yield, Figure 1). Olefinations
Scheme 2. Synthesis of the Key Building Blocks 2 Containing
a Methylthio Linker
(X = −SO2Ph) and 2b (X = −SO2BT) were synthesized by the
application of the two step protocol utilizing indium-mediated
addition of chloroallylic sulfones 8a (R = Ph) and 8b (R = BT) to
4-(methylthio)benzaldehyde (9),21 followed by the oxonia-Cope
rearrangement of the resulting homoallylic alcohols 10a and 10b,
respectively.22 The C5 chloroallylic sulfones 8a and 8b were
prepared from isoprene. Chlorohydrin formation (58% yield) by
NCS in water/DMF followed by bromination (92% yield) with
PBr3 and catalytic CuI accompanying allylic migration produced
allylic dihalide 7 (E:Z = 6:1).23 Selective allylation at the more
reactive carbon containing bromide by NaSO2Ph provided
chloroallylic benzenesulfone 8a (60% yield)24 or by BT-SH using
K2CO3 in acetone produced the corresponding BT-sulfide (95%
yield). Sulfur oxidation by H2O2 with catalytic sodium tungstate
(Na2WO4·2H2O) gave rise to chloroallylic benzothiazolesulfone
8b (51% yield).25 The E/Z alkene configurations were
maintained as 6:1 through the allylation steps.
Indium-mediated Barbier addition of C5 chloroallylic sulfone
8a (R = Ph) to 4-(methylthio)benzaldehyde (9) was carried out
at 80 °C in a 4:1 H2O/THF to produce homoallylic alcohol 10a
(64% yield) with 2:1 anti (OH vs SO2Ph) selectivity.22 The same
condition was not effective for the allylindium formation from
chloroallylic sulfone 8b (R = BT). Activation of the allylic
chloride by Finkelstein reaction (NaI, acetone) was necessary to
produce the corresponding homoallylic alcohol 10b (R = BT) in
45% yield with 2:1 antiselectivity. A new E/Z ratio was
established in the allyl indium species according to the alkenyl
substituents regardless of the original E/Z ratio of allyl halide 8.24
The oxonia-Cope rearrangement of homoallylic alcohol 10a
(R = Ph) was performed using stoichiometric camphoresulfonic
acid and aldehyde 9 at 80 °C to provide dienyl sulfone 2a in 77%
yield (E/Z = 2:1 at C-2).22 Milder condition of catalytic
Sn(OTf)2 and aldehyde 9 at 40 °C was utilized for the
rearrangement of homoallylic alcohol 10b (R = BT) to give
dienyl sulfone 2b in 61% yield (E/Z = 1.5:1 at C-2).24 All-E-
dienyl sulfone 2a and 2b can be easily obtained by
recrystallization from MeOH or EtOH.
Figure 1. Products and intermediates obtained in the synthetic
approaches to carotene wire 1.
were sequentially conducted first by the Ramberg−Backlund
̈
reaction (KOH, t-BuOH, CCl4) and then by base-promoted
(KOMe) double dehydro-desulfonation to exclusively and
unexpectedly produce 9-(Z)-carotene 13 (overall 14% yield
after recrystallization) instead of all-(E)-carotene 1.26 The 9-(Z)-
configuration was assigned by the number of 1H and 13C peaks
from the dissymmetrical structure and more specifically by NOE
(7%) between H11 and H8 in NMR analysis (see the Supporting
Information for COSEY, NOESY, and 1D NOE).
The Julia−Kocienski olefination was then tried to minimize
possible isomerization. Dienyl BT-sulfone 2b (2 equiv) was
coupled with C10 dial 4 at −78 °C and warmed to 25 °C to
produce monocoupled all-(E)-apocarotenal 14a (Y = H, 35%
yield), which was reacted again with 2b to exclusively give 9-(Z)-
carotene 13 (37% yield). Olefination by the Wittig salt 2c (5
equiv) and C10 dial 4 (NaOMe at 80 °C) also produced all-(E)-
apocarotenal 14a (56% yield) as a major product, which was
reacted with the Wittig salt 2c to give 9-(Z)-carotene 13 again
(17% recrystallized yield). A different disconnection approach
utilizing the Wittig reaction of benzyl triphenylphosphonium
bromide 6 (5 equiv) and C20 crocetin dial 5 (NaOMe at 80 °C)
provided again 9-(Z)-carotene 13 exclusively (13% yield after
recrystallization).
A series of questions arose: Is the 9-(Z)-isomer 13 more stable
than all-(E)-carotene 1? How can β-carotene be easily obtained
as all-(E)-form? Is it possible to synthesize all-(E)-9,9′,13,13′-
tetramethylcarotene by introducing o-methyl substituents into
the benzene rings (e.g., compound 15 in Figure 1) just like the
ring o-methyl substituents of β-carotene? In order to answer
these questions, we decided to synthesize Wittig salt 2d (Y = Me,
in Scheme 2). An efficient synthesis of 2,6-dimethyl-4-
(methylthio)benzaldehyde (16) was devised from the Hagem-
man’s ester 18, which was prepared (95% yield) by a one-pot
reaction between ethyl acetoacetate (2 equiv) and acetaldehyde
(Scheme 3).27 Lawesson’s reagent allowed the formation of
thione 19, which was not easily purified. It was suspected to be
consisted of a mixture of 19 and its dimeric form through a
disulfide bond, because S-methylation (NaH, MeI) gave only
The corresponding Wittig salt 2c (Y = H) was obtained from
4-(methylthio)benzaldehyde (9). Aldol condensation with
acetone produced conjugated ketone 11 (87% yield), to which
vinyl Grignard addition at −78 °C yielded the tertiary vinyl
carbinol. The condition for bromination with allylic migration is
crucial in the formation of Wittig salt 2c. Acidic conditions
allowing carbocation intermediate such as PBr3 and HBr were
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Scheme 3. Preparation of the Key Building Block 22 for All-
(E)-Carotene 15
40% yield of methyl sulfide 20; oxidation of the Lawesson’s
reaction product by NBS and catalytic TMS·OTf produced
disulfide 21 in 73% yield.28 Oxidative aromatization of 20 by
NBS produced ethyl 2,6-dimethyl-4-(methylthio)benzoate (22)
in 83% yield.28 The key building block 22 can be better prepared
by Indium reduction29 of disulfide 21 to the monomeric thiol
from, followed by S-methylation (NaH, MeI) in overall 80%
yield.
Wittig salt 2d was prepared as demonstrated for Wittig salt 2c
in Scheme 2. Ethyl benzoate 22 was converted to the
corresponding aldehyde 16 by LAH reduction (50% yield) and
PDC oxidation (73% yield). Aldol condensation with acetone
provided unsaturated ketone 17 (94% yield), which was reacted
with vinylmagnesium bromide to produce tertiary vinylcarbinol.
Allylic bromination and phosphorylation at the terminal vinyl
carbon were routinely carried out by HBr (1 equiv) and PPh3 (1
equiv) to produce Wittig salt 2d quantitatively (Scheme 2).
Wittig reaction of 2d (2.5 equiv) and C10 dialdehyde 4 (NaOMe
in MeOH/toluene at reflux) eventually produced all-(E)-
9,9′,13,13′-tetramethylcarotene 15 (23% yield) and mono-
coupled all-(E)-apocarotenal 14b (67% yield), which was
coupled again with Wittig salt 2d to give all-(E)-carotene 15 in
92% yield. The o-methyl ring substituents really play an
important role in controlling the (E)-configuration of the
polyene chain.
Figure 2. (a, b) Representative current transient for (a) 9-(Z)- and (b)
all-(E)-9,9′,13,13′-tetramethylcarotenes, displaying blinking features as
a result of transient single-carotene molecules being trapped in the
tunneling junction. (c, d) 2-Dimensional blinking maps for (c) 9-(Z)-
and (d) all-(E)-9,9′,13,13′-tetramethylcarotenes, respectively, built out
of more than 30 individual current traces. The left panel of each 2-
dimensional map shows vertically the 1-dimensional counts distribution.
The maxima of the Gaussian fits (solid lines in the vertical 1-D
histograms) projected over the Y-axis (G) provide the averaged
conductance of the single-molecule junction. The applied bias voltage
(V) was set to 7 mV.
Figure 2c,d) by setting all the current jumps to the same time
origin and tunneling background subtraction. The averaged
molecular conductance values (expressed versus the quantum of
conductance, G0 = 77.4 μS) for both carotenoid molecules were
statistically obtained by Gaussian fittings of the peaks in the 1-
dimensional histogram representation of the two blinking maps
(see Figures 2c,d): ((1.53 × 10−4)
(6.37 × 10−5))G0 and
((3.23 × 10−4) (1.23 × 10−4))G0 for 13 and 15, respectively.
The experimental conductance value for 9-(Z)-carotene 13 was
47% of that of all-(E)-carotene 15, which agrees well with the
theoretical (DFT) calculations of 55% reduction for the 7-(Z)-
isomer compared to the all-(E)-carotene.13
The distinctive triplet UV absorptions for 9-(Z)-carotene 13
were observed at 462, 485 (maximum), and 517 nm in CH2Cl2.
On the other hand, only the maximum peak at 472 nm was
discernible with a shoulder around 500 nm for all-(E)-carotene
15 (see the SI). It is interesting to note that λmax for 9-(Z)-
carotene 13 is red-shifted by 13 nm compared to that of all-(E)-
carotene 15, which may be the reason for the exclusive formation
of 9-(Z)-form by effective conjugation of the polyene chain. DFT
calculation (structure optimization: m062x/6-311G(d,p); basis
set for free energy: cc-pVTZ) supports this result that 9-(Z)-
carotene 13 is more stable than all-(E)-carotene 1 by 1.55 kcal/
mol, and that all-(E)-carotene 15 with 2,6-dimethyl groups is
more stable than its 9-(Z)-isomer by 2.64 kcal/mol (see SI).
The static version30 of the STM break junction method31 is a
valuable tool to measure single molecule conductance for
carotenoids without applying mechanical strains to the formed
molecular junction. An electric circuit is stochastically formed
and broken between a voltage-biased gold STM tip and
supporting gold electrodes through a residing carotenoid
molecule with methylthio-linkers in dilute mesitylene (0.5 μM)
solution. The current is then monitored as a function of time.
When a single carotenoid backbone transiently bridges the gap, a
telegraphic signal is observed in the current transient (see Figure
2a,b). Tens of such current telegraphic traces are then
accumulated in a single 2-dimensional map (blinking map, see
It was assumed that both carotenes make stable interactions
with the gold STM tip through methylthio linkers. The blinking
signals in Figure 2 arise from strong tip-molecule interactions.
Forces have been measured in break-junction experiments and
the breaking features have been ascribed to the formation of a
covalent Au−S bond.32 The lower accessibility of the linker
group might affect the yield of the single-molecule junction
experiments, but the observed result shows that this is not the
case. STM tips are known to present a number of asperities on
their surface. They are far from being a smooth concave element,
and such asperities can act as anchoring points to the methylthio
group of 9-Z-isomer.
Short switching molecules under UV/vis irradiation such as
azobenzene and diphenylethylene were reported to exhibit high
conducting profile for cis-isomer, which is mainly because of the
difference in tunneling length of the molecule spanned between
the electrodes.11 Controversially, cis-azobenzene was also
reported to give lower conductance by breaking π-conjugation
along the molecular frame.12 We experimentally demonstrated
that the trans-isomer is more conductive for the polyene chain of
carotenoids. DFT calculations of frontier molecular orbitals in
both cases show good delocalization of orbitals, being the
HOMO−1 and −2 energetically the closest orbitals to the Au
electrode Fermi level (−5 eV). The slight closer proximity in
energy in all-(E) case (up to 70 mV in HOMO−2 case) might
C
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15 (PDF)
1
Analytical data and H 13C NMR spectra for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: ismael.diez_perez@kcl.ac.uk.
*E-mail: sangkoo@mju.ac.kr.
ORCID
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Sangho Koo: 0000-0003-4725-1117
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by the Basic Science Research
Program (NRF-2016R1A2B4007684) and by the Priority
Research Centers Program (NRF-2009-0093816), both through
the National Research Foundation of Korea, and also by the
MINECO Spanish national project CTQ2015-64579-C3-3-P
(MINECO/FEDER, EU) and start-up King’s College London
financial support.
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