Chemoselective layer-by-layer approach utilizing click reactions with ethynylcyclooctynes and diazides

Article abstract of DOI:10.1021/acs.orglett.6b02048

Ethynylcyclooctynes and diazides were synthesized and applied for a chemoselective sequence of copper(I)-catalyzed azide-alkyne cycloadditions and strain-promoted azide-alkyne cycloadditions. Chemoselectivity within the reaction sequence was achieved by balancing three factors: Cu-catalysis/ring strain/steric shielding. A cholic acid derived triazide was subjected to the cycloaddition sequence as a model system for a layer-by-layer synthesis on surfaces.

Full text of DOI:10.1021/acs.orglett.6b02048

Letter
pubs.acs.org/OrgLett
Chemoselective Layer-by-Layer Approach Utilizing Click Reactions
with Ethynylcyclooctynes and Diazides
Niels Munster, Paul Nikodemiak, and Ulrich Koert*
̈
Fachbereich Chemie, Philipps-University Marburg, Hans-Meerwein-Strasse 4, D-35043 Marburg, Germany
S
* Supporting Information
ABSTRACT: Ethynylcyclooctynes and diazides were synthesized
and applied for a chemoselective sequence of copper(I)-catalyzed
azide−alkyne cycloadditions and strain-promoted azide−alkyne
cycloadditions. Chemoselectivity within the reaction sequence was
achieved by balancing three factors: Cu-catalysis/ring strain/steric
shielding. A cholic acid derived triazide was subjected to the cyclo-
addition sequence as a model system for a layer-by-layer synthesis on
surfaces.
he tailored modification of surface substrates is an
Timportant goal to regulate their physical, electronic, photo-
physical and chemical properties. For constructing well-defined
thin films of controlled thickness and composition the layer-by-
layer (LbL) assembly has turned out to be a versatile and efficient
method. The original approach developed by Decher is based on
the sequential deposition of polyelectrolytes (PE) on a charged
substrate.1 Because of the limited stability of this noncovalently
bonded PE film, there are several approaches to assemble LbL
films by covalent bonding.2 Caruso was the first who combined
the efficient copper(I)-catalyzed azide−alkyne cycloaddition
(CuAAC) with LbL to prepare multilayer films of poly(acrylic
acid).3 Following this basic idea, the approach was extended to
multilayers of small molecules,4 dendrimers,5 and polymer/small
molecule combinations.6 Although this method is very powerful
and was used for applications, usually only symmetrical building
blocks are utilized. This communication reports a molecular LbL
approach using unsymmetrical small molecules in chemo-
selective “click” reactions.7
A previous reported concept of molecular LbL thin film
fabrication utilizing CuAAC is shown in Figure 1A.4 First, an
azide-modified substrate is reacted with a symmetrical multi-
acetylene functionalized molecule in the presence of Cu(I) to
create a surface which is now terminated with acetylene moieties.
Next, a multiazide functionalized molecule is reacted with the
substrate under similar conditions to regenerate an azide-terminated
surface. These two CuAAC reactions can be repeated indefinitely
until the desired film thickness is achieved.
Inspired by the work of Dinolfo, we thought about an exten-
sion of this concept using unsymmetrical molecules (Figure 1B).
In order to get well-defined layers, the choice of an appropriate
multialkyne as well as multiazide is crucial. For the alkyne
building block, a cyclooctyne of type 1 and 2 was envisaged
(Figure 2). Due to their strained structure, cyclooctynes react
Figure 1. (A) Typical CuAAC-based LbL assembly using symmetrical
small molecules. (B) Presented approach using sequentially chemo-
selective “click” reactions.
with azides without the need of a Cu catalyst (strain-promoted
azide−alkyne cycloaddition, SPAAC).8 Subsequent CuAAC with
a bis-azide would provide the azide functionalized surface again.
To achieve chemoselectivity in the CuAAC bisazide, 3 was
Received: July 13, 2016
© XXXX American Chemical Society
A
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Letter
envisaged in which the two azido groups have different
steric hindrance. It would also be possible to take bis-azide 4,9
which reacts chemoselectively because of chelating effects.
Following these basic considerations, we report here the
synthesis of compounds 1−3. Additionally, initial studies for
LbL assembly were performed on molecular model systems in
solution.
of 13%. Although the synthesis was reliable and could be
performed in gram scale up to the alcohol 8, the lack of high
regioselectivity in the hydroboration reaction was unsatis-
factory. Thus, an alternative, more regioselective synthe-
sis to alcohol 8 was developed using a Weinreb amide as a
directing group for the hydroboration step (regioselectivity
25:1). The details of this route are shown in the Supporting
Information.
The use of chiral cyclooctynes such as 1 in cycloaddition
reactions raises stereoselectivity issues. In order to circum-
vent such stereoselectivity challenges, synthesis of an achiral
(ethynylcyclopropyl)cyclooctyne 2 was envisaged. One further
advantage of the use of a Cs-symmetrical cyclooctyne is the
formation of a single regioisomer upon cycloaddition with an
organoazide. The exo-diastereomer was chosen in order to
avoid intramolecular side reactions of both triple bonds. The
synthesis of cyclooctyne 2 is described in Scheme 2 and began
with a Rh-catalyzed cyclopropanation of COD (5) with diazo
compound 14,12 which gave exo-11 in moderate yield and
excellent diastereoselectivity (dr 41:2). Following the reversed
protocol of van Delft, exo-11 was converted to 12 in quan-
titative yield after bromination and reduction. The subsequent
treatment with KO-t-Bu gave the corresponding alkenyl bro-
mide (not shown) in good yield. The terminal alkyne was
installed via the Ohira-Bestmann reaction and afforded 13 in
60% yield. Finally, cyclooctyne 2 was formed after LDA-induced
elimination to yield the product in a total of seven steps in
20% yield from COD (5). Notably, attempts to get the desired
product directly from the corresponding dibromide by double
elimination failed.
Figure 2. Appropriate molecules for chemoselective LbL approach.
The starting point for the synthesis of cyclooctyne 1 was
the cycloctene ester 6, which is accessible from COD (5) in two
steps (Scheme 1).10 Subsequent hydroboration with thexylbor-
ane provided the desired alcohol as a mixture of regio- and
diastereomers which were oxidized directly with PCC to the
corresponding ketones (2:1 regioselectivity for the hydro-
boration). It was possible to separate the regioisomeric ketones
by SiO2 flash chromatography to give the desired product 7 in
moderate yield.
Scheme 1. Synthesis of Cyclooctyne 1
Scheme 2. Synthesis of Cyclooctyne 2
Treatment of 7 with KHMDS in the presence of phenyl
triflimide led to the formation of the corresponding vinyl
triflate. Subsequent reduction of the ester group was performed
with DIBAH to obtain alcohol 8 in 69% yield over two steps.
The terminal alkyne group was introduced via a two-step
sequence. Oxidation of the primary alcohol in 8 to the
corresponding aldehyde was afforded with Dess−Martin
periodinane (DMP) under basic conditions. The sensitive
aldehyde therefore was directly converted into alkyne 9 via an
Ohira−Bestmann reaction. With cyclooctyne precursor in
hand, we turned our attention to the final elimination step.
Fortunately, the elimination to cyclooctyne 1 proceeded very
smoothly with LDA at −78 °C. In contrast to previous results in
the field of cyclooctyne synthesis,11 no warming to ambient
temperature was necessary to afford the elimination reaction.
With the presented synthetic route, racemic ethynylcyclooc-
tyne 1 was available in nine steps with an overall yield
A necessary prerequisite for the defined construction of layers
with a “double-click” approach is the use of a bis-azide with
inherently different reactivities for the two azido groups in AAC.
The utilization of steric effects is a reliable strategy to influence
the reactivity of functional groups. Therefore, a comparison of
the AAC reactivities of the primary azide 17 and the tertiary azide
18 was undertaken (Scheme 3). Treatment of the α-pyrone 15
with cyclooctyne 1 led, via Diels−Alder/retro-Diels−Alder
reaction, to the benzocyclooctene 16. With compound 16, the
impact of steric shielding of the azido group in CuAAC was
examined. In the presence of CuSO4 at 60 °C, alkyne 16
B
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selectively reacted with benzyl azide 17 to afford the triazole 19 in
high yield. Under the same conditions, no reaction of 16 with the
sterically more hindered azide 18 was observed. To get the
desired triazole 20, higher temperatures (80 °C) and longer
reaction times were needed. The differences in reactivity opened
up an opportunity to introduce two azido groups with different
steric demand into one substrate. This diazide allows for
sequential “click” reactions to build up defined chains without a
protection/deprotection procedure. Thus, unsymmetrical dia-
zide 3 was identified as an appropriate candidate for the intended
subsequent chemistry.
(16 → 25) proves the envisaged chemoselectivity in the reaction
of the bifunctional building blocks 1 and 3. The regioselectivity
problem with the SPAAC of 23 and 1 can be circumvented by use
of the symmetrical bis-alkyne 2.
Scheme 5. CuAAC−SPAAC Reaction Sequence
Scheme 3. Reactivity Studies of Alkyne 1 in CuAAC
In order to develop the chemoselective CuAAC-SPAAC
reaction toward a surface LBL sequence, a molecular surface
was chosen as model system first. Due to its rigid subunit
as well as its high level of functionality, literature known
cholic acid derivative 2614 (Figure 3) was identified as an
appropriate molecule to mimic surface chemistry. Put in sim-
plified terms, compound 26 could be considered as a model
system for an azide-terminated surface. Performing the LbL
assembly with 26, the bis-alkynes (1, 2) and the diazide 3
should give a meaningful prediction about the expected
chemoselectivity, particularly of the CuAAC, on a real surface
(e.g., Si(001)).15
The selected diazide 3 was synthesized starting from
commercially available benzoate 21 (Scheme 4). First, 21 was
converted into diol 22 using methylmagnesium bromide. Next,
the tertiary alcohol was substituted onto an azido group under
SN1 conditions.13 The remaining alcohol was then transformed
into the corresponding mesylate, which was treated with sodium
azide in DMSO to give the desired diazide 3 in overall moderate
yield.
Figure 3. Structure of the cholic acid derived triazide 26.
Scheme 4. Synthesis of Diazide 3
SPAAC of the bis-alkyne 1 and the triazide 26 provided
the tris-triazole 27 in quantitative yield as a mixture of regio-
and diastereomers (Scheme 6). The subsequent 3-fold CuAAC
with the diazide 3 led to a second triazole layer. The third triazole
layer was prepared by another SPAAC with the bis-alkyne 1
1
to deliver the nonatriazole 29. Inspection of the H NMR
data and the ESI MS spectra revealed that no intramolecular
side reactions took place during the cycloaddition sequence
(26 → 29). The formation of regioisomers in the SPAAC
could be avoided using the symmetrical bis-alkyne 2. SPAAC
of 26 with 2 gave the tris-triazole 30 as only product. Subse-
quent 3-fold CuAAC with the diazide 3 installed chemo-
selectively the second triazole layer in 31. SPAAC of the latter
with 2 resulted in formation of the nonatriazole 32 with three
triazole layers.
With the building blocks 1, 3, and 16 in hand, the sequential
chemoselective combination of CuAAC−SPAAC reactions was
examined next (Scheme 5). The CuAAC of 16 with diazide 3
gave the triazole 23 chemoselectively; only the reaction of the
primary azido group was observed. Subsequent SPAAC of 23
with cyclooctyne 1 led to the chemoselective formation of bis-
triazole 24 as a mixture of regioisomers. Another CuAAC with
diazide 3 led to the cycloadduct 25 as a mixture of regioisomers
with respect to the central triazole ring. The reaction sequence
In conclusion, a LBL approach for an “azide surface” has been
developed by combining bis-alkynes and diazides with different
reactivities in SPAAC/CuAAc reaction sequences. The strategy
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Scheme 6. CuAAC−SPAAC LbL Synthesis Using the Triazide 26
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developed in solution here should be adaptable to solid surfaces
with potential applications in for semiconductors.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02048.
Experimental details; spectroscopic and analytical data for
all new compounds (PDF)
(7) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004−2021. (b) Evans, R. A. Aust. J. Chem. 2007, 60, 384−
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Arumugam, S.; Guo, J.; Boltje, T. J.; Popik, V. V.; Boons, G.-J. J. Am.
Chem. Soc. 2011, 133, 949−957.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: koert@chemie.uni-marburg.de.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the Deutsche Forschungsgemeinschaft
(Grant No. SFB 1083) is gratefully acknowledged. Verena Gruth
is gratefully acknowledged for experimental support.
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Longo, J. M.; Abruna, H. D.; Coates, G. W. Macromolecules 2010, 43,
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