Cuaac and ruaac with alkyne-functionalised dihydroazulene photoswitches and determination of hammett r-constants for triazoles

Article abstract of DOI:10.1071/CH13544

Dihydroazulene (DHA)-vinylheptafulvene (VHF) photoswitches have attracted attention as potentially useful components in molecular electronics. The p-conjugated dihydroazulene system is a rigid structure and can be strategically functionalised to place handles for further elaboration. Here we show that alkyne-functionalised dihydroazulenes can be subjected to copper and ruthenium catalysed azide-alkyne cycloadditions (CuAAC and RuAAC) with tolylazide, furnishing 1,4- and 1,5-disubstituted triazoles. The rates of ring-closure of the corresponding vinylheptafulvenes were compared with those of reference systems, which allowed determination of Hammett substituent constants (meta and para) for N-tolyl-substituted 1,2,3-triazoles. CSIRO 2014.

Full text of DOI:10.1071/CH13544

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2014, 67, 531–534
Communication
http://dx.doi.org/10.1071/CH13544
CuAAC and RuAAC with Alkyne-functionalised
Dihydroazulene Photoswitches and Determination
of Hammett r-Constants for Triazoles
A
A
A
Henriette Lissau, Søren Lindbæk Broman, Martyn Jevric,
A
A B
,
Anders Ø. Madsen, and Mogens Brøndsted Nielsen
A
Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100
Copenhagen Ø, Denmark.
B
Corresponding author. Email: mbn@kiku.dk
Dihydroazulene (DHA)–vinylheptafulvene (VHF) photoswitches have attracted attention as potentially useful compo-
nents in molecular electronics. The p-conjugated dihydroazulene system is a rigid structure and can be strategically
functionalised to place handles for further elaboration. Here we show that alkyne-functionalised dihydroazulenes can be
subjected to copper and ruthenium catalysed azide–alkyne cycloadditions (CuAAC and RuAAC) with tolylazide,
furnishing 1,4- and 1,5-disubstituted triazoles. The rates of ring-closure of the corresponding vinylheptafulvenes were
compared with those of reference systems, which allowed determination of Hammett substituent constants (meta and
para) for N-tolyl-substituted 1,2,3-triazoles.
Manuscript received: 9 October 2013.
Manuscript accepted: 21 November 2013.
Published online: 6 January 2014.
Introduction
under mild conditions. Using instead a ruthenium catalyst, it is
possible to obtain the 1,5-disubstituted triazoles.[8] This cyclo-
addition (RuAAC) typically requires elevated temperatures and
specialised ruthenium-containing organometallic catalysts. The
scope of this reaction with DHA-alkynes is also presented here.
In addition, we became interested in elucidating the effect of the
triazole moiety on the kinetics of the VHF ring-closure reaction.
From a large selection of donor- and acceptor-substituted VHFs,
we have previously established Hammett correlations for this
reaction.[3c] From one of these correlations, we were able to
estimate, by interpolation, Hammett s-values[9] for differently
substituted triazole rings.
Molecular photoswitches, undergoing light-induced isomerisa-
tions with changes in geometrical and electronic properties, are
interesting as building blocks for biotechnology applications,
advanced materials, and as components for molecular elec-
tronics.[1] Suitably functionalised dihydroazulenes (DHAs)
provide examples of such molecules, as on irradiation they
convert to isomeric vinylheptafulvenes (VHFs), which ther-
mally will return to the lower-energy DHA isomer.[2] Inter-
conversion between one such pair, DHA 1–VHF 2, is shown in
Scheme 1.
The DHA–VHF system has been less explored than other
photoswitches such as azobenzenes, dithienylethenes, and spir-
opyrans.[1h] However, recent advances in synthetic protocols to
DHA derivatives along with convenient tuning of switching
properties by electron-donating and -withdrawing groups[3]
have paved the way for exploitation of this system in more
advanced devices. Indeed, derivatives were recently found to
show conductance switching in single-molecule junctions.[4]
Incorporation of an alkyne unit at the phenyl substituent of
1 is relatively easy.[5] Such modules are particularly useful for
palladium-catalysed cross-coupling reactions, which have
allowed formation of fullerene–DHA hybrid molecules.[5a]
In the present work, we turn to another application of alkyne-
functionalised DHAs, namely as substrates for the copper-
catalysed azide–alkyne cycloaddition (CuAAC),[6] which is
involved in many facets of organic synthesis, generating pro-
ducts of many properties ranging from supramolecular to
pharmaceutical.[7] The CuAAC reaction gives 1,4-disubstituted
triazoles with high regioselectivity and typically in good yields
Alkynes 3a[5a] and 3b[5b] (Scheme 2) can be fabricated from a
DHA-iodophenyl precursor[10] employing a Sonogashira reac-
tion with a trialkylsilylacetylene followed by fluoride-mediated
desilylation.[5] For the purpose of the current study, we chose
4-tolylazide 4 as the coupling partner for these cycloadditions.
The copper-mediated reactions, which consisted of catalytic
cuprous iodide and triethylamine in acetonitrile, effected the
formation of the 1,4-triazole products 5a and 5b (Scheme 2).
Before recrystallisation, 5a and 5b were obtained in yields of 83
and 94 % respectively, which according to NMR spectroscopy
only showed trace impurities. Recrystallisation gave analytical-
ly pure compounds in yields of 68 and 49 % respectively.
However, when the reaction was subjected to RuAAC condi-
tions using the metal complex Cp*Ru(PPh3)2Cl (where Cp* is
pentamethylcyclopentadienyl anion), which required heating
of the contents in THF (using microwave irradiation, mW), the
1,5-triazoles 6a and 6b were formed in substantially lower
yields (19 and 24 % respectively). This was associated with
Journal compilation Ó CSIRO 2014
www.publish.csiro.au/journals/ajc

532
H. Lissau et al.
the recovery of significant amounts of starting material. Regard-
less of the use of 2 molar equivalents of 4 and a higher catalyst
loading, these reactions would unfortunately not proceed to
completion.
In all cases, the products were isolated by standard column
chromatography (performed in the dark). 1H NMR spectroscopy
showed that the terminal alkyne proton resonance of 3a and 3b
had been replaced by a new single resonance at d ,7.9–8.2 ppm
representative of the proton of the triazole moiety. The substitu-
tion patterns of 5a and 6b were confirmed by X-ray crystallo-
graphic analysis (Fig. 1).
NC
CN
NC
CN
hν
The longest-wavelength absorption maxima of the four new
DHAs 5a, 5b, 6a, and 6b are listed in Table 1. They all
underwent smooth light-induced ring-opening to VHFs with
red-shifted longest-wavelength absorption maxima. The
absorption spectra of DHA 5a and its corresponding VHF are
shown in Fig. 2 along with the spectral evolution during the VHF
to DHA conversion. For each of the VHFs, we determined the
rate constant (k) of ring-closure in MeCN by following the first-
order decay of the characteristic VHF absorption (Table 1).
We have previously shown that the rate constant for the VHF
to DHA conversion follows a linear free energy relationship
(Fig. 3).[3c] This so-called Hammett correlation shows the
electronic influence of various substituents on the phenyl group
of VHF 2. Electron-withdrawing substituents (e.g. NO2) provide
a faster ring-closure, whereas electron-donating substituents
(e.g. NH2) retard the reaction. By interpolation from the line
of best fit (Fig. 3), we estimated Hammett s-values for the
triazoles in the four different substitution patterns as shown in
Fig. 4. When placed as para-substituents via either C4 or C5 of
the triazole, the N-tolyl-substituted triazoles have very similar
and positive s-values (0.23 and 0.26), which signals that they
exert an electron-withdrawing effect close to that exerted by the
halogens Cl and Br.[9] The influence of the triazole ring is
negligible when placed at a meta position via C4 of the triazole,
whereas a slight positive s-value (0.07) is found when anchor-
ing at C5.
Δ
DHA 1
VHF 2
Scheme
1. Dihydroazulene
(DHA)–vinylheptafulvene
(VHF)
photoswitch.
N
N
N
NC
CN
para- 5a 83 % (68 %)
meta- 5b 94 % (49 %)
Cul, NEt3
CH3CN, 25ꢁC
NC
CN
N3
ꢀ
para- 3a
meta- 3b
4
∗
Cp Ru(PPh3)2CI
THF, 80ꢁC (μw)
N
N
NC
CN
N
In summary, we have shown that the DHA–VHF system is
compatible with transition metal-mediated cycloaddition reac-
tions. In particular, the CuAAC reaction may present a useful
tool for future incorporation of DHAs in more elaborate func-
tional systems via triazole junctions. From VHF to DHA ring-
closure studies, we have quantified the electron-withdrawing
effect of N-tolyl-substituted triazoles when anchored via C4 or
C5; as a para-substituent, its net effect is similar to that of
halogens. This electron-withdrawing effect is paralleled by the
para- 6a 19 %
meta- 6b 24 %
Scheme 2. Copper- and ruthenium-catalysed azide–alkyne cycloaddition
(CuAAC and RuAAC) reactions with dihydroazulene (DHA)–alkynes.
Cp* ¼ pentamethylcyclopentadienyl anion. Values in brackets refer to
yields after recrystallisation, whereby traces of impurities were removed.
Fig. 1. Top: molecular structure of 5a, as derived from X-ray diffraction measurements (crystals grown
from CH2Cl2/heptane; Cambridge Crystallographic Data Centre (CCDC) number 964942). Thermal
ellipsoids are shown at the 50 % probability level. One asymmetric unit of the centrosymmetric structure
is shown. Each site in the crystal is occupied by both enantiomers as depicted in the drawing, in a ratio of
,1 : 3/3 : 1. Bottom: molecular structure of 6b (crystals grown from CH2Cl2/heptane; CCDC 971995).

Azide–alkyne Cycloadditions
533
Table 1. Longest-wavelength absorption maxima (lmax) in MeCN
and rate constants and half-lives for the vinylheptafulvene (VHF) to
dihydroazulene (DHA) ring-closure at 258C
significant CH acidity[11] and ability of 1,2,3-triazoles to engage
in CH–anion hydrogen-bonding interactions,[12] which makes
the triazole junction itself an interesting scaffold in supramolec-
ular chemistry. Moreover, it is worth mentioning that a triazole
can act as a ligand for metal ions via coordination to N.[13] Thus,
DHA–triazole dyads may find future use in the development of
photoactive anion and cation sensors.
CompoundA
lDHA [nm]
l
VHF [nm] k [10ꢀ5 sꢀ1
]
Half-life [min]
5a (p-1,4)
6a (p-1,5)
5b (m-1,4)
6b (m-1,5)
371
367
359
358
477
478
475
477
7.45
7.73
5.69
6.18
155
149
203
187
Experimental
Synthesis of 2-(4-(1-(p-tolyl)-1H-1,2,3-triazol-4-yl)phenyl)-
1,8a-dihydroazulene-1,1-dicarbonitrile 5a
AThe numbers 4 and 5 refer to C4 and C5 of the triazole ring and are the ring
atoms being attached to the phenyl group in a para or meta position relative
to the VHF.
To an argon-degassed solution of 2-(4-ethynylphenyl)-1,8a-
dihydroazulene-1,1-dicarbonitrile 3a (100 mg, 0.36 mmol) in
CH3CN (15 mL) were added 4-tolylazide 4 (0.7 mL, 0.36 mmol,
0.5 M in tert-butyl methyl ether), CuI (68.2 mg, 0.36 mmol), and
degassed NEt3 (100 mL, 0.72 mmol). The mixture was degassed
for a further 10 min, and stirring at room temperature was
maintained overnight. Then the volatiles were removed under
reduced pressure. The residue was subjected to flash column
chromatography (SiO2, 1 : 5 EtOAc/toluene) to afford the
product as a yellow powder (122 mg, 83 %, minor impurities),
which was recrystallised from hot EtOAc to give 5a (101 mg,
68 %) as a bright yellow powder. TLC (30 % THF/heptane) Rf
0.27. Mp 2288C (dec.). dH (500 MHz, CDCl3) 8.22 (s, 1H,
triazole CH), 8.02 (d, J 8.6, 2H), 7.84 (d, J 8.6, 2H), 7.68 (d, J
8.2, 2H), 7.36 (d, J 8.2, 2H), 6.95 (s, 1H, DHA H3), 6.59 (dd, J
11.3, 6.2, 1H), 6.49 (dd, J 11.3, 6.1, 1H), 6.37 (d, J 6.1, 1H), 6.32
(ddd, J 10.2, 6.2, 2.1, 1H), 5.84 (dd, J 10.2, 3.8, 1H), 3.82 (dt, J
3.8, 2.1, 1H, DHA H8a), 2.45 (s, 3H, CH3). dC (125 MHz,
CDCl3) 147.3, 139.8, 139.3, 138.8, 134.8, 132.6, 132.0, 131.14,
131.08, 130.5, 130.4, 127.9, 127.0, 126.6, 121.3, 120.7, 119.6,
118.3, 115.3, 112.9, 51.3, 45.3, 21.3. m/z (electrospray ionisa-
tion, ESPþ) 436.1527 ([M þ Na]þ); calc. for C27H19N5Naþ
436.1533. Anal. Calc. for C27H19N5: C 78.43, H 4.63, N 16.94.
Found: C 78.07, H 4.31, N 16.76 %.
0.6
0.5
0.4
0.3
0.2
0.1
0
DHA
5a
VHF
200
300
400
500
600
700
Wavelength [nm]
Fig. 2. UV-vis absorption spectra in MeCN of 5a and its corresponding
vinylheptafulvene (VHF) and the spectral evolution during thermal ring-
closure of the VHF (indicated by arrows).
ꢂ8.8
ln(k) ꢃ 1.21σ( 0.1) ꢂ 9.78( 0.04)
ꢂ9.0
ꢂ9.2
p-1,5
Supplementary Material
p-1,4
ꢂ9.4
Synthetic protocols, UV-vis spectroscopic data, and NMR
spectra are available on the Journal’s website.
m-1,5
ꢂ9.6
ꢂ9.8
m-1,4
Acknowledgements
The University of Copenhagen, The Danish Council for Independent
Research, Technology and Production Sciences (Grant no. 12–126668), and
the Villum Foundation are acknowledged for financial support. Mr Micke
Lisbjerg and Dr Theis Brock-Nannestad are acknowledged for recording of
mass spectra.
ꢂ10.0
ꢂ10.2
ꢂ0.2
0
0.2
0.4
0.6
0.8
σm/p
References
[1] (a) M. Irie, Chem. Rev. 2000, 100, 1683. doi:10.1021/CR980068L
(b) V. Balzani, A. Credi, S. Silvi, M. Venturi, Chem. Soc. Rev. 2006,
35, 1135. doi:10.1039/B517102B
Fig. 3. Correlation between rate constant of vinylheptafulvene (VHF)
ring-closure ([k] ¼ sꢀ1) at 258C in MeCN and the Hammett s-values for a
selection of reference compounds (open circles[3c]). The measured rate
constants for the triazole-functionalised VHFs (present work) are shown
by filled circles and interpolation of the Hammett s-value is shown for the
VHF of 5a (p-1,4).
(c) N. Weibel, S. Grunder, M. Mayor, Org. Biomol. Chem. 2007, 5,
2343.
(d) I. Yildiz, E. Deniz, F. M. Raymo, Chem. Soc. Rev. 2009, 38, 1859.
doi:10.1039/B804151M
(e) A. Credi, Aust. J. Chem. 2011, 64, 127. doi:10.1071/CH10451
(f) H. M. D. Bandara, S. C. Burdette, Chem. Soc. Rev. 2012, 41, 1809.
doi:10.1039/C1CS15179G
(g) I. Tochitsky, M. R. Banghart, A. Mourot, J. Z. Zhao, B. Gaub,
R. Kramer, D. Trauner, Nat. Chem. 2012, 4, 105. doi:10.1038/
NCHEM.1234
1
5 1
σp ꢃ 0.23
m ꢃ 0.005
σp ꢃ 0.26
σm ꢃ 0.07
4
N
N
σ
N
N
N
N
Fig. 4. Interpolated Hammett s-values for 1,4-substituted (left) and
1,5-substituted (right) triazoles.
(h) W. Szyman´ski, J. M. Beierle, H. A. V. Kistemaker, W. A. Velema,
B. L. Feringa, Chem. Rev. 2013, 113, 6114. doi:10.1021/CR300179F

534
H. Lissau et al.
[2] (a) J. Daub, T. Kno¨chel, A. Mannschreck, Angew. Chem. Int. Ed. Engl.
[7] (a) M. Meldal, C. W. Tornøe, Chem. Rev. 2008, 108, 2952.
doi:10.1021/CR0783479
1984, 23, 960. doi:10.1002/ANIE.198409601
(b) H. Go¨rner, C. Fischer, S. Gierisch, J. Daub, J. Phys. Chem. 1993,
97, 4110. doi:10.1021/J100118A030
(c) M. B. Nielsen, S. L. Broman, M. A. Petersen, A. S. Andersson, T. S.
(b) Special issue (Eds M. G. Finn, V. V. Fokin) Chem. Soc. Rev. 2010,
39, 1231. doi:10.1039/C003740K
[8] (a) L. Zhang, X. Chen, P. Xue, H. H. Y. Sun, I. D. Williams,
K. B. Sharpless, V. V. Fokin, G. Jia, J. Am. Chem. Soc. 2005, 127,
15998. doi:10.1021/JA054114S
˚
˚
Jensen, K. Kilsa, A. Kadziola, Pure Appl. Chem. 2010, 82, 843.
doi:10.1351/PAC-CON-09-07-08
˚
˚
[3] (a) S. L. Broman, M. A. Petersen, C. G. Tortzen, A. Kadziola, K. Kilsa,
M. B. Nielsen, J. Am. Chem. Soc. 2010, 132, 9165. doi:10.1021/
JA103235G
(b) L. K. Rasmussen, B. C. Boren, V. V. Fokin, Org. Lett. 2007, 9,
5337. doi:10.1021/OL701912S
(c) B. C. Boren, S. Narayan, L. K. Rasmussen, L. Zhang, H. Zhao,
Z. Lin, G. Jia, V. V. Fokin, J. Am. Chem. Soc. 2008, 130, 8923.
doi:10.1021/JA0749993
˚
˚
(b) M. A. Petersen, S. L. Broman, K. Kilsa, A. Kadziola, M. B. Nielsen,
Eur. J. Org. Chem. 2011, 1033. doi:10.1002/EJOC.201001554
(c) S. L. Broman, M. Jevric, M. B. Nielsen, Chem. Eur. J. 2013, 19,
9542. doi:10.1002/CHEM.201300167
[9] (a) L. P. Hammett, J. Am. Chem. Soc. 1937, 59, 96. doi:10.1021/
JA01280A022
[4] (a) S. Lara-Avila, A. V. Danilov, S. E. Kubatkin, S. L. Broman,
C. R. Parker, M. B. Nielsen, J. Phys. Chem. C 2011, 115, 18372.
doi:10.1021/JP205638B
(b) H. H. Jaffe´, Chem. Rev. 1953, 53, 191. doi:10.1021/CR60165A003
(c) C. Hansch, A. Leo, R. W. Taft, Chem. Rev. 1991, 91, 165.
doi:10.1021/CR00002A004
(b) S. L. Broman, S. Lara-Avila, C. L. Thisted, A. D. Bond,
A. V. Danilov, S. E. Kubatkin, M. B. Nielsen, Adv. Funct. Mater. 2012,
22, 4249. doi:10.1002/ADFM.201200897
[10] L. Gobbi, P. Seiler, F. Diederich, Helv. Chim. Acta 2001, 84, 743.
doi:10.1002/1522-2675(20010418)84:4,743::AID-HLCA743.3.0.
CO;2-1
[5] (a) M. Santella, V. Mazzanti, M. Jevric, C. R. Parker, S. L. Broman,
A. D. Bond, M. B. Nielsen, J. Org. Chem. 2012, 77, 8922. doi:10.1021/
JO301306Y
[11] V. E. Matulis, Y. S. Halauko, O. A. Ivashkevich, P. N. Gaponik, J. Mol.
Struct. THEOCHEM 2009, 909, 19. doi:10.1016/J.THEOCHEM.
2009.05.024
(b) S. L. Broman, M. Jevric, M. B. Nielsen, J. Org. Chem. 2014,
In press. doi:10.1021/JO4020326
[12] Y. Hua, A. H. Flood, Chem. Soc. Rev. 2010, 39, 1262. doi:10.1039/
B818033B
[6] (a) C. W. Tornøe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67,
3057. doi:10.1021/JO011148J
[13] X.-L. Hao, Y.-Y. Ma, C. Zhang, Q. Wang, X. Cheng, Y.-H. Wang,
Y.-G. Li, E.-B. Wang, CrystEngComm 2012, 14, 6573. doi:10.1039/
C2CE25747E
(b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless,
Angew. Chem. Int. Ed. 2002, 41, 2596. doi:10.1002/1521-3773
(20020715)41:14,2596::AID-ANIE2596.3.0.CO;2-4