Effect of fluorine or oxygen atom(s) in propargylic position on the reactivity in click chemistry

Article abstract of DOI:10.1016/j.tetlet.2010.02.083

The use of especially designed ω-diynes allows to establish, through competitive reactions, the effect of C-F, C-OH, CF₂, C{double bond, long}O and C(OMe)₂ substituents on the reactivity of neighbouring triple bonds in click chemistry and this gives not only a reactivity scale but also a direct access to the difference in activation energies between the competitive reaction pathways.

Full text of DOI:10.1016/j.tetlet.2010.02.083

Tetrahedron Letters 51 (2010) 2218–2221
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Effect of fluorine or oxygen atom(s) in propargylic position on the reactivity
in click chemistry
*
Danielle Grée, René Grée
Université de Rennes 1, Laboratoire de Chimie et Photonique Moléculaires CNRS UMR 6510, France
et Laboratoire Sciences Chimiques de Rennes CNRS UMR 6226, France
Avenue du Général Leclerc, 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of especially designed
x-diynes allows to establish, through competitive reactions, the effect of
Received 23 January 2010
Revised 10 February 2010
Accepted 12 February 2010
Available online 18 February 2010
C–F, C–OH, CF2, C@O and C(OMe)2 substituents on the reactivity of neighbouring triple bonds in click
chemistry and this gives not only a reactivity scale but also a direct access to the difference in activation
energies between the competitive reaction pathways.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Fluorine
Click chemistry
Triazoles
1,3 Dipolar cycloadditions
x
-Diynes
Click chemistry is now being extensively studied, with many
what could be the effect of fluorine, as well as other atoms, on
the reactivity of the neighbouring triple bond but on simple linear
systems.9,10 Towards this goal, we have designed novel model sys-
developments in various scientific fields.1 In particular the reaction
of azides on alkynes catalyzed, or not, by copper salts proved to be
a very efficient reaction.2 It is widely used in many areas but par-
ticular attention has been paid to bioorganic chemistry. Elegant
applications of this copper-promoted Huisgen reaction have been
reported already in medicinal chemistry,3 for instance in the de-
sign of enzyme inhibitors at the femtomolar level,4 for labelling
of proteins5 as well as for in vivo imaging.6,7 In latter area, the
use of cyclooctyne derivatives proved to be very important due
to their high reactivity as dipolarophiles. Furthermore, adding a
gemdifluoro substituent on such molecules increased their reactiv-
ity, allowing fast reactions even at room temperature.6b The high
reactivity of such fluorinated molecules has been rationalized by
extensive computational studies and the effect of the CF2 group
has been explained by the interaction of the two fluorine atoms
with the triple bond.8 This lowers the level of the frontier orbitals
and increases the reactivity with a gain of 2.0 kcal molꢀ1 in the
activation energy of the reaction corresponding to the difluorinat-
ed analogue.8a Extension of these effects to other substituents in
propargylic position and other cycloalkynes has also been reported
recently.8b
tems containing two differentially substituted
x-diynes as indi-
cated in Figure 1. Each diyne has a different substitution pattern
close to the triple bonds: CH2 and CH(OH) for 1a, CH2 and CHF
for 1b, CH2 and C@O for 1c, CH2 and C(OMe) for 1d, CH2 and
2
CF2 for 1e, CH(OH) and CHF for 1f and CF2 and C@O for 1g.
The competition between the reactions on each independent
triple bond will give useful informations on the reactivity of the
two differentiated systems. This can be translated into quantitative
data on the difference in activation energies between the two pro-
cesses and therefore into the effect of the corresponding propargy-
lic substituents on this click reaction.
The synthesis of diynes 1a–e is reported in Scheme 1. It started
from alkyne 2, readily available through a zip reaction.11 PCC oxi-
dation, followed by the addition of ethynyl Grignard, afforded in
60% overall yield the first molecule 1a which allows to study the
competition between the CH2 and CH(OH) groups.
a: R1=R2=R3=H; R4=OH; n=5
b: R1=R2=R3=H; R4=F; n=5
c: R1=R2=H; R3,R4=CO; n=5
d: R1=R2=H; R3=R4=OMe; n=5
e: R1=R2=H; R3=R4=F; n=5
f: R1=R3=H; R2=OH; R4=F; n=3
g: R1=R2=F; R3,R4=CO; n=3
R3
R4
R1 R2
( )n
1a-g
All previous studies have been performed on highly reactive
cyclic systems and therefore the question remains to be studied
H
H
* Corresponding author. Tel.: + 33 2 23235715; fax: +33 2 23236978.
E-mail address: rene.gree@univ-rennes1.fr (R. Grée).
Figure 1. The x-diynes designed for studying, by competition between two
different reacting sites, the effect of substituents in click chemistry.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.083

D. Grée, R. Grée / Tetrahedron Letters 51 (2010) 2218–2221
2219
H
H
=
addition, followed by IBX oxidation afforded the last target mole-
cule 1g in 10% (unoptimized) overall yield from 8.
HC=CMgBr,THF
H
H
PCC, CH2Cl2
RT, 4h
-20°C to RT, 3h
( )5
O
H
( )5
OH
Having the desired diynes in hand, the stage was set for study-
ing their reactivity in click chemistry. For this purpose we selected
the classical reaction conditions, as described in the original publi-
cation by Sharpless and co-workers (benzyl azide with a catalytic
system using copper sulfate and sodium ascorbate).2 Starting from
diynes 1a–g, these cycloadditions can afford the monotriazoles
10a–g and/or the monotriazoles 11a–g as well as the bistriazoles
12a–g (Scheme 3). All reactions were performed with a large ex-
cess of diyne (using 0.15–0.25 equiv of azide) in order to minimize
the formation of bisadducts 12 and to take into account only the
competition between the two triple bonds. All reactions have been
performed at 25 °C for two hours and the results are reported in
Table 1. Analysis of the crude reaction mixtures by 1H and, when
appropriate, by 19F NMR gave the ratio of the different products ob-
tained in the click reactions. The structures of the triazoles are eas-
ily established by NMR: the multiplicity of the remaining
acetylenic proton, indicating the coupling with the R1–R2 or with
the R3–R4 substituents is particularly relevant from the structure
of the adduct (Table 2).
84%
72%
H
H
H
3
2
H
F
H
H
H
OH
H
DAST, CH2Cl2
-10°C, 20 min
( )5
1b
( )5
1a
IBX, DMSO,
THF, 30°C,
5h
H
65%
H
H
H
88%
F
H
F
H
O
H
H
DAST, 5 h,
56°C, 72%
( )5
1e
( )5
1c
H
H
H
MeO OMe
( )5
H
H
MeOH, CH2Cl2
CH(OMe)3
H+ (cat), 12h, 65%
H
H
1d
Scheme 1. Synthesis of
x
-diynes 1a–e.
The reaction of diyne 1a afforded a 22/78 ratio of monotriazoles
10a and 11a with only traces (<1%) of bistriazole 12a. Triazoles 10a
and 11a have been isolated by chromatography on SiO2 and their
structure was established unambiguously by NMR using the mul-
tiplicity of the acetylenic protons.
For 11a, it appeared at 1.93 ppm as a triplet (with J = 2.6 Hz, by
coupling with the propargylic CH2). On the other hand, in the case
of 10a, the same proton appears at 2.46 ppm as a doublet only
(with J = 2.1 Hz) by coupling with the CH(OH) proton. Therefore,
the click reaction is 3.54 times faster on the triple bond bearing
the CH(OH) substituent than on the other one with the CH2 group.
A similar sequence was followed starting with diyne 1b, affording
triazoles 10b (18%), 11b (80%) and a very small amount of bistriaz-
ole 12b. Triazoles 10b and 11b were isolated by chromatography
and their structures were established by NMR, as previously (Table
Then, classical reactions were performed to obtain the next tar-
gets: dehydroxyfluorination using diethylaminosulfurtrifluoride
(DAST) afforded the monofluorinated derivative 1b in 65% yield.
On the other hand, oxidation using 2-iodoxybenzoic acid (IBX) in
a DMSO/THF mixture gave propargylic ketone 1c in 88% yield. Pro-
tection of the latter derivative afforded ketal 1d in 65% yield. The
gemdifluoro propargylic derivative 1e was obtained in 72% yield
by reaction of 1c with DAST (neat at 56 °C).
For the last two molecules 1f and 1g, other synthetic routes had
to be followed, as indicated in Scheme 2. For 1f, it started from
known aldehyde 4,12 which reacted with ethynyl Grignard to af-
ford intermediate 5. DAST-mediated dehydroxyfluorination fol-
lowed by deprotection afforded propargylic fluoride 6 which,
after oxidation by IBX gave aldehyde 7. A final addition of the Grig-
nard reagent gave the targeted diyne 1f in 20% overall yield. On the
other hand, LiAlH4 reduction of the known13 difluoro propargylic
derivative 8, followed by PCC oxidation, gave aldehyde 9. Grignard
R3 R4
R1 R2
( )n
1a-g
H
H
=
HC=CMgBr, THF
H
OH
( )3
1) DAST, CH2Cl2
-10°C
H2O / tBuOH,
CuSO4, Na ascorbate
-20°c to RT, 3h
PhCH2N3
(0.2eq)
OTBDPS
OTBDPS
( )3
O
2) TBAF, THF,
RT, 2h
H
R3 R4
R3 R4
R1 R2
( )n
10a-g
R1 R2
4
5
( )n
H
F
+
H
F
N
N
IBX, DMSO-THF
30°C, 3h
Ph
H
N
N
Ph
N
N
( )3
H
( )3
OH
O
11a-g
H
H
R3 R4
R1 R2
7
6
H
OH
F
H
( )n
+
N
=
N
HC=CMgBr, THF
-20°c to RT, 12h
Ph
( )3
1f
N
N
Ph
N
N
H
12a-g
20% (4 steps)
H
Scheme 3. Click reactions of
x
-diynes 1a–g.
F
F
F
F
1) LiAlH4, THF,
1h 0°C then 3h RT
CO2Me
CHO
( )3
( )3
Table 1
Click chemistry on
2) PCC, CH2Cl2,
4h RT
x-diynes 1a–1g
H
H
O
8
9
DE
–(11)ꢀ
DE
–(10)
Diyne
10
11
12
Ratio 11:10
=
1) HC=CMgBr, THF
-20°c to RT, 12h
1a
1b
1c
1d
1e
1f
22
18
2
45
5
78
80
97
45
90
55
75
Traces
2
1
10
5
3.54
4.35
48.5
1
18
1.22
3
ꢀ0.76 kcal molꢀ1
ꢀ0.89 kcal molꢀ1
ꢀ2.31 kcal molꢀ1
0 kcal molꢀ1
F
F
( )3
1g
2) IBX, DMSO-THF
30°C, 6h
10% yield
(overall from 8)
H
H
ꢀ1.72 kcal molꢀ1
ꢀ0.12 kcal molꢀ1
ꢀ0.65 kcal molꢀ1
45
25
0
0
1g
Scheme 2. Synthesis of
x-diynes 1f and 1g.

2220
D. Grée, R. Grée / Tetrahedron Letters 51 (2010) 2218–2221
Table 2
other hand, we can compare the same CF2 with the strong elec-
Selected key NMR data on triazoles 10 and 11
tron-withdrawing carbonyl group. The 1:3 ratio obtained in the
case of 1g, translates in an activation energy difference which is
only 0.65 kcal molꢀ1 and this clearly establishes the strength of
the effect of the CF2 group.
Triazole
H–C„C–C (R3)(R4)–
H–C„C–C (R1)(R2)–
10a
11a
10b
2.46 (d, JHH = 2.1 Hz)
—
2.66 (dd, JHH = 2.1 Hz,
JHF = 5.5 Hz)
—
1.93 (t, JHH = 2.6 Hz)
—
– A single fluorine also accelerates significantly this reaction with
a
DDE– of ꢀ0.89 kcal molꢀ1 to be compared with the ꢀ1.4 kcal -
11b
10c
11c
10d
11d
10e
11e
10f (2 dias)
—
1.95 (t, JHH = 2.7 Hz)
—
1.93 (t, JHH = 2.7 Hz)
—
1.92 (t, JHH = 2.6 Hz)
—
1.86 (t, JHH = 2.7 Hz)
—
molꢀ1 obtained by computational studies for monofluorocyc-
looctyne.8b For cyclooctynes introduction of a fluorine atom
increased the rate of click reaction by a 3.6 factor,6,8b which is
also consistent with the 4.35 increase observed with 1b.
– It is a common practice in fluorine chemistry to emphasize the
similarity between a fluorine atom and an hydroxyl group. Our
data confirm that this is correct in the case of the click reaction
since the 1.22 ratio of triazoles obtained starting with 1f, trans-
lates into a very small DDE– (ꢀ0.12 kcal molꢀ1).
3.22 (s)
—
2.53 (s)
—
2.75 (t, JHF = 5.0 Hz)
—
2.44 (d, JHH = 2.0 Hz)
2.45 (d, JHH = 2.0 Hz)
—
11f (2 dias)
2.66 (dd, JHH = 2.1 Hz,
JHF = 5.6 Hz)
2.67 (dd, JHH = 2.1 Hz,
JHF = 5.5 Hz)
– The results obtained with alcohol 1a are also consistent with the
twofold increase in the reaction rate on a benzyloxycyclooctyne
derivative,6,8b while computational studies gave a DDE– value of
ꢀ1.7 kcal molꢀ1 for a methoxycyclooctyne.8b
10g
11g
3.22 (s)
—
—
2.77 (t, JHF = 5.0 Hz)
– Finally, possibly for a combination of steric and electronic con-
tributions, the dimethylacetal had no global effect on this reac-
tion since a 1:1 mixture of regioisomers was obtained starting
from 1d.
2). Therefore, the click reaction is 4.35 times faster on the triple
bond with the CHF substituent than the CH2 group. This shows that
the CHF substituent is a slightly better activator for the click reac-
tion than the CH(OH) group. The next step was the comparison of
the CH2 substituent with a carbonyl group. Not surprisingly the
reaction of diyne 1c afforded almost exclusively reaction on the
activated triple bond to give 11c (97%) with a small amount of
10c (2%) and bisadduct 12c (1%). Triazoles 10c and 11c were iso-
lated by chromatography and their structures were established
by the same NMR method. Therefore the reaction of the propargy-
lic ketone is 48.5 times faster than the addition on the triple bond
with the CH2 group. Next was the comparison with the dimethyl-
acetal group. The reaction of diyne 1d afforded a 1:1 mixture of
monotriazoles 10d and 11d together with 12d (10%). So, in that
case, the reactivity of the triple bonds with CH2 and C(OMe)2
groups is equal. On the contrary, in the case of 1e, the reaction
was strongly in favour of 11e (90%) with small amounts of 10e
(5%) and 12e (5%). Therefore the reactivity of the triple bond with
the CF2 substituent is 18 times faster than the addition on the tri-
ple bond with the CH2 group. Finally, as a cross check for this study,
the click reaction was performed on diynes 1f and 1g. The first
reaction afforded a 45:55 mixture of monotriazoles 10f and 11f
without bistriazole 12f. This result confirms previous data ob-
tained with 1a and 1b, indicating that the triple bond with CHF
group has a slightly higher reactivity (ratio 1.22) than the triple
bond bearing a CH(OH)substituent. On the other hand, the reaction
of 1g afforded a 25:75 ratio of 10g and 11g. This indicates that the
carbonyl group activates the click chemistry by a threefold ratio as
compared to the CF2 moiety. Therefore for this azide-type click
reaction, the reactivity order is:
In conclusion, we have demonstrated that
x-diynes 1 are useful
models to study the effect of substituents in click chemistry,
through the competition between the two reactive sites. This
method allows to establish not only a reactivity order for the se-
lected substituents but also allows to quantify the differences in
the activation energies for the corresponding click reactions.
Acknowledgements
We thank CNRS and MESR for support of this research. We
thank A. Lancou for preliminary studies on the click reactions of
propargylic fluorides. We thank Professor A. Boucekkine for fruitful
discussions and CRMPO (Rennes) for the MS studies.
Supplementary data
Supplementary data (experimental procedures, spectral and
analytical data) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2010.02.083.
References and notes
1. For a general review on click chemistry see: (a) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–2021. and references cited
therein; see also: (b) Huisgen, R. Angew. Chem., Int. Ed. 1968, 7, 321–328; (c)
Huisgen, R.. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; John Wiley &
Sons: New York, 1984; Vol. 1,.
2. (a) Rostovtsev, V. V.; Green, L. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41,
2596–2599; (b) Tornoe, C. W.; Christensen, C.; Medal, M. J. Org. Chem. 2002, 67,
3057–3064; for a recent review see: (c) Lutz, J.-F. Angew. Chem., Int. Ed. 2008,
47, 2182–2184. and references cited therein.
3. For a recent review see: Moorhouse, A. D.; Moses, J. E. ChemMedChem 2008, 3,
715–723. and references cited therein.
4. Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.; Finn,
M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 1053–1057.
5. Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am.
Chem. Soc. 2003, 125, 3192–3193.
6. (a) Agard, N. J.; Prescher, J. A.; Bertozzi, C. J. Am. Chem. Soc. 2004, 126, 15046–
15047; (b) Baskin, J. M.; Prescher, J. A.; Laughlin, S. C.; Agard, N. J.; Chang, P. M.;
Miller, I. A.; Lo, A.; Codelli, J. A.; Bertozzi, C. R. Proc. Natl. Acad. Sci. U.S.A. 2007,
104, 16793–16797.
C@O > CF2 ꢁ CF ꢂ CðOHÞ ꢁ CH@CðOMeÞ2
An important aspect of such a method using
x-diynes is that
the ratio of the two monotriazoles can be used to access directly
the difference in the activation energies for the two competitive
pathways and corresponding results are given in Table 1.14 It is
interesting to remark that the results obtained with these linear
systems appear in good agreement with the literature data ob-
tained with the cyclooctyne derivatives and several interesting re-
marks can be made:15
– For the CF2 group we observe a decrease of 1.72 kcal molꢀ1 in
activation energy as compared to the CH2 unit. This appears to
be consistent with the 1.9 kcal molꢀ1 obtained by high level
DFT calculations in the case of difluorocyclooctyne.8b On the
7. Mamat, C.; Ramenda, T.; Wuest, F. R. Mini Rev. Org. Chem. 2009, 6, 21–34. and
references cited therein.
8. (a) Ess, D. H.; Jones, G. O.; Houk, K. N. Org. Lett. 2008, 10, 1633–1636; (b)
Schoenebeck, F.; Ess, D. H.; Jones, G. O.; Houk, K. N. J. Am. Chem. Soc. 2009, 131,
8121–8133.

D. Grée, R. Grée / Tetrahedron Letters 51 (2010) 2218–2221
2221
9. For a recent review on propargylic fluorides see: Pacheco, Ma. C.; Purseur, S.;
Gouverneur, V. Chem. Rev. 2008, 108, 1943–1981.
12. Zhu, G.; Negishi, E.-I. Org. Lett. 2007, 9, 2771–2774. and references cited therein.
13. Manthati, V.; Grée, D.; Grée, R. Eur. J. Org. Chem. 2005, 3825–3829.
10. For a recent example of click reaction with simple propargylic fluorides see:
Hiang, H.; Falcicchio, A.; Paixao, M. W.; Bertensen, S.; Jorgensen, K. A. J. Am.
Chem. Soc. 2009, 131, 7153–7157.
11. Organ, M. C.; Ghaseni, H. J. Org. Chem. 2004, 69, 695–700. and references cited
therein.
14. For reaction of molecules 1, the difference in the activation energies for the
competitive processes leading to 10 and 11 is given by:
DE
–(11)ꢀ
D
E–(10) = DDE– = ꢀRT Log[11]/[10].
15. High level computational studies are ongoing in order to analyze in more depth
the effects of substituents on the reactivity in these linear systems.