Template-directed olefin cross metathesis

Article abstract of DOI:10.1021/ol051599g

(Figure Presented) A template containing two secondary dialkylammonium ion recognition sites for encirclement by olefin-bearing dibenzo[24]crown-8 derivatives has been used to promote olefin cross metatheses with ruthenium-alkylidene catalysts. For monoolefin monomers, the rates of metatheses and yields of the dimers are both amplified in the presence of the template. Likewise, for a diolefin monomer, the yield of the dimer is enhanced in the presence of the template under conditions where higher oligomers are not formed.

Full text of DOI:10.1021/ol051599g

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4213-4216
Template-Directed Olefin Cross
Metathesis
Stuart J. Cantrill,† Robert H. Grubbs,*,‡ Daniela Lanari,† Ken C.-F. Leung,†
Alshakim Nelson,‡ Katherine G. Poulin-Kerstien,‡ Sebastian P. Smidt,‡
J. Fraser Stoddart,*,† and David A. Tirrell‡
California NanoSystems Institute & Department of Chemistry and Biochemistry,
UniVersity of California, Los Angeles, 405 Hilgard AVenue,
Los Angeles, California 90095, and The Arnold and
Mabel Beckman Laboratory of Chemical Synthesis, California Institute of Technology,
1200 East California BouleVard, Pasadena, California 91125
rhg@caltech.edu; stoddart@chem.ucla.edu
Received July 7, 2005
ABSTRACT
A template containing two secondary dialkylammonium ion recognition sites for encirclement by olefin-bearing dibenzo[24]crown-8 derivatives
has been used to promote olefin cross metatheses with ruthenium alkylidene catalysts. For monoolefin monomers, the rates of metatheses
−
and yields of the dimers are both amplified in the presence of the template. Likewise, for a diolefin monomer, the yield of the dimer is
enhanced in the presence of the template under conditions where higher oligomers are not formed.
Nature employs template-directed synthesis1,2 by using
noncovalent bonding and π-π stacking, in the formation of
DNA, RNA, and proteins, to obtain well-defined biopolymers
in respect to their precise lengths and specific sequences.
For chemists to be able to synthesize artificial heteropolymers
with such well-defined structures, an alternative set of
molecular recognition motifs and catalysts have to be
identified and developed. Ruthenium-alkylidene-mediated
olefin metathesis,3 using catalysts such as 1 and 2 shown in
Figure 1. Ruthenium-alkylidene catalysts 1 and 2.
† University of California, Los Angeles.
‡ California Institute of Technology.
(1) Diederich, F., Stang, P. J., Eds. Templated Organic Synthesis; Wiley-
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Figure 1, has proved to be a highly convenient method for
the synthesis of natural products4 and artificial polymers,5
as well as mechanically interlocked compounds,6 e.g.,
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T.; Vassilikogiannakis, G.; Mathison, C. J. N. J. Am. Chem. Soc. 2005,
127, 8872-8888.
10.1021/ol051599g CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/13/2005

used in concert with the molecular recognition that exists7,8
+
between secondary dialkylammonium ions (RCH2NH2 -
Scheme 1. Templated Dimerization of the DB24C8
Derivatives 3a/b and 4
CH2R) and dibenzo[24]crown-8 (DB24C8), which readily
form [2]pseudorotaxanes in aprotic solvents as a result of
highly stabilizing [N+-H‚‚‚O] hydrogen bonds and
[C-H‚‚‚O] interactions, has led previously6,9 to the template-
directed synthesis1,2 of catenanes,6f rotaxanes,6d and a mo-
lecular bundle6e under thermodynamic control.
Olefin cross metathesis (CM) has also been investigated
with peptides10 and peptide-based templates11 where the
formation of the new carbon-carbon bond is controlled by
the preorganization exerted by the conformation of the
peptide chain. Herein, we report an approach utilizing a
+
template-mediated CM, employing the (RCH2NH2 CH2R)/
DB24C8 recognition motif, in the formation of dimeric
crown ethers, a satisfactory outcome of our preliminary
efforts to template the synthesis of oligomeric and polymeric
structures by acyclic diene metathesis (ADMET).
(5) (a) Irin, K. J.; Mol, J. C. Olefin Metatheses and Metathesis
Polymerization; Academic Press: London, 1997. (b) Grubbs, R. H., Ed.
Handbook of Metathesis; Wiley-VCH: Weinheim, 2003. (c) Bielawski, C.
W.; Benitez, D.; Grubbs, R. H. Science 2002, 297, 2041-2044. (d) Choi,
T.-L.; Grubbs, R. H. Angew Chem., Int. Ed. 2003, 42, 1743-1746. (e)
Baughman, T. W.; Wagener, K. B. AdV. Polym. Sci. 2005, 176, 1-42.
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K. M. New J. Chem. 1998, 1019-1021. (c) Weck, M.; Mohr, B.; Sauvage,
J.-P.; Grubbs, R. H. J. Org. Chem. 1999, 64, 5463-5471. (d) Kilbinger,
A. F. M.; Cantrill, S. J.; Waltman, A. W.; Day, M. W.; Grubbs, R. H.
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S. J.; Grubbs, R. H.; Guidry, E. N.; Orenes, R.; Stoddart, J. F. Angew.
Chem., Int. Ed. 2004, 43, 3273-3278. (f) Guidry, E. N.; Cantrill, S. J.;
Stoddart, J. F.; Grubbs, R. H. Org. Lett. 2005, 7, 2129-2132.
(7) (a) Ashton, P. R.; Campbell, P. J.; Chrystal, E. J. T.; Glink, P. T.;
Menzer, S.; Philp, D.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; Williams,
D. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 1865-1869. (b) Fyfe, M. C.
T.; Stoddart, J. F. AdV. Supramol. Chem. 1999, 5, 1-53. (c) Fyfe, M. C.
T.; Stoddart, J. F. Coord. Chem. ReV. 1999, 183, 139-155. (d) Fyfe, M. C.
T.; Stoddart, J. F.; Williams, D. J. Struct. Chem. 1999, 10, 243-259. (e)
Cantrill, S. J.; Pease, A. R.; Stoddart, J. F. J. Chem. Soc., Dalton Trans.
2000, 3715-3734.
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Chem. Commun. 1995, 1289-1291. (b) Kolchinski, A. G.; Alcock, N. W.;
Roesner, R. A.; Busch, D. H. Chem. Commun. 1998, 1437-1438. (c)
Johnson, B. F. G.; Judkins, C. M. G.; Matters, J. M.; Shephard, D. S.;
Parsons, S. Chem. Commun. 2000, 1549-1550. (d) Duggan, S. A.; Fallon,
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T. Chem. Lett. 2002, 174-175. (f) Tokunaga, Y.; Seo, T. Chem. Commun.
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N.; Jones, J. W. J. Am. Chem. Soc. 2003, 125, 3522-3533. (i) Furusho,
Y.; Oku, T.; Hasegawa, T.; Tsuboi, A.; Kihara, N.; Takata, T. Chem. Eur.
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Fukazawa, Y. Tetrahedron Lett. 2003, 44, 5773-5776. (l) Dvornikovs, V.;
House, B. E.; Kaetzel, M.; Dedman, J. R.; Smithrud, D. B. J. Am. Chem.
Soc. 2003, 125, 8290-8301. (m) Kawano, S. I.; Fujita, N.; Shinkai, S. Chem.
Commun. 2003, 1352-1353. (n) Horie, M.; Suzaki, Y.; Kohtaro, O. J. Am.
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Particularly relevant to the task we have in hand is the
ability to use the thermodynamic control we associate with
supramolecular12 and dynamic covalent13 chemistry (DCC),
both practices in chemistry which rely upon the reversible
noncovalent and covalent bond making and breaking pro-
cesses as part of key proofreading and crucial error-checking
mechanisms, to template the formation of a well-defined mol-
ecular compound during a reaction that, if it were performed
under kinetic control, would afford a myriad of products. Thus,
the thermodynamically controlled protocol depends, at the
outset for its success, on the formation of ternary and higher
complexes that are extremely stable prior to the catalyst (1
and 2 in Figure 1) carrying out an olefin cross metathesis.
Our initial experiments were carried out (Scheme 1) with
a DB24C8 derivative (3a or 3b in Figure 1) to which a tether
comprising a single terminal olefin was added and a
+
dicationic template 5‚2BArF containing two -CH2NH2 -
CH2- centers (Figure 2). It has been demonstrated previ-
+
ously14 that the two -CH2NH2 CH2- centers present in 52+
(9) Other recognition motifs have also been employed in supramolecular
assistance to covalent synthesis. For example, dimerization via an N-
alkylation has been facilitated by hydrogen bonding interactions with a linear
template ((a) Kelly, T. R.; Gridger, G. J.; Zhao, C. J. Am. Chem. Soc. 1990,
112, 8024-8034), and metal-ligand interactions have been used to promote
transacylation reactions using a cyclic Zn-porphyrin-based template ((b)
Walter, C. J.; Anderson, H. L.; Sanders, J. K. M. J. Chem. Soc., Chem.
Commun. 1993, 458-460).
(as its 2PF6- salt) can each thread and bind a DB24C8. Since
5‚2PF6 is insoluble in solvents such as CHCl3 and CH2Cl2,
where the noncovalent bonding interactions between the two
recognition partners is strongest, the BArF- salt of 52+, which
is soluble in these solvents, was prepared for use in the
preliminary experiments. The association constants, Ka1 and
(10) Blackwell, H. K.; Sadowsky, J. D.; Howard, R. J.; Sampson, J. N.;
Chao, J. A.; Steinmetz, W. E.; O’Leary, D. J.; Grubbs, R. H. J. Org. Chem.
2001, 66, 5291-5302.
(11) Yang, X.; Gong, B. Angew. Chem., Int. Ed. 2005, 44, 1352-1356.
(12) Lehn, J.-M. Supramolecular Chemistry; VCH: Weinheim, 1996.
Org. Lett., Vol. 7, No. 19, 2005
4214

metathesis of 3a occurred faster than the reaction in the
absence of the template.
The homodimerizations of the olefin-bearing DB24C8
derivatives 3a and 3b were studied17 (Table 1) at a
Table 1. Conversion of Either 3a or 3b,a in the Presence and
Absence of the Template 52+, to the Expected Dimer as
Determined by HPLC
component
catalyst
yield (%) of dimer
3a
10 mol % 1
10 mol % 1
10 mol % 2
10 mol % 2
20 mol % 2
20 mol % 2
10 mol % 1
10 mol % 1
25 mol % 2
25 mol % 2
35
72
6
39
27
56
35
72
17
78
[(3a)2 ⊃ 5]2+
3a
[(3a)2 ⊃ 5]2+
3a
Figure 2. Olefin-bearing crown derivatives 3a/3b and 4.
[(3a)2 ⊃ 5]2+
3b
[(3b)2 ⊃ 5]2+
3b
Ka2, in CH2Cl2 (at 298 K) for the complexation of 5‚2BArF
with 1 and then 2 equiv of DB24C8, forming first a 1:1
complex and then subsequently a 1:2 complex, were found15
to be 4.53 × 106 and 7.17 × 107 M-1, respectively. The
relationship between Ka1 and Ka2 (i.e., Ka2/Ka1 > 0.25)16a
implies that there is positive cooperativity16 between the two
binding sites. When a 5 mM solution of 5‚2BArF in CD2Cl2
is treated with 2 equiv of 3a, the template is bound by this
olefin-bearing DB24C8 derivative as determined (see Sup-
porting Information) by 1H NMR spectroscopy. The 1H NMR
spectrum reveals that both sites on the 52+ template are
occupied (>95%) by crown ethers, namely, 3a. After the
formation of [(3a)2 ⊃ 5]2+, the catalyst 1 was added to the
CD2Cl2 solution, which was then heated to 40 °C; the
formation of the dimer was followed by 1H NMR spectros-
copy. The dimerization of [(3a)2 ⊃ 5]2+ was established to
be 73% complete within 40 min, whereas the dimerization
of 3a in the absence of the template 52+ resulted in only
48% conversion under identical reaction conditions in the
same amount of time. The template affected (Figure 3) the
rate of the reaction as well. In the presence of 52+, the cross
[(3b)2 ⊃ 5]2+
a Concentration of crown ether ) 1 mM.
concentration of 1 mM by HPLC. Each reaction was
performed in the presence of both catalysts 1 and 2 separately
for a period of 2 h at 40 °C. In the presence of 10 mol % 1,
the dimerization of either 3a or 3b in the absence of a
template resulted in a 35% yield of the respective dimers in
each case. However, under the same conditions, [(3a/b)2 ⊃
4]2+ reacted to afford a 72% yield of the respective dimer.
Using catalyst 2 in the reactions of either 3a or 3b in the
absence of the template resulted in much lower conversions
to dimers. Templating the dimerization of the olefin-bearing
DB24C8 derivatives using catalyst 2 produced higher yields
of the dimers relative to the reactions without the added
template. Notably, when [(3a)2 ⊃ 5]2+ was treated with 25
mol % 2, a 78% yield of the dimer was obtained, compared
with only 17% for the reaction in the absence of the template.
(13) (a) Lehn, J.-M. Chem. Eur. J. 1999, 5, 2455-2463. (b) Rowan, S.
J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.; Stoddart, J. F. Angew.
Chem., Int. Ed. 2002, 41, 898-952. (c) Fuchs, B.; Nelson, A.; Star, A.;
Stoddart, J. F.; Vidal, S. B. Angew. Chem., Int. Ed. 2003, 42, 4220-4224.
(d) Chichak, K. S.; Cantrill, S. J.; Pease, A. R.; Chiu, S.-H.; Cave, G. W.
V.; Atwood, J. L.; Stoddart, J. F. Science 2004, 304, 1308-1312. (e) Arico´,
F.; Chang, T.; Cantrill, S. J.; Khan, S. I.; Stoddart, J. F. Chem. Eur. J.
2005, 11, 4655-4666.
(14) Ashton, P. R.; Chrystal, E. J. T.; Glink, P. T.; Menzer, S.; Schiavo,
C.; Spencer, N.; Stoddart, J. F.; Tasker, P. A.; White, A. J. P.; Williams,
D. J. Chem. Eur. J. 1996, 2, 709-728.
(15) Binding constants (Ka) were determined by isothermal titration
calorimetry. The details of the determinations are given in Supporting
Information.
(16) (a) Connors, K. A. Binding Constants; Wiley: New York, 1987.
(b) Ercolani, G. J. Am. Chem. Soc. 2003, 125, 16097-16103. (c) Mulder,
A.; Huskens, J.; Reinhoudt, D. N. Org. Biomol. Chem. 2004, 2, 3409-
3424. (d) Badjic´, J. D.; Nelson, A.; Cantrill, S. J.; Turnbull, W. B.; Stoddart,
J. F. Acc. Chem. Res. 2005, 38, ASAP Article (DOI: 10.1021/ar040223k).
(17) During the CM of 3a and 3b at this dilute concentration (1 mM)
and in the absence of a template, olefin isomerization products were
observed (for recent references regarding olefin isomerization, see: Schmidt,
B. Eur. J. Org. Chem. 2004, 1865-1880. Hong, S. H.; Sanders, D. P.;
Lee, C. W.; Grubbs, R. H. J. Am. Chem. Soc. Submitted) in both the HPLC
traces and the mass spectra ([M - 14]+) recorded on the reaction mixtures.
The presence of the template during the reaction, however, minimizes the
amount of isomerized products, while increasing the rate of dimerization
relative to olefin isomerization.
Figure 3. Formation over time (using catalyst 1) in CD2Cl2 at
40 °C of the dimer from the monomer 3a for the reaction in the
presence (b) and absence (9) of the template 52+, as determined
from 1H NMR spectroscopy using the olefin resonances as a probe.
The concentration of 3a and 5‚2BArF were both 0.1 mM.
Org. Lett., Vol. 7, No. 19, 2005
4215

To extend the concept of a template-directed olefin
metathesis toward the formation of oligomers (Scheme 1),
the DB24C8 derivative 4, carrying an aromatic tether bearing
two olefin-containing sidearms, was synthesized. While this
monomer is expected to have the ability to form polymers
by ADMET at higher concentrations, the templated reaction
under more dilute conditions should yield only well-defined
oligomers. When a 1 mM solution of crown 4 in CH2Cl2
was exposed to the catalyst 1, the dimer was formed (Table
2) in 56% yield. The concentration of terminal olefin
elevated to a yield of 76%. Similar trends were observed
for the dimerization of 4 using the catalyst 2.
In conclusion, a template presenting two RCH2NH2 CH2R
+
recognition sites promotes the efficient formation in dichlo-
romethane at low concentrations of dimeric DB24C8 deriva-
tives by means of CM from olefin-bearing DB24C8 mono-
mers in the presence of ruthenium-alkylidene catalysts. The
CM experiments with both monoolefins 3a and 3b as
monomers demonstrated that the rates as well as the yields
of dimers in the catalyzed reactions are enhanced by the
presence of the template 52+. When the diolefin 4 was used
as the monomer instead of 3a or 3b, the same template was
found to be effective in amplifying the production of the
expected dimer at the expense of higher oligomers.18 Cur-
rently, our efforts are being focused on developing templates
capable of templating the formation of larger oligomers of
well-defined constitutions and chain lengths by ADMET.
Table 2. Conversion of 4 in the Presence and Absence of the
Template 52+ to the Expected Dimer as Determined by HPLC
component
catalyst
yield (%) of dimer
4
10 mol % 1
10 mol % 1
10 mol % 1
10 mol % 1
20 mol % 2
20 mol % 2
56a
76a
34b
72b
37a
71a
[(4)2 ⊃ 5]2+
4
Acknowledgment. The authors thank the Office of Naval
Research (ONR) for its support through the Multidisciplinary
University Research Initiative (MURI) program, the Alex-
ander von Humboldt Foundation for a Feodor Lynen post-
doctoral fellowship to S.P.S., the Croucher Foundation
(HKSAR) for a postdoctoral fellowship to K.C.-F.L., and
the National Institutes of Health for a postdoctoral fellowship
to A.N.
[(4)2 ⊃ 5]2+
4
[(4)2 ⊃ 5]2+
a Concentration of crown ether ) 1 mM. b Concentration of crown ether
) 0.5 mM.
functions in this case is twice that of the DB24C8 derivative
since 4 contains two homoallyl functionalities. Thus, when
the dimerization of 4 was performed where the concentration
of the crown was decreased to 0.5 mM (and therefore 1 mM
in olefin), the yields employing catalyst 1 were comparable
to those for the dimerization of 3a and 3b. Higher oligomers
were not observed as a result of the dilute concentration of
the reactions. In the presence of 5‚2BArF, the DB24C8
derivative 4 forms a 2:1 complex ([(4)2 ⊃ 5]2+) with the
template 5. The productive CM for this complex at 1 mM
in the template-directed reaction using the catalyst 1 was
Supporting Information Available: Synthetic and tem-
plate-directed catalytic procedures, in addition to spectro-
scopic and thermodynamic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL051599G
(18) During the preparation of this manuscript, Constable and co-workers
reported the templated formation of a dimer using metal-ligand interactions
(as an alternative recognition motif) to mediate olefin cross metathesis;
see: Constable, E. C.; Housecroft, C. E.; Lambert, J. N.; Malarek, D. A.
Chem. Commun. 2005, 3739-3741.
4216
Org. Lett., Vol. 7, No. 19, 2005