Molecular Shuttles by the Protecting Group Approach

Article abstract of DOI:10.1021/jo991397w

Two new [2]rotaxane-based molecular shuttles, in which a mechanically bound dibenzo[24]crown-8 (DB24C8) macroring shunts back and forth between two dialkylammonium recognition sites situated on a chemical dumbbell, have been constructed by a novel synthetic strategy that relies upon the use of the tert-butoxycarbonyl (Boc) protecting group. During the syntheses of both molecular shuttles, this protecting group masks a dialkylammonium recognition center which is liberated only after the [2]rotaxane constitution is established. In both cases, the molecular shuttles' other dialkylammonium center is essential for the rotaxane-forming reactions and it ensures that DB24C8 is interpenetrated by threadlike precursors, as a result of noncovalent bonding interactions, to produce [2]pseudorotaxanes which are stoppered subsequently through 1,3-dipolar cycloadditions between azides and bulky acetylenedicarboxylates. The new molecular shuttles have been examined by means of dynamic ¹H NMR spectroscopy, which reveals that the movements of the DB24C8 macroring are very highly dependent both on solvent properties and on the nature of the spacer unit linking the two dialkylammonium centers. Thus, DB24C8 shunts facilely between the dialkylammonium centers when the shuttles are dissolved in solvents that readily donate their nonbonding electrons into noncovalent bonds, e.g., DMF, and when spacer units that do not offer much steric resistance to shuttling, e.g., hexamethylene, are used. On the other hand, shuttling is difficult in solvents that are less inclined to donate their electrons into noncovalent bonds, e.g., (CDCl₂)₂, and when relatively bulky benzenoid spacer units, e.g., p-xylylene, link the two dialkylammonium centers. It has been proposed that the DB24C8 might act as a "ferry" which carries a proton between dialkylammonium and dialkylamine moieties in a singly protonated [2]rotaxane by means of ion-dipole interactions.

Full text of DOI:10.1021/jo991397w

J . Org. Chem. 2000, 65, 1937-1946
1937
Molecu la r Sh u ttles by th e P r otectin g Gr ou p Ap p r oa ch †
J ianguo Cao, Matthew C. T. Fyfe, and J . Fraser Stoddart*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095
Graham R. L. Cousins and Peter T. Glink
School of Chemistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Received September 3, 1999
Two new [2]rotaxane-based molecular shuttles, in which a mechanically bound dibenzo[24]crown-
8 (DB24C8) macroring shunts back and forth between two dialkylammonium recognition sites
situated on a chemical dumbbell, have been constructed by a novel synthetic strategy that relies
upon the use of the tert-butoxycarbonyl (Boc) protecting group. During the syntheses of both
molecular shuttles, this protecting group masks a dialkylammonium recognition center which is
liberated only after the [2]rotaxane constitution is established. In both cases, the molecular shuttles’
other dialkylammonium center is essential for the rotaxane-forming reactions and it ensures that
DB24C8 is interpenetrated by threadlike precursors, as a result of noncovalent bonding interactions,
to produce [2]pseudorotaxanes which are stoppered subsequently through 1,3-dipolar cycloadditions
between azides and bulky acetylenedicarboxylates. The new molecular shuttles have been examined
1
by means of dynamic H NMR spectroscopy, which reveals that the movements of the DB24C8
macroring are very highly dependent both on solvent properties and on the nature of the spacer
unit linking the two dialkylammonium centers. Thus, DB24C8 shunts facilely between the
dialkylammonium centers when the shuttles are dissolved in solvents that readily donate their
nonbonding electrons into noncovalent bonds, e.g., DMF, and when spacer units that do not offer
much steric resistance to shuttling, e.g., hexamethylene, are used. On the other hand, shuttling is
difficult in solvents that are less inclined to donate their electrons into noncovalent bonds, e.g.,
(CDCl2)2, and when relatively bulky benzenoid spacer units, e.g., p-xylylene, link the two
dialkylammonium centers. It has been proposed that the DB24C8 might act as a “ferry” which
carries a proton between dialkylammonium and dialkylamine moieties in a singly protonated
[2]rotaxane by means of ion-dipole interactions.
In tr od u ction
The so-called rotaxanes have fascinated chemists for
some years now,1 not only because of their unique,
mechanically interlocked, “bead on a dumbbell” structure,
but also because of their potential to form the basis of
functioning nanoscale devices,2 e.g., molecular shuttles
and switches,3 in the future. In the simplest rotaxane-
based molecular shuttle4 (Figure 1), a macrocyclic “bead”
travels back and forth between two identical “stations”,
i.e., molecular recognition sites, located on a chemical
“dumbbell”. The bead interacts with each of the stations
through noncovalent bonding interactions5 and is con-
F igu r e 1. Elementary rotaxane-based molecular shuttle. The
macrocyclic bead (open square) moves back and forth, like a
shuttle, between two identical molecular recognition sites (S)
with which it interacts through noncovalent bonds.
strained to be bound mechanically to the dumbbell whose
bulky terminal stopper groups it cannot traverse.
The present investigation addresses an irregularity
that stems from our studies on rotaxane synthesis by a
protocol relying on (1) the binding6 of dialkylammonium
ions by the crown ether dibenzo[24]crown-8 (DB24C8)
† “Molecular Meccano”, 55. For part 54, see: Balzani, V.; Credi, A.;
Mattersteig, G.; Matthews, O. A.; Raymo, F. M.; Stoddart, J . F.;
Venturi, M.; White, A. J . P.; Williams, D. J . J . Org. Chem. 2000, 65,
1924-1936.
* To whom correspondence should be addressed. Tel: (310) 206-
7078. Fax: (310) 206-1843. E-mail: stoddart@chem.ucla.edu.
(1) (a) Amabilino, D. B.; Stoddart, J . F. Chem. Rev. 1995, 95, 2725-
2828. (b) Gibson, H. W. in Large Ring Molecules; Semlyen, J . A., Ed.;
Wiley: Chichester, 1996; pp 191-262. (c) J a¨ger, R.; Vo¨gtle, F. Angew.
Chem., Int. Ed. Engl. 1997, 36, 930-944. (d) Chambron, J .-C.; Sauvage,
J .-P. Chem. Eur. J . 1998, 4, 1362-1366. (e) Nepogodiev, S. A.; Stoddart,
J . F. Chem. Rev. 1998, 98, 1959-1976. (f) Leigh, D. A.; Murphy, A.
Chem. Ind. (London) 1999, 178-183. (g) Hubin, T. J .; Kolchinski, A.
G.; Vance, A. L.; Busch, D. H. Adv. Supramol. Chem. 1999, 5, 237-
357. (h) Breault, G. A.; Hunter, C. A.; Mayers, P. C. Tetrahedron 1999,
55, 5265-5293. (i) Molecular Catenanes, Rotaxanes and Knots; Sau-
vage, J .-P., Dietrich-Buckecher, C. O., Eds.; Wiley-VCH: Weinheim,
1999. (j) Raymo, F. M.; Stoddart, J . F. Chem. Rev. 1999, 99, 1643-
1664.
(2) (a) Fabbrizzi, L.; Poggi, A. Chem. Soc. Rev. 1995, 24, 197-202.
(b) de Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Huxley, A.
J . M.; McCoy, C. P.; Rademacher, J . T.; Rice, T. E. Chem. Rev. 1997,
97, 1515-1566. (c) Ward, M. D. Chem. Ind. (London) 1997, 640-645.
(d) Balzani, V.; Go´mez-Lo´pez, M.; Stoddart, J . F. Acc. Chem. Res. 1998,
31, 405-414. (e) Sauvage, J .-P. Acc. Chem. Res. 1998, 31, 611-619.
(f) Kaifer, A. E. Acc. Chem. Res. 1999, 32, 62-71. (g) Neimz, A.; Rotello,
V. M. Acc. Chem. Res. 1999, 32, 42-52. (h) Collier, C. P.; Wong, E.
W.; Belohradsky, M.; Raymo, F. M.; Stoddart, J . F.; Kuekes, P. J .;
Williams, R. S.; Heath, J . R. Science 1999, 285, 391-394.
10.1021/jo991397w CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/24/2000

1938 J . Org. Chem., Vol. 65, No. 7, 2000
Cao et al.
Sch em e 1. Th e On ly Rota xa n e Isola ted follow in g Rea ction of DB24C8, 2-H2‚2P F 6, a n d 3 Wa s th e
[3]Rota xa n e 1-H2‚2P F 6
Sch em e 2. P r otectin g Gr ou p Ap p r oa ch for th e
and (2) the 1,3-dipolar cycloaddition between azides and
Syn th esis of DB24C8-Bis(d ia lk yla m m on iu m )
bulky acetylenedicarboxylates to form 1,2,3-triazoles that
Molecu la r Sh u ttlesa
act as terminal stopper units. It was found7 that the
[3]rotaxane 1-H2‚2PF6 was the only rotaxane isolated
(Scheme 1) when 1 equiv of DB24C8 was reacted with
bisazide 2-H2‚2PF6 and di-tert-butyl acetylenedicarboxy-
late (3) in a range of organic solvents. Under no circum-
stances was the corresponding “two-station” [2]rotaxane
4-H2‚2PF6 (Figure 2), i.e., a potential DB24C8-bis-
(dialkylammonium) molecular shuttle, isolated from the
reaction mixture. This compound was not formed pre-
sumably because the solubility of threadlike bis(dialkyl-
ammonium) dications in organic solvents is reliant upon
the complexation of both of their dialkylammonium
(3) (a) Anelli, P.-L.; Asakawa, M.; Ashton, P. R.; Bissell, R. A.;
Clavier, G.; Go´rski, R.; Kaifer, A. E.; Langford, S. J .; Mattersteig, G.;
Menzer, S.; Philp, D.; Slawin, A. M. Z.; Spencer, N.; Stoddart, J . F.;
Tolley, M. S.; Williams, D. J . Chem. Eur. J . 1997, 3, 1113-1135. (b)
a
Murakami, H.; Kawabuchi, A.; Kotoo, K.; Kunitake, M.; Nakashima,
N. J . Am. Chem. Soc. 1997, 119, 7605-7606. (c) Ashton, P. R.;
Ballardini, R.; Balzani, V.; Baxter, I.; Credi, A.; Fyfe, M. C. T.; Gandolfi,
M. T.; Go´mez-Lo´pez, M.; Mart´ınez-D´ıaz, M.-V.; Piersanti, A.; Spencer,
N.; Stoddart, J . F.; Venturi, M.; White, A. J . P.; Williams, D. J . J . Am.
Chem. Soc. 1998, 120, 11932-11942. (d) Leigh, D. A.; Troisi, A.;
Zerbetto, F. Angew. Chem., Int. Ed. 2000, 39, 350-353. (e) Rowan, S.
J .; Stoddart, J . F. J . Am. Chem. Soc. 2000, 122, 164-165.
(4) Anelli, P.-L.; Spencer, N.; Stoddart, J . F. J . Am. Chem. Soc. 1991,
113, 5131-5133.
The key element of this approach is the use of a latent
dialkylammonium center, formed by the attachment of a protecting
group (PG) to a dialkylamine, which is maintained throughout the
rotaxane-forming reaction (Step 1) between DB24C8 and another,
“real” dialkylammonium unit. The synthetic approach concludes
when the latent dialkylammonium center is transformed into its
active counterpart by deprotection and protonation (Step 2).
centers by DB24C8. Thus, the [2]pseudorotaxane8 pre-
cursors of 4-H2‚2PF6 are practically insoluble in organic
solvents and either precipitate out from solution during
the reaction or are complexed by another DB24C8
molecule to generate the corresponding [3]pseudorotax-
anes. On the other hand, the [3]pseudorotaxane8 inter-
mediates created during the reaction are soluble in
organic solvents and therefore undergo stoppering reac-
tions which produce 1-H2‚2PF6. Following on from these
observations, we have devised a new protecting group
approach for the syntheses of the degenerate DB24C8-
bis(dialkylammonium) molecular shuttles 5a -H2‚2PF6
(5) (a) Mascal, M. Contemp. Org. Synth. 1994, 1, 31-46. (b) Lehn,
J .-M. Supramolecular Chemistry; VCH: Weinheim, 1995. (c) Fyfe, M.
C. T.; Stoddart, J . F. Acc. Chem. Res. 1997, 30, 393-401. (d) Reinhoudt,
D. N.; Stoddart, J . F.; Ungaro, R. Chem. Eur. J . 1998, 4, 1349-1351.
(6) (a) 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. (b) Ashton, P. R.;
Fyfe, M. C. T.; Hickingbottom, S. K.; Stoddart, J . F.; White, A. J . P.;
Williams, D. J . J . Chem. Soc., Perkin Trans. 2 1998, 2117-2128. (c)
Fyfe, M. C. T.; Stoddart, J . F.; Adv. Supramol. Chem. 1999, 5, 1-53.
(d) Fyfe, M. C. T.; Stoddart, J . F.; Williams, D. J . Struct. Chem. 1999,
10, 243-259.
(7) (a) Ashton, P. R.; Glink, P. T.; Stoddart, J . F.; Tasker, P. A.;
White, A. J . P.; Williams, D. J . Chem. Eur. J . 1996, 2, 729-736. (b)
Ashton, P. R.; Glink, P. T.; Stoddart, J . F.; Menzer, S.; Tasker, P. A.;
White, A. J . P.; Williams, D. J . Tetrahedron Lett. 1996, 37, 6217-6220.

Molecular Shuttles
J . Org. Chem., Vol. 65, No. 7, 2000 1939
F igu r e 2. Potential molecular shuttles created by the interlocking of DB24C8 and bis(dialkylammonium) dumbbells.
and 5b-H2‚2PF6 (Figure 2). This approach relies (Scheme
2) on the employment of a latent dialkylammonium group
that remains protected while another, “real” dialkylam-
monium center interacts, via noncovalent bonds, with
DB24C8 during [2]rotaxane formation. Upon deprotec-
tion, the latent group is transformed into a further “real”
dialkylammonium center, furnishing a two-station [2]ro-
taxane, i.e., a molecular shuttle with two sites for
molecular recognition events between DB24C8 and a
dialkylammonium unit, in the process. Here, we report
the realization of the protecting group approach for the
construction of molecular shuttles 5a -H2‚2PF6 and 5b-
H2‚2PF6 and our subsequent investigation into the shut-
tling of the DB24C8 macroring in these two new com-
well as being unreactive in this instance; and (4) its tert-
butyl moiety resonates as a characteristic singlet in the
1H NMR spectrum, allowing the protected rotaxane and
its precursors to be characterized unambiguously, thus
making it easy to follow the deprotection step by 1H NMR
spectroscopy. However, the weakly acidic reagents gener-
ally employed to remove the Boc group, e.g., CF3CO2H,
are incompatible with the tert-butyl ester groups present
in the products of the original7 rotaxane synthesis.
Cleavage of these tert-butyl ester moieties would decrease
the size of the stoppers, possibly rendering them inca-
pable of preventing dissociation of the macrocycle from
the dumbbell. We therefore investigated the employment
of esters that were not as acid sensitive for the rotaxane
syntheses.
1
pounds by variable temperature H NMR spectroscopy.
Syn th esis. After an inspection of the original crystal
structures7 and CPK space-filling models, we concluded
that ethyl ester groups would be sufficiently bulky to
make the terminal stopper groups large enough to ensure
dumbbell-macrocycle interlocking. In fact, we found that
the [2]rotaxane 6-H‚PF6swith ethoxycarbonyl groups
appended to its triazole terminiscould be isolated in 77%
yield when 7-H‚PF6 was reacted (Scheme 3) with a large
excess of DB24C8 and diethyl acetylenedicarboxylate (8).
Without a doubt, the dumbbell and macrocycle compo-
nents of this rotaxane are mechanically interlocked with
one another, since (1) the compound survives column
chromatography, (2) the LSI mass spectrum of 6-H‚PF6
displays a strong base peak at m/z ) 1096 corresponding
Resu lts a n d Discu ssion
Design Logic. We decided to utilize a Boc-protected
dialkylamine as the latent dialkylammonium center
necessary for our novel synthetic strategy. The Boc (tert-
butoxycarbonyl) moiety was chosen as the protecting
group because (1) we had employed it previously7a,9 with
much success for the syntheses of dialkylammonium-
containing compounds; (2) of its facile introduction/
removal;10 (3) the byproducts following removal of this
groupsviz., CO2 and 2-methylpropenesare volatile, as
(8) Pseudorotaxanes1a,6 are complexes wherein one or more macro-
cycles encircle one or more threadlike species by virtue of noncovalent
bonding interactions. The fundamental difference between pseudoro-
taxanes and their mechanically interlocked congeners, the rotaxanes,
is that either one or both of their termini do not possess stopper groups
that are bulky enough to prevent dissociation of the thread(s) from
the macrocycle(s). The number of components, n, of which a pseudoro-
taxane is comprised is indicated by the descriptor [n]. Three [2]pseu-
dorotaxanes could reasonably be formed en route to the [2]rotaxane
4-H2‚2PF6, viz., the “unstoppered” complex [DB24C8‚2-H2][PF6]2 and
the two complexes in which one DB24C8 molecule is pierced by the
singly stoppered thread (SST) produced by reaction of one of the azido
groups of 2-H2‚2PF6 with 3. By the same token, there are two
[3]pseudorotaxanes that could be produced during the assembly of
[3]rotaxane 1-H2‚2PF6, viz., “unstoppered” [(DB24C8)2‚2-H2][PF6]2
and the complex where the SST interpenetrates two DB24C8s.
1
to [6-H]+, and (3) the H NMR spectrum of 6-H‚PF6 is
similar to that of its congener with tert-butyl ester groups
and also shows that DB24C8 and the dumbbell compo-
nent are present in a 1:1 ratio. The fact that the ethyl
esters make the termini of a dumbbell bulky enough to
(9) (a) Feiters, M. C.; Fyfe, M. C. T.; Mart´ınez-D´ıaz, M.-V.; Menzer,
S.; Nolte, R. J . M.; Stoddart, J . F.; van Kan, P. J . M.; Williams, D. J .
J . Am. Chem. Soc. 1997, 119, 8119-8120. (b) Ashton, P. R.; Fyfe, M.
C. T.; Glink, P. T.; Menzer, S.; Stoddart, J . F.; White, A. J . P.; Williams,
D. J . J . Am. Chem. Soc. 1997, 119, 12514-12524.
(10) Kocienski, P. J . Protecting Groups; Thieme: Stuttgart, 1994;
pp 192-195.

1940 J . Org. Chem., Vol. 65, No. 7, 2000
Cao et al.
Sch em e 3. Syn th esis of th e Rota xa n es 6-H‚P F 6
a n d 9-H2‚2P F 6, Wh er ein Eith er On e or Tw o
DB24C8 Ma cr or in gs Ar e Con str a in ed To Be Bou n d
Mech a n ica lly on Dia lk yla m m on iu m -Bea r in g
Du m bbells by th e Dieth yl
Sch em e 4. Syn th esis of th e P r ecu r sor Th r ea d lik e
a
Com p ou n d s 10a -H‚P F 6 a n d 10b-H‚P F 6
1,2,3-Tr ia zole-4,5-d ica r boxyla te Moiety
prevent DB24C8 expulsion is also highlighted by the
synthesis of the corresponding [3]rotaxane 9-H2‚2PF6 in
54% yield from the reaction (Scheme 3) of an excess of
DB24C8 with 2-H2‚2PF6 and 8. It should be noted that
the isolated yields obtained for 6-H‚PF6 and 9-H2‚2PF6
are very much larger than those reported7 for the
corresponding rotaxanes constructed with di-tert-butyl
1,2,3-triazole-4,5-dicarboxylates, e.g., 1-H2‚2PF6. This
increase in efficiency arises presumably because of the
enhanced stability of diethyl 1,2,3-triazole-4,5-dicarboxy-
lates compared to their di-tert-butyl-containing conge-
ners.11
a
As defined previously in Figure 2, the units labeled SPACER
are p-C6H4 and (CH2)4 for the compounds in series a and b,
respectively.
Compounds 10a -H‚PF6 and 10b-H‚PF6 (Scheme 4)
were selected as suitable threadlike precursors of the
DB24C8-bis(dialkylammonium) molecular shuttles 5a -
H2‚2PF6 and 5b-H2‚2PF6 (Figure 2), whose two dialkyl-
ammonium centers are separated by p-xylylene and 1,6-
hexamethylene spacers, respectively. These compounds
possess both an active dialkylammonium center, thus
permitting rotaxane formation with DB24C8, and a
latent dialkylammonium group in the form of a Boc-
protected dialkylamine. Two approaches were envisaged
for the syntheses of the respective conjugate bases of
these compounds, i.e., 10a and 10b. The first of these
approaches involved treating the doubly Boc-protected
compounds 12a and 12bssynthesized in several steps
from methyl 4-formylbenzoate and either p-xylylenedi-
amine or 1,6-hexanediamine, respectivelyswith 1 mol
equiv of CF3CO2H. Unfortunately, however, the yields
obtained for this monodeprotection reaction were ex-
tremely inconsistent. Therefore, we preferred a second,
more reliable approach in which one of the amino groups
from bis(dialkylamines) 2 and 13b was protected with
the Boc moiety by reaction with 1 mol equiv of Boc2O. In
all instances, 10a and 10b were obtained in yields close
to the theoretical maximum (50%) using this procedure.
Fortunately, 10a and 10b could be transformed into their
conjugate acids, viz., 10a -H‚PF6 and 10b-H‚PF6, with-
out significant cleavage of the Boc protecting groups
occurring. These transformations took advantage of the
fact that the salts 10a -H‚Cl and 10b-H‚Cl are CH2Cl2
soluble and remained in the organic phase when their
respective conjugate bases were dissolved in CH2Cl2 and
shaken with aqueous HCl.
1
The H NMR spectrum (300.1 MHz, CD2Cl2, 293 K) of
a 1:1 mixture of DB24C8 and the threadlike salt 10a -
H‚PF6 revealed that both components are complexed to
greater than 95%. Armed with this information, we then
carried out the rotaxane-forming reactions depicted in
Scheme 5. The “protected” [2]rotaxanes 14a -H‚PF6 and
(11) Abu-Orabi, S. T.; Atfah, A.; J ibril, I.; Ali, A. A.-S.; Marii, F.
Gazz. Chim. Ital. 1992, 122, 29-33.

Molecular Shuttles
J . Org. Chem., Vol. 65, No. 7, 2000 1941
Sch em e 5. Syn th esis of th e DB248C8-Bis(d ia lk yla m m on iu m ) Molecu la r Sh u ttles 5a -H2‚2P F 6 a n d
a
5b-H2‚2P F 6 by Wa y of th e “P r otected ” Rota xa n es 14a -H‚P F 6 a n d 14b-H‚P F 6
a
As indicated in Figure 2, the units marked SPACER are p-C6H4 and (CH2)4 in the series a and b, respectively.
14b-H‚PF6 were procured in reasonable yields when
their respective [2]pseudorotaxane precursorssi.e., the
complexes [DB24C8‚10a -H][PF6] and [DB24C8‚10b-
H][PF6]swere doubly stoppered by reaction with diethyl
acetylenedicarboxylate (8). To complete the fulfillment
of the protecting group approach, the Boc-protected
amino moieties of 14a -H‚PF6 and 14b-H‚PF6 were
transformed into ammonium centers, via deprotection
and protonation, leading to the formation of the molec-
ular shuttles 5a -H2‚2PF6 and 5b-H2‚2PF6.
Sh u ttle Ch a r a cter iza tion by 1H NMR Sp ectr os-
cop y. As was the case with the first degenerate molec-
1
ular shuttle to be reported,4 the H NMR spectra of both
5a -H2‚2PF6 and 5b -H2‚2PF6 display temperature-
dependent behavior in a range of solvents. By using the
1
data obtained from variable temperature H NMR spec-
troscopic studies, we have been able to determine the free
‡
energies of activation for shuttling (∆Gc ) of the DB24C8
macroring in the rotaxanes 5a -H2‚2PF6 and 5b-H2‚
2PF6.
F igu r e 3. Partial 1H NMR spectrum (400.1 MHz, CD2Cl2, 300
K) of 5a -H2‚2PF6. The descriptors R, â and γsused to classify
DB24C8’s OCH2 protonssare defined in Figure 2. The signals
labeled CH2NH2 (ocpd) and CH2NH2 (unocpd) refer to the
CH2 protons whose neighboring NH2+ groups are and are not
encircled by the DB24C8 macroring, respectively. The reso-
nance labeled with an asterisk results from residual protons
in the solvent.
The 1H NMR spectrum of 5a -H2‚2PF6 in CD2Cl2 at
ambient temperature shows (Figure 3) that the dumbbell
has two distinct halves, as highlighted by the observance
of two peaks for both (1) the CH2 protons linking the
triazole units to the terminal p-xylylenyl rings and (2)
the CH2NH2+ protons. In one of these halves, the dialkyl-
ammonium center is encircled, in characteristic6 fashion,
by the DB24C8 macroring, while, in the other, the
dialkylammonium moiety is free, i.e., not complexed. The
two halves are interconverting very slowly with one
+
+
1
another on the H NMR time scale, as evidenced by the
two different sets of peaks for occupied and unoccupied
dialkylammonium sites. We then decided to study the
shuttle’s dynamic properties in (CD3)2SO, a solvent with

1942 J . Org. Chem., Vol. 65, No. 7, 2000
Cao et al.
Ta ble 1. 1H NMR Sp ectr oscop ic,a Kin etic, a n d Th er m od yn a m ic Da ta Associa ted w ith th e Sh u ttlin g of th e DB24C8
Ma cr or in g in Com p ou n d s 5a -H2‚2P F 6 a n d 5b-H2‚2P F 6 Sid e by Sid e w ith Solven t P r op er ties a n d Sta bility Con sta n ts for
th e [DB24C8‚DBA-H][P F 6] Com p lex a t 298 K
b
‡ c
∆ν
(Hz)
kc
(s-1
Tc
(K)
∆Gc
compound
solvent
)
(kcal mol-1
)
DNd
Kae (M-1
)
5a -H2‚2PF6
5b-H2‚2PF6
5b-H2‚2PF6
5b-H2‚2PF6
5b-H2‚2PF6
5b-H2‚2PF6
(CD3)2SO
(CDCl2)2
CD3NO2
44
28
69
81
47
49
98
62
155
182
106
108
424
353
303
286
275
217
21.3
17.9
14.7
13.8
13.5
10.5
29.8
0.0
0f
>25000
22000
420f
360f
0
2.7
CD3CN
14.1
17.0
26.6
(CD3)2CO
(CD3)2NCDO
a
b
The CH2 protons attached to the triazole unit were used to probe the dynamic processes in all examples. Estimated by using the
coalescence method as described in Sutherland, I. O. Annu. Rep. NMR Spectrosc. 1971, 4, 71-235. Thus, the rate constants for shuttling
(kc) at the coalescence temperature (Tc) were evaluated by employing the approximate expression kc ) π(∆ν)/(2)1/2, where ∆ν is the chemical
shift difference between coalescing signals in the absence of exchange. c The relationship ∆Gc ) -RTc ln(kch/kBTc)swhere R, h and kB
‡
correspond, respectively, to the gas, Planck and Boltzmann constantsswas used to obtain values for the free energy of activation for
shuttling (∆Gc‡) at Tc. Values for the Gutmann donor numbers (DN) were taken from ref 12. e Stability constants for the complex formed
d
between DB24C8 and dibenzylammonium hexafluorophosphate (DBA-H‚PF6) at 298 K. Unless noted otherwise, the values were obtained
by the single-point method6 (percentage errors < 10%). f The values were acquired from ref 6a.
F igu r e 4. Partial variable temperature 1H NMR spectra
(400.1 MHz, (CD3)2SO) of 5a -H2‚2PF6 which highlight the two
signals associated with the CH2-triazole protons. These
signals are well-separated at ambient temperature but gradu-
F igu r e 5. Partial variable temperature 1H NMR spectra
ally merge together at higher temperatures, coalescing ulti-
mately at 424 K.
(400.1 MHz, (CD3)2NCDO) of 5b-H2‚2PF6 which highlight the
CH2-triazole resonance(s). The resonances for the two CH2-
triazole units coalesce at 217 K in this case. These resonances
coalesce at much higher temperatures in solvents with lower
DNs.
a relatively high boiling point (462 K), thus permitting
1H NMR spectra to be recorded at elevated temperatures,
Ta ble 2. Effect of Ad d ed i-P r 2NEt on th e 1H NMR
Sp ectr oscop ic,a Kin etic, a n d Th er m od yn a m ic Da ta
Associa ted w ith th e Sh u ttlin g of th e DB24C8 Ma cr or in g
and a strong propensity to enter into hydrogen-bonding
interactions with dialkylammonium centers, thereby
weakening the DB24C8-dialkylammonium interactions
and making it easier for the DB24C8 macroring to travel
back and forth between the dialkylammonium centers.
The 1H NMR spectrum of 5a -H2‚2PF6 in (CD3)2SO at
ambient temperature shows, like the corresponding
spectrum recorded in CD2Cl2, two distinct singlets for the
CH2 protons located between the triazole stoppers and
the terminal p-xylylenyl rings. However, these two
signals coalesce (Figure 4) at elevated temperatures
because the shuttling process speeds up and occurs at a
b
in 5b-H2‚2P F 6
c
‡ c
i-Pr2NEt
(mol equiv)
∆ν
(Hz)
kc
(s-1
Tc
(K)
∆Gc
)
(kcal mol-1
)
0
1
2
3
4
49
43
42
42
42
108
97
217
257
269
275
275
10.5
12.6
13.3
13.6
13.6
94
94
94
a
b
Probe protons ) CH2-triazole. Concentration ) 6.7 × 10-3
M in (CD3)2NCDO. c Determined as described in the Footnotes to
Table 1.
1
rate similar to the H NMR time scale. By using the data
from the dynamic 1H NMR spectroscopic studies in
We hoped that the reduced steric bulk of the hexa-
methylene spacer in 5b-H2‚2PF6 would make it easier
for DB24C8 to pass between the two dialkylammonium
stations. If this conjecture did indeed hold true, we would
‡
(CD3)2SO, we were able to determine a ∆Gc value for
the shuttling process associated with 5a -H2‚2PF6. The
value obtained (Table 1) is very much larger than the
values we have observed for other molecular shuttles3a
and highlights the difficulty associated with passing a
benzenoid ringswhich originates, in this case, from the
p-xylylenyl spacersthrough the cavity of the DB24C8
macroring.6
‡
be able to determine ∆Gc values at less elevated tem-
peratures, making it possible to study the shuttling
processes in a much wider range of solvents. Gratifyingly,
the 1H NMR spectrum of 5b-H2‚2PF6 in (CD3)2NCDO
at ambient temperature reveals that, in this instance,

Molecular Shuttles
J . Org. Chem., Vol. 65, No. 7, 2000 1943
F igu r e 6. “Proton ferry” in which DB24C8 utilizes noncovalent bonds to transport a proton between two dialkylamine units in
5b-H‚PF6. Also see ref 14.
1
shuttling is faster than the H NMR time scale; only one
signal is observed for the CH2 protons located between
the triazole unit and the terminal p-xylylenyl ring. This
signal broadens out and splits into two separate signals
at lower temperatures (Figure 5). The temperature at
which the signals coalesce (Tc) varies drastically (Table
1) with the nature of the solvent employed for the studies.
For example, Tc for 5b-H2‚2PF6 is 136 K higher in
(CDCl2)2 than it is in (CD3)2NCDO. We noticed that both
intramolecularly14 between dialkylammonium and di-
alkylamine moieties, at elevated temperatures in the
singly deprotonated compound 5b-H‚PF6, by harnessing
ion-dipole interactions between the proton and some of
the DB24C8 macroring’s oxygen atoms.
Con clu sion s
Molecular shuttles, in the shape of two-station
[2]rotaxanes constituted by DB24C8 and bis(dialkylam-
monium) dumbbells, cannot be acquired by the one-pot
reaction between DB24C8, a bulky acetylenedicarboxy-
late, and a bis(dialkylammonium) thread with two azido
groups. Consequently, a novel synthetic approach was
developed for the construction of the molecular shuttles
5a -H2‚2PF6 and 5b-H2‚2PF6, compounds which show
interesting solvent-dependent shuttling phenomena and
highlight the steric issues that are important to the
chemistry of DB24C8 and dialkylammonium ions. The
key to the new synthetic approach was the use of the Boc
protecting group, which masked latent dialkylammonium
sites during rotaxane formation. We believe that protect-
ing group approaches, such as the one delineated here,
Tc and ∆Gc increase as the Gutmann donor number12
‡
(DN) decreases. Put another way, it becomes more
difficult for the DB24C8 macroring to shuttle between
the two dialkylammonium stations as the ability of the
solvent to donate its electrons into noncovalent bonds
decreases and the dialkylammonium centers become less
solvated. Notably, the marked dependence of ∆Gc‡ on the
DN mirrors the reliance6 of the stability constants
(Ka) of the [2]pseudorotaxane complex created from
DB24C8 and dibenzylammonium hexafluorophosphate
(DBA-H‚PF6) on the same set of numbers.
Finally, we examined the effect of base on the shuttling
of the DB24C8 macroring in 5b-H2‚2PF6. It was found
that ∆Gc‡ rises, i.e., it becomes more difficult for shuttling
to occur, when the relative amount of i-Pr2NEt present
is increased (Table 2). Moreover, the ∆Gc‡ values obtained
do not change when the concentration of 5b-H2‚2PF6 is
altered. If we assume that a proton is removed from only
one13 of the two dialkylammonium centers in 5b-H2‚
(13) Dibenzylammonium centers that are interlocked with DB24C8
in [2]rotaxanes are much less acidic than their noninterlocked coun-
terparts (Cantrill, S. J .; Stoddart, J . F. Unpublished observations) and,
thus, are extremely difficult to deprotonate.
(14) The intermediate illustrated in Figure 6 could be further
stabilized by interactions of a “distal” nature to the “bound” proton
from both the secondary amine centers simultaneously. Since these
additional intramolecular interactions are attainable within the
confines of a nine-membered ring, their involvement in an intramo-
lecular proton ferrying mechanism is certainly plausible. This proposed
mechanism will be the subject of further investigations in our labora-
tory.
‡
2PF6, it is not inconceivable thatsbecause the ∆Gc
values are not concentration dependentsDB24C8 acts as
a “proton ferry” (Figure 6) which transfers a proton
(12) Gutmann, V. Electrochim. Acta 1976, 21, 661-670.

1944 J . Org. Chem., Vol. 65, No. 7, 2000
Cao et al.
of N,N′-bis(4-azidomethylbenzyl)-p-xylylenediamine7a (2, 8.00
g, 19.0 mmol), Boc2O (4.10 g, 19.0 mmol), and DMAP (0.10 g,
0.8 mmol) in CH2Cl2 (200 mL) was stirred at 20 °C for 3 h.
The solvent was removed under reduced pressure and the
residue chromatographed (SiO2, EtOAc-n-C6H14, 1:4) to pro-
vide the amine 10a as a thick oil (4.90 g, 50%): 1H NMR (400.1
MHz, CDCl3, 300 K) δ ) 1.49 (s, 9H), 3.80 (s, 2H), 3.82 (s,
2H), 4.30-4.45 (br m, 8H), 7.14-7.49 (m, 12H); 13C NMR
(100.6 MHz, CDCl3, 300 K) δ ) 28.4, 49.0 (br), 52.8, 54.5, 80.1,
128.3, 128.4, 128.6, 134.0, 139.2, 140.4, 155.9; MS (FAB) m/z
) 527 [M + H]+. A solution of 10a (0.90 g, 1.7 mmol) in
CH2Cl2 (50 mL) was washed with 10% aqueous HCl. The
organic phase was concentrated, then the residue was dis-
solved in Me2CO-H2O (1:1) and saturated aqueous NH4PF6
was added. The Me2CO was evaporated off under reduced
pressure, then the H2O was decanted off from the oil formed.
This oil was washed further with H2O and vacuum-dried to
provide the title compound (1.00 g, 87%): 1H NMR (400.1 MHz,
CDCl3, 300 K) δ ) 1.42 (s, 9H), 4.12-4.44 (br m, 12H), 6.95-
7.60 (m, 12H); 13C NMR (100.6 MHz, CDCl3, 300 K) δ ) 28.3,
49.2 (br), 51.4 (br), 53.9, 54.3, 81.2, 127.7, 128.0, 128.2, 128.5,
129.0, 129.2, 130.3, 134.5, 137.6, 156.2; HRMS (LSI) C29H35N8O2
[M - PF6]+ calcd m/z ) 527.2911, found m/z ) 527.2882.
{[2]-[N-(4-((4,5-Biset h oxyca r b on yl-1,2,3-t r ia zo-1-yl)-
methyl)benzyl)-N-(4-(N′-(4-((4,5-bisethoxycarbonyl-1,2,3-tri-
a zo1-yl)m eth yl)ben zyl)-N′-(ter t-bu toxyca r bon yl)a m in o-
methyl)benzyl)ammonium][dibenzo[24]crown-8]rotaxane}
Hexa flu or op h osp h a te (14a -H‚P F 6). DB24C8 (0.55 g, 1.2
mmol), 10a -H‚PF6 (0.41 g, 0.6 mmol), and diethyl acetylene-
dicarboxylate (8, 0.20 g, 1.2 mmol) were heated under reflux
for 2 d in anhydrous CH2Cl2 (10 mL). The solvent was
evaporated off in vacuo and the residue was chromatographed
(SiO2, Me2CO-n-C6H14, 1:1), yielding the title compound as a
white solid (0.30 g, 34%): 1H NMR (360.1 MHz, CD3CN, 300
K) δ ) 1.22-1.33 (m, 12H), 1.38 (s, 9H), 3.54 (br s, 8H), 3.74
(br, 8H), 4.00 (br, 8H), 4.14-4.38 (m, 12H), 4.66 (br, 4H), 5.59
(s, 2H), 5.72 (s, 2H), 6.70-6.80 (m, 8H), 7.02 (d, J ) 8 Hz,
4H), 7.18-7.25 (m, 4H), 7.30 (d, J ) 8 Hz, 4H), 7.56 (br, 2H);
13C NMR (90.6 MHz, CD3CN, 300 K) δ ) 13.4, 13.6, 14.1, 14.3,
14.8, 15.0, 28.5, 29.6, 30.9, 52.8, 53.0, 53.9, 54.2, 54.9, 62.7,
64.0, 68.7, 71.0, 71.4, 80.7, 113.2, 121.1, 122.0, 122.9, 123.0,
128.0, 128.9, 129.0, 129.9, 130.4, 130.8, 131.0, 131.4, 131.8,
133.2, 134.5, 136.3, 139.8, 140.1, 140.6, 141.0, 148.2, 156.4,
159.1, 159.4, 161.1, 161.2; HRMS (FAB) C69H87N8O18 [M -
PF6]+ calcd m/z ) 1315.6138, found m/z ) 1315.6147.
should be generally applicable to problems in contempo-
rary synthetic supramolecular chemistry,5c where specific
molecular recognition interactions need to be turned on
and off with precision during the construction of intricate
molecular compounds using prior supramolecular as-
sistance.
Exp er im en ta l Section
Gen er a l P r oced u r es. Anhydrous CH2Cl2 and MeCN were
obtained by distillation from CaH2 under N2. Anhydrous THF
was obtained by distillation from Na-Ph2CO under N2.
Column chromatography was carried out using silica gel 60F
(Merck 9385, 0.040-0.063 mm). Melting points are uncor-
1
rected. H NMR spectra were recorded at either 300.1, 360.1,
or 400.1 MHz. The deuterated solvent was used as the lock,
while either the solvent’s residual protons or TMS was
employed as the internal standard. 13C NMR spectra were
recorded at either 75.5, 90.6 or 100.6 MHz. Accurate mass
measurements by liquid secondary ion (LSI) mass spectrom-
etry were performed using a m-nitrobenzyl alcohol matrix and
employing narrow range voltage scanning at a resolution of
6000 with either poly(ethylene glycol) or cesium iodide as
reference compounds. Accurate mass measurements by fast
atom bombardment (FAB) mass spectrometry were performed
using a krypton primary atom beam in conjunction with a
m-nitrobenzyl alcohol matrix.
{[2]-[Bis(4-((4,5-b iset h oxyca r b on yl-1,2,3-t r ia zo-1-yl)-
m et h yl)b en zyl)a m m on iu m ][d ib en zo[24]cr ow n -8]r ot a x-
a n e} Hexa flu or op h osp h a te (6-H‚P F 6). Bis(4-azidometh-
ylbenzyl)ammonium hexafluorophosphate7a (7-H‚PF6, 0.22 g,
0.49 mmol) was dissolved in a CH2Cl2 (2 mL) solution of
DB24C8 (0.70 g, 1.57 mmol), then the whole was treated with
diethyl acetylenedicarboxylate (8, 0.28 g, 1.65 mmol) and
heated under reflux for 4 d. After cooling to 20 °C and solvent
evaporation under reduced pressure, the residue was subjected
to column chromatography (SiO2, Me2CO-n-C6H14, 3:7 to 1:1),
furnishing the title compound as a yellow oil (0.41 g, 77%):
1H NMR (300.1 MHz, CDCl3, 293 K) δ ) 1.35 (t, J ) 6 Hz,
6H), 1.40 (t, J ) 6 Hz, 6H), 3.42 (s, 8H), 3.72 (m, 8H), 4.05 (m,
8H), 4.40 (q, J ) 6 Hz, 4H), 4.43 (q, J ) 6 Hz, 4H), 4.56 (m,
4H), 5.69 (s, 4H), 6.71 (m, 4H), 6.85 (m, 4H), 7.12 (d, J ) 8
Hz, 4H), 7.23 (d, J ) 8 Hz, 4H), 7.60 (br, 2H); 13C NMR (75.5
MHz, CDCl3, 293 K) δ ) 13.9, 14.2, 52.1, 53.2, 62.1, 63.2, 68.1,
70.2, 70.6, 112.7, 121.8, 128.3, 129.8, 129.9, 132.1, 135.3, 140.5,
147.2, 158.2, 160.2; HRMS (LSI) C56H70N7O16 [M - PF6]+ calcd
m/z ) 1096.4879, found m/z ) 1096.4886.
{[2]-[N ,N ′-Bis(4-((4,5-b ise t h oxyca r b on yl-1,2,3-t r ia -
zo-1-yl)m eth yl)ben zyl)-p-xylylen ed ia m m on iu m ][d iben -
zo[24]cr ow n -8]r ota xa n e} Bis(h exa flu or op h osp h a te)(5a -
H2‚2P F 6). The “protected” rotaxane 14a -H‚PF6 (0.30 g, 0.2
mmol) was dissolved in CDCl3 (5 mL), before being treated
with CF3CO2H (0.5 mL). The reaction was monitored by 1H
NMR spectroscopy, and after 3 h, the solution was concen-
trated and the residue dissolved in CH2Cl2. The organic
extracts were washed with saturated aqueous NH4PF6, dried
(MgSO4), concentrated, and chromatographed (SiO2, CH2Cl2-
MeOH, 19:1) to furnish the title compound as a white foamlike
solid (0.17 g, 55%): mp 69-72 °C; 1H NMR (400.1 MHz, CDCl3,
300 K) δ ) 1.29-1.37 (m, 12H), 3.47 (s, 8H), 3.73-3.75 (m,
8H), 3.79 (s, 4H), 4.04 (br m, 8H), 4.33-4.39 (m, 8H), 4.56-
4.70 (m, 4H), 5.64 (s, 2H), 5.75 (s, 2H), 6.71-6.74 (m, 4H),
6.83-6.86 (m, 4H), 7.07 (d, J ) 8 Hz, 2H), 7.22-7.30 (m, 8H),
7.35 (d, J ) 8 Hz, 2H), 7.48-7.66 (br, 4H); 13C NMR (90.6 MHz,
CD3CN, 300 K) δ ) 13.7, 14.0, 52.1, 52.4, 53.0, 53.4, 61.8, 61.9,
62.9, 63.1, 67.9, 70.0, 70.5, 112.5, 121.5, 128.0, 128.5, 128.7,
129.0, 129.6, 129.8, 130.3, 132.0, 132.9, 135.1, 140.0, 140.2,
140.3,147.2,158.0,158.3,160.0,160.1;HRMS (FAB)C64H80N8O16
[M - 2PF6]+ calcd m/z ) 1216.5692, found m/z ) 1216.5673.
N,N′-Bis(ter t-bu toxyca r bon yl)-N,N′-bis(4-h yd r oxym e-
th ylben zyl)-1,6-h exa n ed ia m in e (11b). 1,6-Hexanediamine
(2.20 g, 18.6 mmol) and methyl 4-formylbenzoate (6.10 g, 37.2
mmol) were heated together in refluxing PhMe (250 mL) for
30 min. The reaction mixture was cooled to 20 °C and the
solvent was evaporated off in vacuo to yield 1,6-bis(4-meth-
oxycarbonylbenzylidene)hexanediamine as a white solid (7.74
{[3]-[Dib en zo[24]cr ow n -8][N,N′-b is(4-((4,5-b iset h ox-
ca r b on yl-1,2,3-t r ia zo-1-yl)m et h yl)b en zyl)-p -xylylen ed i-
a m m on iu m ][d iben zo[24]cr ow n -8]r ota xa n e} Bis(h exa flu -
or op h osp h a te) (9-H2‚2P F 6). N,N′-Bis(4-azidomethylbenzyl)-
p-xylylenediammonium bis(hexafluorophosphate)7a (2-H2‚
2PF6, 0.20 g, 0.28 mmol) was dissolved in a MeCN (2 mL)
solution of DB24C8 (0.63 g, 1.39 mmol). The solvents were
removed under reduced pressure, and the residue was taken
up in CH2Cl2. The resulting cloudy solution was treated with
diethyl acetylenedicarboxylate (8, 0.24 g, 1.40 mmol), before
being heated under reflux for 4 d. Upon cooling, the solvents
were evaporated off in vacuo, and the residue was subjected
to column chromatography (SiO2, Me2CO-n-C6H14, 1:1 to 4:1),
furnishing the title compound as a white solid (0.29 g, 54%):
1H NMR (300.1 MHz, CDCl3, 293 K) δ ) 1.28 (t, J ) 6 Hz,
6H), 1.37 (t, J ) 6 Hz, 6H), 3.48 (m, 8H), 3.73 (br, 24H), 3.90
(m, 8H), 4.07 (m, 8H), 4.29 (br m, 8H), 4.49 (m, 4H), 4.69 (m,
4H), 5.64 (s, 4H), 6.65 (m, 8H), 6.72 (m, 8H), 7.02 (s, 4H), 7.04
(d, J ) 9 Hz, 4H), 7.26 (d, J ) 9 Hz, 4H), 7.44 (br, 4H); 13C
NMR (75.5 MHz, CDCl3, 293 K) δ ) 13.8, 14.1, 51.8, 52.0, 53.1,
62.0, 63.0, 67.6, 70.2, 70.7, 112.3, 121.2, 128.0, 129.4, 129.8,
132.0, 132.6, 134.9, 139.5, 147.2, 158.1, 159.5; HRMS (LSI)
C
88H112F6N8O24P [M - PF6]+ calcd m/z ) 1809.7431, found m/z
) 1809.7401.
N-(4-Azid om eth ylben zyl)-N-(4-(N′-(4-a zid om eth ylben -
zyl)-N′-(ter t-b u t oxyca r b on yl)a m in om et h yl)b en zyl)a m -
m on iu m Hexa flu or op h osp h a te (10a -H‚P F 6). A solution
1
g, 100%): mp 102-104 °C; H NMR (360.1 MHz, CDCl3, 300

Molecular Shuttles
J . Org. Chem., Vol. 65, No. 7, 2000 1945
K) δ ) 1.28-1.32 (m, 4H), 1.58-1.68 (m, 4H), 3.52 (t, J ) 8
Hz, 4H), 3.81 (s, 6H), 7.66 (d, J ) 8 Hz, 4H), 7.95 (d, J ) 8 Hz,
4H), 8.19 (s, 2H); 13C NMR (90.6 MHz, CDCl3, 300 K) δ ) 27.1,
30.7, 52.2, 61.8, 127.8, 129.8, 131.6, 140.2, 159.8, 166.6; MS
(FAB) m/z ) 409 [M + H]+. This solid was suspended in MeOH
(300 mL), then the mixture was heated under reflux and
treated with NaBH4 (4 × 1.40 g, 4 × 37.0 mmol) over 1 h. The
reaction mixture was cooled to 20 °C and treated cautiously
with 2 M HCl. The solvents were evaporated off under reduced
pressure, then the residue was partitioned between CH2Cl2
and 3 M NaOH. The aqueous phase was extracted with
additional portions of CH2Cl2, then the combined organic
extracts were dried (MgSO4), filtered, and concentrated to yield
N,N′-bis(4-methoxycarbonylbenzyl)-1,6-hexanediamine as a
white solid (7.30 g, 93%): mp 99-100 °C; 1H NMR (360.1 MHz,
CDCl3, 300 K) δ ) 1.28-1.46 (m, 8H), 2.56 (t, J ) 7 Hz, 4H),
3.79 (s, 4H), 3.86 (s, 6H), 7.34 (d, J ) 8 Hz, 4H), 7.94 (d, J )
8 Hz, 4H); 13C NMR (90.6 MHz, CDCl3, 300 K) δ ) 27.1, 30.0,
49.3, 51.9, 53.6, 127.8, 128.7, 129.6, 145.9, 166.9; MS (FAB)
m/z ) 413 [M + H]+. A solution of this diamine (7.00 g, 17.0
mmol), Boc2O (7.50 g, 34.4 mmol), and DMAP (0.10 g, 0.9
mmol) in CH2Cl2 (300 mL) was stirred for 3 h at 20 °C. The
solution was washed successively with 10% aqueous HCl and
saturated aqueous NaHCO3 and dried (MgSO4). Filtration,
solvent evaporation and column chromatography (SiO2, EtOAc-
n-C6H14, 3:7) furnished N,N′-bis(tert-butoxycarbonyl)-N,N′-bis-
(4-methoxycarbonylbenzyl)-1,6-hexanediamine as a thick oil
as a colorless oil (4.80 g, 98%): 1H NMR (360.1 MHz, CDCl3,
300 K) δ ) 1.15-1.26 (br, 4H), 1.38-1.52 (br m, 22H), 3.03-
3.22 (br, 4H), 4.30 (s, 4H), 4.40 (br, 4H), 7.21-7.28 (m, 8H);
13C NMR (90.6 MHz, CDCl3, 300 K) δ ) 14.1, 21.0, 26.5, 28.4,
46.6, 49.5, 50.1, 60.3, 79.6, 127.4, 128.0, 128.3, 134.1, 139.0,
156.2; MS (FAB) m/z ) 607 [M + H]+; C32H46N8O4 (606.8)
calcd: C, 63.34; H, 7.64; N, 18.47. Found: C, 63.20; H, 7.58;
N, 18.20.
N,N′-Bis(4-azidom eth ylben zyl)-1,6-h exan ediam in e (13b).
CF3CO2H (5 mL) was added to a CHCl3 (100 mL) solution of
12b (4.70 g, 7.8 mmol) and the whole was stirred at 20 °C for
20 h. The solution was concentrated in vacuo and the residue
was partitioned between 3 M NaOH and CHCl3. The aqueous
phase was extracted further with CHCl3, then the combined
organic extracts were dried, filtered, and concentrated to afford
13b as a colorless oil (3.10 g, 99%): 1H NMR (360.1 MHz,
CDCl3, 300 K) δ ) 1.29-1.33 (m, 4H), 1.45-1.52 (m, 4H), 2.59
(t, J ) 7 Hz, 4H), 3.76 (s, 4H), 4.29 (s, 4H), 7.24 (d, J ) 8 Hz,
4H), 7.31 (d, J ) 8 Hz, 4H); 13C NMR (90.6 MHz, CDCl3, 300
K) δ ) 27.2, 30.0, 49.4, 53.6, 54.5, 128.2, 128.5, 133.8, 140.8;
MS (FAB) m/z ) 407 [M + H]+.
N-(4-Azid om eth ylben zyl)-N-(6-(N′-(4-a zid om eth ylben -
zyl)-N′-(ter t-b u t oxyca r b on yl)a m in oh exyl))a m m on iu m
Hexa flu or op h osp h a te (10b-H‚P F 6). By employing a pro-
cedure similar to that described above for 10a , 13b (3.10 g,
7.6 mmol), Boc2O (1.60 g, 7.6 mmol), and DMAP (0.05 g, 0.4
mmol) were reacted together to provide, after column chro-
matography (SiO2, EtOAc), 10b as a thick oil (1.70 g, 44%):
1H NMR (360.1 MHz, CDCl3, 300 K) δ ) 1.19-1.28 (m, 6H),
1.34-1.49 (m, 11H), 2.57 (t, J ) 7 Hz, 2H), 3.05-3.20 (br m,
2H), 3.76 (s, 2H), 4.29 (s, 4H), 4.40 (br, 2H), 7.24 (m, 6H), 7.31
(d, J ) 8 Hz, 2H); 13C NMR (90.6 MHz, CDCl3, 300 K) δ )
26.7, 27.0, 28.4, 30.0, 48.3 (br), 49.4, 53.7, 54.4, 54.5, 128.3,
128.4, 128.5, 133.8, 134.1, 140.8, 155.4; MS (FAB) m/z ) 507
[M + H]+; C27H38N8O2 (506.6) calcd: C, 64.01; H, 7.56; N, 22.12.
Found: C, 63.81; H, 7.34; N, 21.84. By using the protocol
described above for the synthesis of 10a -H‚PF6, 10b-H‚PF6
was obtained as an oil (1.67 g, 100%) from 10b (1.30 g, 2.6
mmol): 1H NMR (360.1 MHz, CDCl3, 300 K) δ ) 1.11-1.45
(m, 15H), 1.66 (br, 2H), 2.98 (br, 2H), 3.07 (t, J ) 7 Hz, 2H),
4.18 (s, 2H), 4.28-4.34 (m, 6H), 7.16-7.26 (m, 4H), 7.32 (d, J
) 8 Hz, 2H), 7.43 (d, J ) 8 Hz, 2H); 13C NMR (90.6 MHz,
CDCl3, 300 K) δ ) 25.3, 25.7, 25.8, 27.0, 28.3, 30.9, 47.6, 50.3,
51.7, 54.0, 54.4, 80.4, 115.0, 127.5, 128.5, 129.0, 129.3, 130.5,
134.3, 137.6, 138.5, 156.2; MS (FAB) m/z ) 507 [M - PF6]+;
1
that eventually solidified (10.40 g, 100%): mp 98-99 °C; H
NMR (360.1 MHz, CDCl3, 300 K) δ ) 1.12-1.24 (br, 4H), 1.30-
1.55 (br m, 22H), 3.07-3.20 (br m, 4H), 3.87 (s, 6H), 4.37-
4.49 (br, 4H), 7.16-7.27 (br, 4H), 7.95 (d, J ) 8 Hz, 4H); 13C
NMR (90.6 MHz, CDCl3, 300 K) δ ) 14.1, 21.0, 26.5, 27.7, 28.0,
28.3, 29.1, 46.9, 49.7, 50.5, 51.2, 52.0, 52.8, 60.3, 79.7, 126.7,
127.3, 128.9, 129.7, 130.6, 144.2, 156.8, 166.8; MS (FAB) m/z
) 514 [M - Boc]+. LiAlH4 (3 × 0.80 g, 3 × 20.0 mmol) was
added to an anhydrous THF (300 mL) solution of this oil, then
the mixture was heated under reflux for a further 30 min.
When the reaction mixture had cooled to 20 °C, 2 M HCl was
added to adjust the pH to less than 2. The solvents were
removed in vacuo, and the residue was partitioned between
H2O and CH2Cl2. After further extraction of the aqueous phase
with CH2Cl2, the combined organic extracts were dried (Mg-
SO4), filtered, and concentrated to afford 11b as a thick oil
that eventually solidified (8.10 g, 86%): mp 69-70 °C; 1H NMR
(360.1 MHz, CDCl3, 300 K) δ ) 1.14 (br s, 4H), 1.34-1.52 (br,
22H), 2.63 (br s, 2H), 2.99-3.15 (br, 4H), 4.35 (s, 4H), 4.61 (s,
4H), 7.15 (d, J ) 8 Hz, 4H), 7.26 (d, J ) 8 Hz, 4H); 13C NMR
(90.6 MHz, CDCl3, 300 K) δ ) 26.5, 27.7, 28.4, 29.1, 46.4, 49.5,
50.1, 53.4, 64.7, 79.6, 126.2, 127.0, 127.2, 127.7, 127.9, 137.7,
140.0, 155.6, 156.0; MS (FAB) m/z ) 558 [M + H]+.
C
27H39F6N8O2P (652.6) calcd: C, 49.69; H, 6.02; N, 17.17.
Found: C, 49.12; H, 6.00; N, 16.75.
{[2]-[N-(4-((4,5-biseth oxyca r bon yl-1,2,3-tr ia zo-1-yl)m e-
thyl)benzyl)-N-(6-(N′-(4-((4,5-bisethoxycarbonyl-1,2,3-triazo-1-yl)-
methyl)benzyl)-N′-(tert-butoxycarbonyl)aminohexyl))ammo-
n iu m ][d iben zo[24]cr ow n -8]r ota xa n e} Hexa flu or op h os-
p h a te (14b-H‚P F 6). DB24C8 (0.70 g, 1.5 mmol), 10b-H‚PF6
(0.50 g, 0.7 mmol), and diethyl acetylenedicarboxylate (8, 0.40
g, 2.3 mmol) were heated under reflux for 3 d in anhydrous
CH2Cl2 (10 mL). The solution was concentrated in vacuo and
the residue chromatographed (SiO2, Me2CO-n-C6H14, 7:3) to
yield the title compound as white solid (0.32 g, 29%): mp 62-
64 °C; 1H NMR (360.1 MHz, CDCl3, 300 K) δ ) 0.89 (br s,
4H), 1.17-1.45 (m, 25H), 2.85-3.02 (br m, 4H), 3.30-3.36 (m,
4H), 3.50-3.57 (m, 4H), 3.75 (s, 8H), 3.94-4.04 (m, 4H), 4.06-
4.16 (m, 4H), 4.22-4.41 (m, 10H), 4.53-4.62 (br m, 2H), 5.65
(s, 2H), 5.72 (s, 2H), 6.73-6.82 (m, 8H), 7.00-7.21 (m, 8H),
7.29 (d, J ) 8 Hz, 2H); 13C NMR (90.6 MHz, CDCl3, 300 K) δ
) 13.5, 13.8, 25.7, 28.0, 30.5, 46.1, 48.6, 51.3, 52.9, 53.1, 61.5,
61.6, 62.7, 62.9, 67.8, 69.8, 70.3, 79.3, 112.4, 121.4, 127.8, 129.7,
130.0, 132.6, 132.7, 134.9, 139.9, 140.0, 147.0, 157.8, 158.0,
159.9; HRMS (FAB) C67H91N8O18 [M - PF6]+ calcd m/z )
1295.6451, found m/z ) 1295.6494.
N,N′-Bis(ter t-bu toxyca r bon yl)-N,N′-bis(4-a zid om eth yl-
ben zyl)-1,6-h exa n ed ia m in e (12b). NCS (7.70 g, 58.0 mmol)
and PPh3 (15.00 g, 58.0 mmol) were stirred in anhydrous THF
(300 mL) for 15 min, then the whole was treated with a THF
(100 mL) solution of 11b (8.00 g, 14.0 mmol). The reaction
mixture was stirred at 20 °C overnight, then the white solid
generated was collected and washed with THF. The combined
THF solutions were evaporated, and the residue was chro-
matographed (SiO2, EtOAc-n-C6H14, 1:4), affording N,N′-bis-
(tert-butoxycarbonyl)-N,N′-bis(4-chloromethylbenzyl)-1,6-hex-
anediamine as a thick oil (4.80 g, 56%): 1H NMR (360.1 MHz,
CDCl3, 300 K) δ ) 1.17-1.27 (br m, 4H), 1.32-1.49 (br, 22H),
3.02-3.19 (br m, 4H), 4.32-4.44 (br, 4H), 4.55 (s, 4H), 7.15-
7.23 (br, 4H), 7.31 (d, J ) 8 Hz, 4H); 13C NMR (90.6 MHz,
CDCl3, 300 K) δ ) 14.1, 21.0, 22.6, 26.6, 28.4, 31.5, 46.0, 46.5,
49.5, 50.1, 79.6, 127.4, 127.9, 128.7, 136.3, 138.8, 156.0; MS
(FAB) m/z ) 594 [M]+; C32H46Cl2N2O4 (593.6) calcd: C, 64.75;
H, 7.81; N, 4.72. Found: C, 64.79; H, 7.87; N, 4.57. This
dichloride was heated under reflux with NaN3 (1.00 g, 15.4
mmol) in Me2CO (200 mL). After 20 h, an additional portion
of NaN3 (1.00 g, 15.4 mmol) was added and refluxing was
continued for another 24 h. After cooling to 20 °C, the residual
salts were filtered off and washed with CH2Cl2. The combined
solutions were evaporated to dryness, and the residue was
chromatographed (SiO2, EtOAc-n-C6H14, 3:7) to provide 12b
{[2]-[N ,N ′-Bis(4-((4,5-b ise t h oxyca r b on yl-1,2,3-t r ia -
zo-1-yl)m eth yl)ben zyl)-1,6-h exa n ed ia m m on iu m ][d iben -
zo[24]cr own -8]r otaxan e} Bis(h exaflu or oph osph ate) (5b-
H2‚2P F 6). By employing a procedure similar to that described
for the synthesis of 5a -H2‚2PF6, 14b-H‚PF6 (0.30 g, 0.2 mmol)
was reacted with CF3CO2H (0.5 mL) in CDCl3 (5 mL) over 5
h. Following a comparable workup and chromatography (SiO2,

1946 J . Org. Chem., Vol. 65, No. 7, 2000
Cao et al.
CH2Cl2-MeOH, 94:6), the title compound was obtained as a
white solid (0.07 g, 23%): mp 65-67 °C; 1H NMR (400.1 MHz,
CDCl3, 300 K) δ ) 0.89 (br m, 2H), 1.01 (br m, 2H), 1.20-1.49
(m, 16H), 2.79-2.84 (br m, 2H), 2.89-2.98 (br, 2H), 3.29-3.31
(m, 4H), 3.53-3.56 (m, 4H), 3.74 (s, 8H), 3.96-4.00 (m, 4H),
4.14-4.19 (m, 4H), 4.27-4.41 (m, 8H), 4.57 (br, 2H), 4.98 (br,
2H), 5.66 (s, 2H), 5.71 (s, 2H), 6.77-6.83 (m, 8H), 7.10-7.18
(br m, 4H), 7.21 (d, J ) 8 Hz, 2H), 7.38-7.42 (m, 4H); 13C NMR
(90.6 MHz, CDCl3, 300 K) δ ) 13.7, 14.0, 21.4, 24.3, 25.4, 25.5,
26.0, 26.1, 48.5, 48.9, 51.5, 53.2, 53.4, 61.8, 62.0, 63.0, 68.1,
70.0, 70.5, 112.7, 121.7, 128.0, 128.5, 129.7, 130.0, 130.3, 132.6,
133.1, 135.0, 140.1, 140.4, 147.2, 158.0, 158.2, 160.0, 160.1;
HRMS (FAB) C62H84N8O18 [M - 2PF6]+ calcd m/z ) 1196.6005,
found m/z ) 1196.5976.
Ack n ow led gm en t. This research was sponsored by
the University of California, Los Angeles, in the USA.
In the UK, funding was provided by the Nuffield
Foundation, the Zeneca Strategic Research Fund and
the University of Birmingham.
J O991397W