The in, out asymmetric pseudo-triple helical form of a D3h diaza-macropentacycle

Article abstract of DOI:10.1021/jo701984z

(Chemical Equation Presented) A sterically encumbered [N₂S ₆] macropentacycle (5) related to diazamacrobicycles and cryptands has been synthesized in 53% yield by the [1+1] condensation reaction between functionalized macrocyclic and

Full text of DOI:10.1021/jo701984z

The in, out Asymmetric Pseudo-Triple Helical Form of a D3h
Diaza-Macropentacycle
Cle´ment Bonnot,† Jean-Claude Chambron,*,† Enrique Espinosa,†,‡ and Roland Graff§
Laboratoire d’Inge´nierie Mole´culaire pour la Reconnaissance et la Se´paration des Me´taux et des
Mole´cules (ICMUB, UMR CNRS no 5260) UniVersite´ de Bourgogne, 9 AVenue Alain SaVary, 21078 Dijon,
France, and SerVice Commun de RMN, Institut de Chimie (UMR CNRS no 7177), UniVersite´ Louis
Pasteur, 1 Rue Blaise Pascal, 67000 Strasbourg, France
jean-claude.chambron@u-bourgogne.fr
ReceiVed September 12, 2007
A sterically encumbered [N2S6] macropentacycle (5) related to diazamacrobicycles and cryptands has
been synthesized in 53% yield by the [1+1] condensation reaction between functionalized macrocyclic
and macrotricyclic precursors. A macrononacycle (18) resulting from the corresponding [2+2] condensation
was isolated in 7% yield from the reaction mixture. Both compounds showed broad features in their
1
room-temperature H NMR spectra, but their maximal average symmetry (D3h and D2h, respectively)
was achieved at high temperature (380 K). At low temperature (200 K, CD2Cl2 solution), the
macropentacycle is “frozen” to a single asymmetric (C1) conformation on the 1H NMR time scale, which
has also the molecular structure observed in the solid state by X-ray crystallography: pseudo-triple helical
(*C3) shape, io (in, out) form resulting from the endo/exo configuration at the nitrogen bridgehead atoms,
and similar orientations of the tosyl substituents. The solution dynamics of the molecule can be described
by coupled bridgehead nitrogen inversion, triple helix symmetrization, and reversal of triple helix
handedness, with ∆Gcq ) 54.2 kJ mol-1 in CD2Cl2 at 300 K. Adoption of the io form by macropentacycle
5 in the crystal and in solution at low-temperature most probably results from the steric crowding and
strain introduced by the [15]ane-N2S2 macrocyclic bridging subunits.
Introduction
Macrobicyclic diamines are hollow molecules that can exist
in three different forms, depending on the orientation of the
lone pairs of the bridgehead nitrogen atoms with respect to the
central cavity. As shown schematically in Figure 1, these forms
FIGURE 1. Homeomorphic isomers of diazamacrobicycles.
are the symmetrical (in, in) (ii) for inside and (out, out) (oo)
for outside orientation of the lone pairs, and the degenerate
unsymmetrical (in, out) (io), for opposite orientations of the
lone pairs. They represent the so-called homeomorphic iso-
mers.1,2
† Universite´ de Bourgogne.
‡ Current address: Laboratoire de Cristallographie et Mode´lisation des
Mate´riaux Mine´raux et Biologiques (LCM3B, UMR CNRS no 7036), Universite´
Henri Poincare´-Nancy 1, boulevard des Aiguillettes, 54506 Vandoeuvre-le`s-
Nancy, France.
§ Universite´ Louis Pasteur.
10.1021/jo701984z CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/29/2007
868
J. Org. Chem. 2008, 73, 868-881

In, out Pseudohelix of a Diaza-Macropentacycle
FIGURE 3. Examples of cryptands (2, 4) and prismand 3.
When not hindered, interconversions between the ii, io (oi),
and oo forms proceed via nitrogen inversion11 rather than
homeomorphic isomerization.2 The nitrogen inversion free
energy barrier of [7.3.1]-1 has been determined by variable
temperature 13C NMR spectroscopy: ∆G218q ) 39.3 kJ mol-1 3
,
FIGURE 2. Preferred forms of small ring 1,(k+2)-diazabicyclo[k.l.m]-
which is at the upper limit of the range observed for simple
amines12 but much lower than the values obtained for systems
with CNC angle strain, such as aziridines13 or 7-azanorbor-
nanes14 and related systems.15 A similar value had been
measured for larger [8.8.8]-1 at 178 K,1b but the corresponding
conformational change was later suggested to involve, rather
than nitrogen inversion, torsional motions around single bonds
alkanes.
The prototypical macrobicyclic diamines are the 1,(k+2)-
diazabicyclo[k.l.m]alkanes [k.l.m]-1, with selected examples
shown in Figure 2.2 With the exception of [2.2.2]-1 (DABCO)
and [3.3.3]-1 (the oo form of the latter has flattened bridgehead
nitrogens), symmetrical systems (k ) l ) m g 4) usually exist
in the ii form, which minimizes interchain nonbonded interac-
tions.1,2 A transition from the symmetrical oo to the unsym-
metrical io form was found in the series of unsymmetrical
tetrahydropyrimidine derivatives [k.3.1]-1, for which the frontier
lies at k ) 6: [5.3.1]-1 and [7.3.1]-1 exist exclusively under
the oo and io forms, respectively, no matter if they are in the
gas phase or in solution, whereas [6.3.1]-1 is a mixture of both,
the oo form being favored in solution by comparison with the
gas phase, because hydrogen bonding with the solvent (CDCl3)
stabilizes the more accessible exo sites.3
Other classical macrobicyclic diamines are the original
cryptands [k.l.m]-2, where k, l, and m are the number of oxygen
atoms in the chains (Figure 3).4 The smallest member of the
series [1.1.1]-2 as well as its next higher symmetrical homologue
[2.2.2]-2 strongly favor the ii form, as shown by protonation
studies,5 molecular mechanics6 and dynamics7 calculations, and
X-ray diffraction.8 However, the latter molecule is more flexible
and shows facile in, out interconversion.5b Prismand 3, which
is an extended analogue of [4.4.4]-1, also exists in the ii form.9
Replacing the triethylamine-derived bridgeheads of [2.2.2]-2 by
o-benzylamine produces cryptand 4a, which was shown to exist
mainly in the oo form.10a
q
of the bridges, as demonstrated for cryptands [1.1.1]-2 (∆G208
) 41 kJ mol-1 16 and [2.2.2]-2 (∆G148q ) 27.2 kJ mol-1 4c
) ) and
q
prismand 3 (∆G178 ) 33.4 kJ mol-1).9
Macrobicycles showing the in, out isomerism are not limited
to diamines. Systems containing N and C,17 C-only,18 and
P-only19 bridgeheads have been described. As the bridgehead
atom cannot normally invert in the latter cases,19c when sterically
possible, interconversion proceeds via homeomorphic isomer-
(10) (a) Atkinson, I. M.; Lindoy, L. F.; Matthews, O. A.; Meehan, G.
V.; Sobolev, A. N.; White, A. H. Aust. J. Chem. 1994, 47, 1155-1162. (b)
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J. Org. Chem, Vol. 73, No. 3, 2008 869

Bonnot et al.
SCHEME 1. Strategies for the Construction of
Macrobicycles and Higher Order Macropolycycles
ization, which can be described as “the passage of any one chain
through the ring formed by the other two chains and the
bridgehead atoms”.20 Because the barrier to homeomorphic
isomerization is usually higher than the barrier to nitrogen
inversion, homeomorphic isomers could be separated by chro-
matography as, for example, in the case of phosphorus-based
cryptands.19b In, out stereoisomerism has also been addressed
in the case of cyclophanes.21
(a) Condensation of two functionalized linear fragments A and A′ leads
to macrocycle B, which is further reacted with a third linear fragment (A′′)
to give macrobicycle C (and macrotricycle D). (b) The linear fragments of
(a) are replaced by functionalized macrocycles (B, B′, and B′′) to form
successively macrotricycle D, macropentacycle E, and macrononacycle F.
Diamine 5 derives from cryptand 4b10c by substitution of the
oxygen atoms of the latter with sulfur atoms and additional
bridging of the benzyl groups with -CH2N(Ts)(CH2)3N(Ts)-
CH2- spacers that are anchored ortho to the S atoms. As a
consequence, the linear bridges of macrobicyclic diamine 4b
are replaced by [15]ane-N2S2 macrocyclic bridges in 5, which
makes this system a macropentacyclic diamine. Its unique
dynamic and protonation properties in the context of in, out
isomerism and chirality have been already communicated.22 This
work examines in more detail the stereochemical properties of
5. It shows that the macropentacycle adopts a unique pseudo-
triple helical io form in solution at 200 K and in the solid state,
achieving its maximal symmetry (D3h) at 380 K, by a combina-
tion of three coupled processes: triple helix symmetrization,
nitrogen inversion, and reversal of triple helicity.
the cylindrical macropentacycle are other exemples of macro-
pentacyclic topologies.25
Nevertheless, the strategy presented above is reminiscent of
the divergent construction of dendrimers, which involves the
iterative duplication of atomic patterns.26 Clearly, as in the case
of dendrimers, the dimensionality of the macropolycycles
obtained by this dichotomy process is limited for steric reasons.
The sequence of reactions leading to the three macrocyclic
intermediates 10, 14, and 16 (respectively B, B′, B′′ of Scheme
1b), and macrotricycle 17 (D of Scheme 1b), together with other
potential precursors (9, 11, and 15) are detailed in Scheme 2.
The key starting material is tetraaldehyde 6, previously
developed by Kersting and co-workers as an organic template
for making thiophenol-incorporating macrocycles in one-pot
reactions.27 In our synthetic scheme it was necessary to
differentiate the two functions ortho to the sulfur, so that one
would be connected to a bridgehead nitrogen, the other being
included in the peripheral part of the [15]ane-N2S2 macrocyclic
subunits of 5. Reduction of tetraaldehyde 6 (1 equiv) with
NaBH4 (0.5 equiv) in THF/EtOH at 0 °C afforded diol 7 in
50% yield after chromatography, twice as much as the statistical
yield (25%). Remarkably, the formation of the isomeric diol
was not observed. The regioselectivity of the double reduction
reaction could result from the decreased reactivity of the
aldehyde meta to a benzylic alcohol function. An alternative is
the intramolecular reduction of the second aldehyde function
by the bound trihydroborate. For steric reasons, this may happen
only when the aldehyde functions belong to two different aryl
systems. In the next step, diol 7 was converted into electro-
philes: reaction with SOBr2 in the presence of pyridine in
dichloromethane afforded the dibromo derivative 8 in 67% yield.
Alternatively, the corresponding dichloride (9) was obtained in
73% yield by use of SOCl2.
Results and Discussion
Synthesis of the Macrocycles and Macropolycycles. Mac-
robicycles are usually synthesized as shown in Scheme 1a, by
covalent bridging of a macrocycle (B),4,10 a common alternative
to the tripod capping route.23 The corresponding [2+2] con-
densation reaction, whenever possible, leads to a macrotricycle
(D).4b,16 If, however, all three linear fragments incorporate a
macrocyclic subunit each (Scheme 1b), then a macropentacycle
(E) will be obtained, the [2+2] condensation product being in
this case a macrononacycle (F). Such a macropentacyclic
intrinsic topology has been previously obtained via either
route.24 Kyuphane, which derives from the cubic graph, and
(20) Gregory, B. J.; Haines, A. H.; Karntiang, P. J. Chem. Soc., Chem.
Commun. 1977, 918-919.
(21) (a) Hohner, G.; Vo¨gtle, F. Chem. Ber. 1977, 110, 3052-3077. (b)
Nakazaki, M.; Yamamoto, K.; Toya, T. J. Org. Chem. 1981, 46, 1611-
1615. (c) Dell, S.; Ho, D. M.; Pascal, R. A., Jr. J. Org. Chem. 1999, 64,
5626-5633.
(22) Bonnot, C.; Chambron, J.-C.; Espinosa, E. J. Am. Chem. Soc. 2004,
126, 11412-11413.
(25) (a) Behr, J.-P.; Bergdoll, M.; Chevrier, B.; Dumas, P.; Lehn, J.-M.;
Moras, D. Tetrahedron Lett. 1987, 28, 1989-1992. (b) Murakami, Y.;
Kikuchi, J.-i.; Ohno, T.; Hirayama, T.; Hisaeda, Y.; Nishimura, H.; Snyder,
J. P.; Steliou, K. J. Am. Chem. Soc. 1991, 113, 8229-8242.
(26) Tomalia, D. A.; Naylor, A. M.; Goddard, W. A., III. Angew. Chem.,
Int. Ed. Engl. 1990, 29, 138-175.
(27) (a) Kersting, B.; Steinfeld, G.; Fritz, T.; Hausmann, J. Eur. J. Inorg.
Chem. 1999, 2167-2172. (b) Klingele, M. H.; Kersting, B. Z. Naturforsch.
2001, 56b, 437-439.
(23) (a) This discussion excludes transition metal template effects. (b)
MacDowell, D.; Nelson, J. Tetrahedron Lett. 1988, 29, 385-386. (c) Beer,
P. D.; Kocian, O.; Mortimer, R. J.; Spencer, P. J. Chem. Soc., Chem.
Commun. 1992, 602-604.
(24) (a) Wester, N.; Vo¨gtle, F. Chem. Ber. 1980, 113, 1487-1493. (b)
Wallon, A.; Werner, U.; Mu¨ller, W. M.; Nieger, M.; Vo¨gtle, F. Chem. Ber.
1990, 123, 859-867.
870 J. Org. Chem., Vol. 73, No. 3, 2008

In, out Pseudohelix of a Diaza-Macropentacycle
SCHEME 2
SCHEME 3
graphic purification. Hydrazinolysis in ethanol at reflux gave
the desired diamino macrocycle 14 cleanly and quantitatively.
Two potentially useful electrophilic macrocycles were made
from diol 12: dichloro derivative 15 was obtained in 81% yield
by reaction with SOCl2/pyridine, whereas diiodo derivative 16
was isolated in 80% yield after reaction with I2 in the presence
of PPh3 and imidazole (ratio 5:5:2) in dichloromethane at 0 °C.30
The next step in the construction of macropentacycle 5
involved at first Schiff base condensation of dialdehyde 10 with
diamine 14 in the presence of 3 Å molecular sieves in diluted
reaction medium (8 mM in CH2Cl2, 30 °C) followed by NaBH4
reduction in MeOH/THF at 0 °C.10c Intermediate macrotricycle
17 was obtained in 71% yield after crystallization (Scheme 2b).
The high yield observed for this macrocyclisation reaction can
be rationalized in terms of preorganization of the reactants.31
The reactive functions (aldehyde for 10, amine for 14) are placed
pairwise on the same side of these 15-membered macrocycles,
thus favoring the [1+1] cyclocondensation.
In the final step, macrotricycle 17 was reacted with macro-
cyclic diiodo derivative 16 in diluted medium (2.8 mM in 1:1
toluene/acetonitrile, 50 °C) and in the presence of Cs2CO3 as
base (Scheme 3).10c
Macropentacycle 5 was best purified as its monoprotonated
form (trifluoromethanesulfonate salt).22 To this end, a controlled
amount of trifluoromethanesulfonic acid was added to the
reaction mixture after workup. Column chromatography of the
crude allowed to isolate [5‚H](CF3SO3) in 53% yield. Gratify-
ingly, macrononacycle 18 was obtained in 7% yield, albeit in
Construction of the first macrocycle (dialdehyde 10) involved
dibromo derivative 8 as the best electrophile. Reaction of 8 with
N,N′-di-p-tosyl-1,3-diaminopropane in the presence of Cs2CO3
as base, in moderate dilution reaction conditions (13 mM in
DMF, 35 °C), produced macrocyclic dialdehyde 10 in 72%
yield. 10 represents an organic equivalent of the dialdehyde-
functionalized Ni(II) complexes described as building blocks
for unsymmetrical dithiophenolate-bridged complexes of com-
partmental ligands.28 We planned to prepare the intermediate
macrotricycle 17 by Schiff base condensation of dialdehyde 10
with the corresponding diamino derivative 14, followed by
NaBH4 reduction. To this end, intermediate dioxime 11 was
prepared by reaction of 10 with hydroxylamine in aqueous
ethanol and isolated in 77% yield. However, our attempts to
convert it to diamine 14 (catalytic hydrogenation or LiAlH4)
failed. Another route (Gabriel-type synthesis) was therefore
developed. At first, dialdehyde 10 was reduced with NaBH4
(MeOH, 0 °C) to macrocyclic diol 12. The reaction was
quantitative. Next, 12 was reacted with phthalimide in Mit-
sunobu reaction conditions (DIAD, PPh3, THF, 0 °C)29 to afford
the diphthalimide derivative 13 in 94% yield after chromato-
(30) (a) Garegg, P. J.; Samuelsson, B. J. Chem. Soc., Chem. Commun.
1979, 978-980. See also: (b) Ireland, R. E.; Gleason, J. L.; Gegnas, L.
D.; Highsmith, T. K. J. Org. Chem. 1996, 61, 6856-6872. (c) Merlic, C.
A.; Aldrich, C. C.; Albaneze-Walker, J.; Saghatelian, A.; Mammen, J. J.
Org. Chem. 2001, 66, 1297-1309.
(28) Christensen, A.; Jensen, H. S.; McKee, V.; McKenzie, C. J.; Munch,
M. Inorg. Chem. 1997, 36, 6080-6085.
(29) Mitsunobu, O. Synthesis 1981, 1-28.
(31) Cram, D. J. Angew. Chem., Int. Ed. Engl. 1986, 25, 1039-1057.
J. Org. Chem, Vol. 73, No. 3, 2008 871

Bonnot et al.
FIGURE 4. ORTEP views of diprotonated macrotricycle [17‚2H](CF3-
CO2)2. (a) Top view. (b) Side view. The positions of hydrogen atoms
shown here were refined. Other hydrogen atoms have been omitted
for clarity. Thermal ellipsoids are drawn at 50% probability level.
FIGURE 5. X-ray crystal structure of macropentacycle 5: ORTEP
side view. The tosyl groups and hydrogen atoms (H3A, H3B, and H3C
excepted) have been omitted for clarity. Thermal ellipsoids are drawn
at 50% probability level.
neutral form, in spite of the acidic treatment. The neutral form
of macropentacycle 5 was recovered quasi quantitatively (98%)
by reaction of [5‚H](CF3SO3) with sodium methoxide. Preor-
ganization of the reactants can again account for the relatively
good yield of sterically crowded macropentacycle 5. The
formation of macrononacycle 18,32 which results from a [2+2]
cyclocondensation reaction, is less favored entropically than that
of 5, which is the [1+1] cyclocondensation product. However,
as shown by 1H NMR (Vide infra), 18 is apparently less strained
and less sterically crowded than 5. This favorable enthalpic
factor may probably account for the observation and isolation
of significant amounts of the macrononacycle in this reaction.
anions that are sitting on top of the cavities, the CF3 groups of
the guests being sandwiched by the t-BuAr groups of the host.
The distances d(H‚‚‚O) are 1.71(1) and 1.73(1) Å, which,
according to their relationship with dissociation energy De
(eq 1):
De(kJ mol-1) ) 25 000 exp[-3.6d(H‚‚‚O)]33
(1)
correspond to De values of 53 and 49 kJ mol-1 respectively.
This is diagnostic of relatively strong hydrogen bonding
interactions. In addition, all the C-O bond distances are
identical to each other (1.237(4) Å), and the same is true for
the N-H distances (1.02(1) Å), indicating that negative and
positive charges are delocalized on carboxylate and ammonium
groups, respectively.
X-Ray Molecular Structure Analyses. All four macropoly-
cycles reported in this work have been structurally characterized
by single-crystal X-ray diffraction (Table S1, Supporting
Information). Crystals of macrocycle 10, a representative of the
series of macromonocycles, were obtained from CH2Cl2/heptane.
ORTEP views of the molecule are shown in Figure S1 (see
Supporting Information). The aldehyde functions are obviously
located on the same side of the molecule but, as the tosyl and
supporting aryl groups, oriented in opposite directions with
respect to the mean plane of the macrocycle.
Macrotricycle 17 could be crystallized from CH2Cl2/cyclo-
hexane in its diprotonated form as the bis-trifluoroacetate salt,
featuring a host-guest system in the solid state ([17‚2H](CF3-
CO2)2). As shown in the ORTEP views of Figure 4, a
crystallographic inversion center is located in the middle of the
molecule. Each resulting half of the macrotricycle is cavity-
shaped by the t-butylaryl (t-BuAr) walls. The bridgehead
secondary amines are protonated, and the resulting ammoniums
are hydrogen bound to the oxygen atoms of two trifluoroacetate
The structure of macropentacycle 5 in protonated form has
been discussed in an earlier report:22 [5‚H](CF3SO3) has a nearly
perfect triple helical structure and takes up the io conformation
in the solid state, the proton being localized on the endo
bridgehead nitrogen atom Ni and hydrogen-bound to the three
proximal sulfur atoms. Crystals of 5 suitable for X-ray diffrac-
tion were obtained by deprotonation of acetonitrile solutions
of [5‚H](CF3SO3) with cryptand [2.2.2]-2. As shown in the
ORTEP view of Figure 5, 5 has also the io conformation in the
solid state. This result is quite surprising, because what was
thought to be the driving force leading to the io conformation
of [5‚H]+ (proton encapsulation in the NiS3 tetrahedral coor-
dination sphere) is now lacking. However, as in the case of
[5‚H]+, hydrogen bonding interactions (see also Figure S2a,
Supporting Information) can be evidenced between the lone pair
of the exo bridgehead nitrogen atom (No) and ortho (Ar)C-H′s,
with H‚‚‚N distances ranging from 2.46 (H3C‚‚‚No) and 2.48
(H3A‚‚‚No) to 2.64 Å (H3B‚‚‚No). Similar observations were
(32) The rare intrinsic macrononacyclic topology is also represented by
a calix[4]arene/resorcarene conjugate. See: Timmerman, P.; Verboom, W.;
van Veggel, F. C. J. M.; van Hoorn, W. P.; Reinhoudt, D. N. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 1292-1295.
(33) Espinosa, E.; Molins, E.; Lecomte, C. Chem. Phys. Lett. 1998, 285,
170-173.
872 J. Org. Chem., Vol. 73, No. 3, 2008

In, out Pseudohelix of a Diaza-Macropentacycle
FIGURE 6. X-ray crystal structure of macropentacycle 5: ORTEP
top view from the exo bridgehead nitrogen atom. Hydrogen atoms have
been omitted for clarity. Thermal ellipsoids are drawn at 50%
probability level.
1
FIGURE 8. Comparison of the H NMR spectra of (a) macropenta-
cycle 5 and (b) macrononacycle 18 at 380 K (500 MHz, C2D2Cl4).
Surprisingly, macrononacycle 18 crystallized in neutral form
(from CH2Cl2/EtOAc), in spite of its acidic treatment (CF3SO3H)
prior to SiO2 chromatography and crystallization. A preliminary
determination of its X-ray crystal structure is presented in Figure
S3 (ORTEP view, see Supporting Information). The ma-
crononacycle features two hinge-shaped cavities made from
macrotricyclic subunits that are interconnected by two macro-
cyclic bridges and that host ethylacetate solvent molecules. All
the tertiary amine bridgehead nitrogens have the exo configu-
ration.
Solution Structure and Dynamics. Macrocycle 10, mac-
rotricycle 17, macropentacycle 5, and macrononacycle 18 are
all constructed from the same [15]ane-N2S2 macrocyclic motif.
In agreement with its symmetry properties (C2V), macrotricycle
17 shows essentially the same 1H NMR features as its precursor,
plus the bridgehead R CH2 protons, which appear at higher field
than the â-CH2. Whereas these species both show well-resolved
signals at room temperature, this is not the case for the higher
order macropenta- and macrononacycles 5 and 18. In particular,
the former (5) shows the broadest features in the series, which
are indicative of the existence of slowly exchanging conforma-
tions on the NMR time scale (see below). The broadest spectra
are obtained in C2D2Cl4 and d6-acetone (Figure S4, Supporting
Information).
FIGURE 7. Schematic drawing of macropentacycle 5 (top view from
the exo nitrogen) showing the 6 different sectors A, B, and C (exo
side) and D, E, and F (endo side).
made by Lindoy and co-workers for the oo form of cryptand
4a.10a Unlike [5‚H]+, which displays a very regular triple helical
structure,22 the triple helix of 5 in the crystal is not C3-symmetric
(Figure 6). It can be described as being made of the three
branches AD, BE, and CF (made from the sectors A, B, C, D,
E, and F) explicited in Figure 7 (see also Figure S10, Supporting
Information). From Figures 5, 6, and 7, branch BE is clearly
different from branches AD and CF, the latter being very similar
to each other. The torsion angles τ that, for each branch of the
molecule, correspond to the mean <C-Ni-No-C> value,
range from 42.2 (branch AD, see Figure 6) and 45.5 (branch
BE) to 49.9° (branch CF), the average value being 45.5°, which
is lower than the value measured for [5‚H](TfO) (49°).22 This
indicates that the molecule is less coiled in its neutral form.
Accordingly, the distance between the bridgehead nitrogen
atoms is longer than in the case of the proton adduct: 6.828 vs
6.325 Å. As shown in Figure S2b (see Supporting Information),
unlike what is observed for [5‚H]+, the triangles (SA, SB, SC)
and (SD, SE, SF) are not equilateral, pointing to a structure that
is not as regular as in the case of the monoprotonated
macropentacycle.
The dynamics of macropentacycle 5 in the 210-380 K
temperature range have been investigated by VT NMR (Figures
S5-S7, Supporting Information) in CD2Cl2 and C2D2Cl4
solution. Stacked spectra recorded between 300 and 380 K are
detailed in Figure S5 (see Supporting Information). A satisfac-
torily resolved spectrum of 5 over the full δ range is obtained
at 380 K, where its maximum D3h symmetry is achieved. This
is due either to the presence of symmetrical ii and/or oo
conformations and to the fast exchange of unsymmetrical io
and oi conformations. Macrononacycle 18 shows broadened
signals in the high-field region of the spectrum (1-4.6 ppm).
Its maximal symmetry (D2h) is again observed at 380 K (Figure
S8, Supporting Information). Comparison of its 380 K spectrum
with that of macropentacycle 5 (Figure 8) shows that all of its
J. Org. Chem, Vol. 73, No. 3, 2008 873

Bonnot et al.
1
FIGURE 9. Stacked plot of the H NMR spectra of macropentacycle 5 in the temperature range 210-300 K (500 MHz, CD2Cl2). The low field
region is enhanced by a factor of 4.
signals are split in a 2:1 ratio. Indeed, the two bridging
macrocycles are not equivalent to the four macrocycles of the
macrotricyclic subunits. In addition, whereas the former contains
one of the symmetry planes of the molecule and have enan-
tiotopic methylene protons, this is not the case for the latter,
the methylene protons of which are diastereotopic. This analysis
is best illustrated by the δ, δ′-CH2 and the â, â′-CH2 protons.
The δ, δ′-CH2 protons show three signals between 1.5 and 2.0
ppm in a 1:1:1 ratio: a singlet for the enantiotopic δ′-CH2 of
the bridging macrocycles and two multiplets for the diaste-
reotopic δ-CH2 of the macrocyclic components of the macrot-
ricyclic subunits. The â′-CH2 protons of the bridging macro-
cycles appear as a singlet (δ ) 4.615 ppm), and the â-CH2 of
the macrotricyclic subunits display an AB pattern (δ ) 4.75
ppm; JAB ) 17 Hz, ∆ν ) 57 Hz). The same is true for the
bridgehead R, R′-CH2; however, the singlet and the AB quartet
are superposed at ca. 3.94 ppm.
Stacked spectra (8.5-6 and 2.5-0.5 ppm) of macropentacycle
5 in the low-temperature (300-210 K) range (CD2Cl2 solution)
are shown in Figure 9 (the full δ range is displayed in Figure
S7, Supporting Information). The 300 K spectrum recorded in
CD2Cl2 is similar to the spectrum obtained at 320 K in C2D2-
Cl4 (Figure S6, Supporting Information). At this temperature,
the molecule still holds its D3h symmetry, because the same
number of signals as in the 380 K spectrum are observed, most
clearly in the aromatic region. Upon cooling down further, the
two aryl (Ts excepted) signals disappear briefly and give rise
below 270 K to several broad signals that are scattered between
6 and 8.5 ppm. Simultaneously, the e (CH3 of Ts) and t-Bu
signals broaden unsymmetrically with intensity decrease and
separate into individual singlets, which sharpen as the temper-
ature is further lowered.
all commensurate (Figure S9, Supporting Information). Com-
parison of the integral values in the full δ range indicates that
only a single species, rather than a mixture of conformers, is
present in solution at low temperature, contrary to our previous
interpretation.22
This contrasts with the diprotonated cryptand ([2.2.2]-2‚
2H)2+, the three forms of which (i+i+, o+o+, and i+o+) could
be clearly identified at low temperature.34 The fully assigned
200 K spectrum of macropentacycle 5 is shown in Figure 11.
Colored labels of the protons are marked on the separated
ORTEP views of the three branches AD, BE, and CF incorpo-
rating the six sectors A, B, C, D, E, and F of the molecule
(Figure 10; see also Figure S10, Supporting Information).35 The
low-temperature structure of macropentacycle 5 in solution has
been studied and solved using two-dimensional NMR (1H/1H
1
1
COSY, H/1H ROESY and H/13C HSQC). Selected views of
the 2D maps are shown in Figures 12-14. Other enlargements
and the full 2D maps are included in Figures S11-S19 (see
Supporting Information). The ROESY correlations are shown
graphically in Figure S20. The following section shows that
the low-temperature structures of macropentacycle 5 in the
solution and in the crystal are correlated to each other.
The 1H/1H ROESY map of Figure S17 is detailed in Figures
12 and 13. Figure 12 highlights all the correlations between
the six t-Bu groups and the proximal aryl protons 3 and 5. In
addition to these, intercomponent correlations between t-Bu and
tosyl (c and e) protons can be evidenced, such as t-BuA/cD (t-
BuA/eD) and t-BuC/cF (t-BuC/eF), which indicate that the tosyl
(Ts) groups D and F have the axial orientations shown in Figure
10a and c, respectively. That TsD (respectively TsF) lies in the
groove formed by branches AD and BE (respectively CF and
AD) as illustrated in Figures 6 and 7 is further supported by
the correlations t-BuB/(cD, eD)(respectively t-BuA/(cF, eF)). Other
correlations resulting directly from the axial orientation of TsD
and TsF are: cD/3B (Figure S17, Supporting Information),R′B/
bD and R′A/bF, as shown in Figure 13. Whereas axial TsD and
At 210 K, six different singlets for the t-Bu groups can be
clearly identified between 0.9 and 1.4 ppm, as well as two sets
of signals for the methyl (e) substituents of the tosyl groups in
the 1.9-2.5 ppm range: a broad singlet at 1.95 ppm, which is
clearly resolved into 2 singlets at 230 K, and 4 singlets between
2.3 and 2.5 ppm. The remainder of the aliphatic region (2.5-
5.5 ppm) shows a quasi-continuum of signals (Figure S7,
Supporting Information). The aromatic region shows well-
resolved peaks between 6.0 and 8.5 ppm, whose integrals are
(34) MacGillivray, L. R.; Atwood, J. L. J. Org. Chem. 1995, 60, 4972-
4973.
(35) Each branch, as represented, features the shape of a blade. Primed
protons are located in the concave region of the blade, whereas unprimed
ones are located in its convex part, see Figure S10 (Supporting Information).
874 J. Org. Chem., Vol. 73, No. 3, 2008

In, out Pseudohelix of a Diaza-Macropentacycle
FIGURE 10. X-ray crystal structure of macropentacycle 5. ORTEP views of the 3 isolated branches : (a) AD, (b) BE, and (c) CF with proton
labels. Thermal ellipsoids are drawn at 50% probability level. Only methylenic hydrogen atoms are shown.
FIGURE 11. 1H NMR spectrum of macropentacycle 5 at 200 K (500 MHz, CD2Cl2). (a) Full spectrum, (b) detail of the aliphatic region, and (c)
detail of the aromatic region.
TsF interact only with the proximal â and γ′ (i.e., âD/bD, âF/bF,
γ′D/bD, and γ′F/bF), and δAD and δCF protons (i.e., bD/δAD and
bF/δCF, Figure S18, Supporting Information), their analogues
TsA and TsC correlate with â, â′, and γ proximal protons (i.e.,
(âA, â′A)/bA, (âC, â′C)/bC, γA/bA, and γC/bC) because of their
equatorial position (Figure 10a and c). Also for this reason, and
contrary to axial TsD and TsF, they do not interact with other
branches. Expectedly, aryl protons 5A and 5C interact with the
nearby oriented â′ and γ′ protons (i.e., â′A/5A, γ′A/5A, â′C/5C,
and γ′C/5C, Figures 13 and S17, Supporting Information). In
J. Org. Chem, Vol. 73, No. 3, 2008 875

Bonnot et al.
1
FIGURE 12. Detail of the NMR H/1H ROESY map of macropentacycle 5 at 200 K (500 MHz, CD2Cl2; mixing time: 450 ms).
1
FIGURE 14. Detail of the NMR H/13C HSQC map of macropenta-
cycle 5 at 219 K (500 MHz, CD2Cl2).
respectively, whereas equatorial RD and RF protons correlate
with 3F and 3E, respectively (see Figure 13).
All of the aliphatic protons can be identified in the HSQC
maps. Pairs of methylene protons (R, R′), (â, â′), (γ, γ′), and
(ꢀ, ꢀ′) are shown in Figure 14, whereas Figure S12 (see
Supporting Information) details all (δ, δ′) pairs, the six methyl
(e) of tosyl groups, and the six t-Bu systems. The relatively
few 1H/1H ROESY correlations between nongeminal methylene
protons are highlighted in Figures S11 and S19 (see Supporting
Information). These correlations (ꢀ′A/âA, ꢀ′B/âE, ꢀ′F/RF, ꢀD/RD,
R′F/R′E, δBE/âE, δBE/âB, δ′AD/â′D, and δAD/γ′D) are all consistent
with the structures that can be predicted from the ORTEP
representations of Figure 10 and confirm the assignements
discussed above.
1
FIGURE 13. Detail of the NMR H/1H ROESY map of macropen-
tacycle 5 at 200 K (500 MHz, CD2Cl2; mixing time: 450 ms). Spots
corresponding to site exchange are labeled in magenta.
contrast to those involving TsA, TsC, TsD, and TsF, there are
few correlations involving TsB and TsE (i.e., γB/bB, δ′BE/bB, δ′BE
bE, â′B/bB, â′E/bE, and t-BuE/cE), and none of them involves
interbranch interactions, which agrees with the obvious periph-
eral orientation shown in Figure 10b.
/
Bridgehead methylenic R, R′ protons are clearly separated
in two sets, which suggests that the molecule has the io form,
with exo (A, B, C) and endo (D, E, F) propellers. Equatorial
R′A, R′B, and R′C correlate with 3C, 3A, and 3B of the neighboring
branch respectively, as would be expected for twisted exo-
NCHRHR′ subunits. Expectedly, the corresponding axial RA, RB,
and RC protons do not show any correlation. The correlation
3A/3C (Figure S17, Supporting Information) indicates that the
supporting aryl subunits are only slightly bent, which favors
CH‚‚‚N hydrogen bonding interactions between 3-Ar protons
and the exo bridgehead nitrogen atom, as evidenced in the X-ray
crystal structure (see Figures 2 and S2a, Supporting Informa-
tion). The endo bridgehead methylenic R′D, R′E, and R′F are
axial and correlate with 3D, 3E, and 3F of the same branch,
1
The fully assigned 200 K H NMR spectrum (Figure 11)
deserves several comments. Methyl eD and eF of axial Ts groups
resonate upfield by comparison with the others (eA, eB, eC, and
eE), because they lie in the shielding fields of t-BuArB and
t-BuArA (for eD), and t-BuArA and t-BuArC (for eF), respectively.
The same is true for cD and cF (respectively bD and bF), as
compared to cA, cB, cC, and cE (respectively bA, bB, bC, and
bE). Reciprocally, t-BuA and t-BuC are in the shielding fields of
TsD and TsF, respectively. 5A (and 5C) are probably shielded
also by TsD (and TsF). The deshielding of 3A, 3B, and 3C, by
comparison with 3D, 3E, and 3F could be due to intramolecular
876 J. Org. Chem., Vol. 73, No. 3, 2008

In, out Pseudohelix of a Diaza-Macropentacycle
TABLE 1. Selected Probe Proton Pairs, DNMR Data and Free Energy Barriers at the Coalescence Temperature
q
probe
∆Gc
(kJ mol-1
)
b
protons
âC/â′C
CF/δ′CF
∆ν (Hz)
kc ) π∆ν/x2 (s-1
)
Tc (K)a
1049
504
202
207
2331c
1120
449
300 (320d)
280
54.2 (57.9d)
52.1
δ
(eA,eB,eC,eE)/(eD,eF)
260 (282d,e
260
)
50.2 (54.7d,e
50.1
)
âC/âE
460
a See Figure S21 (Supporting Information). b Calculated using the following relationship:38a ∆Gc (kJ mol-1) ) 2.303RTc(10.319 + log Tc - log kc), R
q
) 8.314 JK-1mol-1 c For this pair of coupled protons, ∆ν should be replaced by (∆ν2 + 6J2)1/2 in the calculation of kc.38b However, because 6J2 , ∆ν2,
.
the simplified formula holds. d Values obtained in C2D2Cl4. e See ref 22.
hydrogen bonding of the former with the exo bridgehead
nitrogen atom, a feature clearly apparent in the X-ray crystal
structure (Figures 5 and S2a, Supporting Information). All of
the geminal methylenes show individual, mostly doublet signals,
which indicates that they form diastereotopic pairs of atoms.
Typical examples are: (RC, R′C), (RA, R′A), (âE, â′E), (âB, â′B),
and (RD, R′D). ꢀ′D and γB show clear triplet signals in agreement
with their anti relationship with vicinal ꢀA and δBE, respectively
(Figure 10). The lack of COSY and ROESY correlations
between RB and R′B is due to the fact that these protons are
nearly degenerate, as is apparent from the HSQC spectrum, with
bridgehead nitrogen inversion, which exchanges the ii, io, and
oo forms; and triple helix inversion, which exchanges the right-
and left-handed helical conformations and corresponds to a
1
racemization process. All three processes are fast on the H
NMR time scale at T g 360 K, the spectra being consistent
with D3h symmetry of the molecule (Figure S5, Supporting
Information).
The three dynamic processes identified above exchange
homologous protons that either are diastereotopic (helix inver-
sion), or belong to the same propeller (A, B, C) or (D, E, F)
(helix symmetrization), or belong to two different sectors of
the same branch, that is A and D, B and E, or C and F (nitrogen
inversion). Several coalescence phenomena can be noted as the
temperature is increased from 210 to 380 K in the composite
stacked plot of Figure S21 (see Supporting Information).
However, separation of those due to helix symmetrization and
nitrogen inversion is rather delicate, because homologous probe
protons for these latter processes resonate in the same regions
of the spectrum. As a matter of proof, the signals of protons âC
and âE, which are exchanged by a combination of these two
processes, show coalescence (260 K). The same is true for the
two groups of methyl protons eD and eF on the one hand and
eA, eB, eC, and eE on the other hand. Due to extensive broadening
between 260 and 320 K, it is not possible to track the signals
of homologous protons in this temperature range. However, very
broad features between 3.8 and 5.2 ppm at 300 K37 follow
transient sharpening of the 5 ppm signal (at 280 K) and precede
the development of the R and â singlets between 340 and 380
K. They could be reasonably attributed to the coalescence of
pairs of diastereotopic protons such as âC and â′C, which show
the highest ∆ν (1049 Hz) at the slow exchange temperature
limit (200 K). In addition, coalescence of diastereotopic δCF
and δ′CF (∆ν ) 504 Hz) clearly does not occur below 280 K,
which can be reasonably set as the Tc for this pair, because a
very broad signal (δ ≈ 0.25 ppm) corresponding to δ′AD (and
overlapping δ′CF) is last seen at 270 K.
2
∆ν ≈ 0 and JAB ≈ 18 Hz. These protons excepted, all of the
other geminal (R, R′) systems show a very large ∆ν, e.g., 889
Hz for (RC, R′C). As noted in earlier reports, this indicates that
the shielded H is oriented anti to the lone pair, the other being
gauche.36 This explains the apparently abnormal upfield reso-
nance of R′E and R′D of endo-NCHRHR′, because of their removal
from any aromatic shielding field. However, exactly the opposite
is observed for RA and RC, which, according to the views of
Figure 10a and c, should be oriented anti to the lone pair. In
fact, these exo-NCHRHR′ protons lie in the deshielding field of
the neighboring t-BuAr(A,C), and counter ring current effects
could come into interplay. The highest anisotropy is noted for
the pairs of diastereotopic protons (âA, â′A) and (âC, â′C) for
which ∆ν ≈ 1050 Hz. Finally, (δAD, δ′AD) and (δCF, δ′CF) show
the strongest high-field resonances, because they are in the
cumulative shielding fields of t-BuAAr and TsD on the one hand,
and of t-BuCAr and TsF on the other hand (Figure 10). Such
shieldings being absent in the case of (δBE, δ′BE), these latter
protons resonate at lower field than their homologues of
branches AD and CF.
Macropentacycle 5 is asymmetric, because one of its three
constitutive branches (BE) differs from the others (AD and CF).
Although the two latter branches are very similar in the crystal
structure (Figures 10a and c), they have different NMR
signatures, because they do not have matched environments.
Given the correlations found between the NMR data and the
X-ray crystal structure, the molecule also takes up the io form
and a nonsymmetrical (C1), pseudo-triple helical chiral shape
in solution at low temperature.
q
Free energies of activation at the coalescence (∆Gc ) can be
estimated from ∆ν and the coalescence temperatures (Tc).38 They
are collected in Table 1 for the pairs of probe protons examined
above. Remarkably, all of these values are related in a linear
fashion with the coalescence temperatures, which indicates that
a unique dynamic process combines triple helix symmetrization,
bridgehead nitrogen inversion, and reversal of triple helix
handedness in the C1 f D3h conversion of macropentacycle
1
The complete assignement of the low-temperature H NMR
spectrum of macropentacycle 5 allows one to analyze in more
1
detail the sequences of variable-temperature H NMR spectra
between 210 and 380 K shown in Figures 9 and S5-S7 (see
Supporting Information). The C1 f D3h conversion of macro-
pentacycle 5 within this temperature range can be virtually
decomposed into three dynamic exchange processes: C3 helix
symmetrization, which exchanges branches AD, BE, and CF;
1
(37) The H NMR spectrum of 5 at 300 K in CD2Cl2 is very similar to
the one obtained in C2D2Cl4 at 320 K (Figure S21, Supporting Information).
(38) (a) Calder, I. C.; Garratt, P. J. J. Chem. Soc. B 1967, 660-662. (b)
Kost, D.; Carlson, E. H.; Raban, M. J. Chem. Soc., Chem. Commun. 1971,
656-657. (c) Fischer, P.; Fettig, A. Magn. Reson. Chem. 1997, 35, 839-
844.
(36) (a) Hamlow, H. P.; Okuda, S.; Nakagawa, N. Tetrahedron Lett. 1964,
2553-2559. (b) Graf, E.; Kintzinger, J.-P.; Lehn, J.-M.; LeMoigne, J. J.
Am. Chem. Soc. 1982, 104, 1672-1678, note 20. (c) Bell, T. W.; Choi,
H.-J.; Harte, W. J. Am. Chem. Soc. 1986, 108, 7427-7428.
J. Org. Chem, Vol. 73, No. 3, 2008 877

Bonnot et al.
5.38c,39 The coupled processes have a free energy barrier of 54.2
kJ mol-1 at 300 K in CD2Cl2 (57.9 kJ mol-1 at 300 K in C2D2-
Cl4).
time scale. However, their maximal averaged symmetry (D3h
and D2h, respectively) is achieved at high temperature (380 K).
Cooling the temperature of a CD2Cl2 solution of the macro-
pentacycle down to 200 K allows for the observation (at the
NMR time scale) of a single species only, rather than a mixture
of conformers. Remarkably, the structure of the low temperature
conformer is asymmetric, yet the molecule holds a pseudo-triple
helical shape, with endo and exo configurations of the bridge-
head nitrogen atoms, as in the molecular structure obtained by
single-crystal X-ray crystallography. The solution dynamics of
the macropentacycle have been analyzed in terms of three
processes: triple helix symmetrization, bridgehead nitrogen
inversion, and reversal of triple helix handedness. All three of
them are coupled with each other, ∆Gcq being 54.2 kJ mol-1 in
CD2Cl2 at 300 K. Macropentacycle 5 adopts the io C1-
symmetrical form not only in the solid state but also in solution
at low temperature (at the NMR time scale). This latter feature
is unique and shows that the io form, rather than simply resulting
from intermolecular packing forces, has an intramolecular origin,
which is most probably linked up with the steric crowding and
strain introduced by the three [15]ane-N2S2 macrocyclic bridging
subunits.
Discussion
q
Comparison of the ∆Gc data obtained for macropentacycle
5 with those of the literature for related compounds in the
context of helix and nitrogen inversion is difficult, if not
impossible, given the hybrid nature of these dynamic processes
in 5.
Low-temperature dynamics of the relatively strained D3-
symmetrical cryptand [1.1.1]-2 were attributed to helix inversion,
q
which occurred with ∆Gc ) 41.0 kJ mol-1 at Tc ) 208 K.16
By extrapolation to this temperature, a value of ∆G208q ) 44.9
kJ mol-1 can be calculated for the combined processes taking
place in macropentacycle 5.39 The small difference would
suggest that helix inversion is an easier process in the latter
system.
Literature data on the barriers to pyramidal nitrogen inversion
in macrobicycles containing bridgehead nitrogen atoms are
scarce.3 In the case of simple acyclic alkylamines, they lie in
the 21-40 kJ mol-1 range.11 For example, dibenzylmethylamine
q
has ∆Gc ) 25.1 kJ mol-1 at 127 K.12a Usually, the measured
Experimental Section
barriers correspond to net nitrogen inversion and concomitant
N-C bond rotation,40 the overall process being inversion
dominant when trigonal planar nitrogen is the highest energy
point (transition state).41 Incorporation of the nitrogen atom in
a cyclic structure increases the nitrogen inversion barrier
dramatically when the CNC angle of the cycle has a value small
enough to generate angle strain in the trigonal planar transition
state. This situation is found in three-membered ring cyclic
General Information. All reactions were performed under argon
using standard Schlenk techniques. Solvents were distilled over
appropriate drying agents. All other chemicals were used as
received.
X-Ray Crystallography. Colorless and prismatic single-crystal
specimens of macrocycle 10‚0.25(CH2Cl2)‚0.25(CH3NHCH3)‚
0.5(CH3NHCHO), diprotonated macrotricycle [17‚2H]‚2CF3-
CO2‚3(CH2Cl2), macropentacycle 5‚8.5(C2H3N), and macronona-
cycle 18 (from CH2Cl2/EtOAc) were selected for the X-ray
diffraction experiments at T ) 115(2) K. Selected crystals were
mounted with silicon grease on the tips of glass capillaries.
Diffraction data were collected on a Nonius Kappa CCD diffrac-
tometer,42 equipped with a nitrogen jet stream low-temperature
system (Oxford Cryosystems). The X-ray source was graphite
monochromatized Mo-KR radiation (λ ) 0.71073 Å) from a sealed
tube. In all cases, lattice parameters were obtained by a least-squares
fit to the optimized setting angles of the entire set of collected
reflections. Intensity data were recorded as æ and ω scans with κ
offsets. No significant intensity decay or temperature drift was
observed during the data collections. Data reductions were done
by using the DENZO software.43 The structures were solved by
direct methods using the SIR97 program.44 Refinements were
carried out by full-matrix least-squares on F2 using the SHELXL97
program45 and the complete set of reflections. Anisotropic thermal
parameters were used for non-hydrogen atoms. The solvent
molecules were found highly disordered in all the crystal structures,
sometimes making the structure determinations very difficult. In
spite of the fact that a first refinement of the molecular structure
of macrononacycle 18 could be carried out (see Figure S3,
Supporting Information), the too strong disorder of the solvent
molecules could not permit one to clearly identify neither all the
cocrystallised solvent molecules nor their number, leading to an
incomplete crystal structure determination. In all cases, hydrogen
amines,11,13 such as N-methylaziridine (∆Gc ) 79.7 kJ mol-1
q
at 390 K),13c and to a lesser extent in azabicyclic systems with
a rigid bicyclic framework,11,14 such as 7-methyl-7-azanorbor-
q
nane, which has ∆Gc ) 57.6 kJ mol-1 at 298 K in CDCl3.14a
q
Fortunately, the latter value can be directly compared to ∆G300
) 54.2 kJ mol-1 obtained for macropentacycle 5. This shows
that, other intramolecular rearrangements contributing this free
energy barrier, nitrogen inversion in macropentacycle 5 is
probably a lower energy process, thus ranking this compound
with ordinary alkylamines.
Conclusion
Transposition of a classical strategy for synthesizing cryptand-
like macrobicycles has led to the efficient preparation (53%)
of a sterically crowded [N2S6] macropentacycle (5) with nitrogen
bridgehead atoms by [1+1] condensation reaction between a
macrocycle and a macrotricycle. A macrononacycle (18),
resulting from the corresponding [2+2] condensation, was
obtained as byproduct in 7% yield. Both sterically crowded
1
molecules show broad features in their room-temperature H
NMR spectra, which are indicative of slow motions on the NMR
(39) The corresponding relationship is y ) 0.1009x + 23.9000, R2
0.9992.
)
(42) Nonius, B. In COLLECT, Data Collection Software; BV Nonius:
Delft, The Netherlands, 1998.
(43) Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307-
326.
(44) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115-119.
(45) Sheldrick, G. M. In SHELXS-97, Program for the Solution of Crystal
Structures; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(40) (a) Bushweller, C. H.; Anderson, W. G.; Stevenson, P. E.; Burkey,
D. L.; O’Neil, J. W. J. Am. Chem. Soc. 1974, 96, 3892-3899. (b)
Bushweller, C. H.; Anderson, W. G.; Stevenson, P. E.; O’Neil, J. W. J.
Am. Chem. Soc. 1975, 97, 4338-4344. (c) Belostotskii, A. M.; Gottlieb,
H. E.; Hassner, A. J. Am. Chem. Soc. 1996, 118, 7783-7789, and references
cited therein.
(41) Anderson, J. E.; Tocher, D. A.; Casarini, D.; Lunazzi, L. J. Org.
Chem. 1991, 56, 1731-1739.
878 J. Org. Chem., Vol. 73, No. 3, 2008

In, out Pseudohelix of a Diaza-Macropentacycle
atoms were fixed at calculated positions using a riding model, except
those bonded to nitrogen atoms in the macrocycle and in the
diprotonated macrotricycle, which were refined. A global isotropic
thermal factor was refined for the hydrogen atoms of the crystal
structures of 10 and [17‚2H]. For 5‚8.5(C2H3N), their thermal factor
was fixed to 1.5 times that of its bonded atom (i.e., for
X-H : U(H) ) 1.5 Ueq(X)). Crystallographic views were
generated using ORTEP III for Windows.46
filtered, and evaporated to dryness. Column chromatography (silica,
1:1 dichloromethane/heptane) afforded 0.485 g (73% yield) of 9
as a pale-yellow solid, mp 139-140 °C; 1H NMR (300 MHz,
CDCl3): δ 1.35 (s, 18H; t-Bu-H), 2.91 (s, 4H; ꢀ-H), 4.90 (s, 4H;
â-H), 7.74 (d, J ) 2.4 Hz, 2H; 5-H), 7.92 (d, J ) 2.4 Hz, 2H;
3-H), 10.69 ppm (s, 2H; CHO); 13C NMR (75 MHz, CDCl3): δ
31.3 (C(CH3)3), 35.4 (C(CH3)3), 38.0 (ꢀ-C), 44.5 (â-C), 126.9 (3-
C), 133.7 (5-C), 134.1 (1-C), 138.5 (2-C), 143.0 (6-C), 153.8 (4-
C), 192.9 ppm (CHO); IR (neat): ν 1679 (vs, CO), 2867 and 2958
(s, C(O)-H), 3070 cm-1 (w, ArH); MS (70 eV, EI): m/z (%): 511
(9) [M+].
4
4
NMR Spectroscopy. Low-temperature 2D NMR experiments
were performed at 500.13 (1H) and 121.77 (13C) MHz, using a
Broad Band Inverse probe equipped with Z-gradients (BBI/GrZ).
Relaxation delays were 3 s; 4K × 512 data matrices were processed
in 4K × 2K (ROESY) and 4K × 4K (HSQC) sizes. HSQC spectra
were obtained with inverse sequences and Z-gradients. ROESY
spectra were obtained off resonance at a 54.7° angle, using adiabatic
spin lock pulses, the mixing times ranging from 250 to 450 ms.47
1,2-Bis(4-tert-butyl-2-formyl-6-hydroxymethylphenylsulfanyl)-
ethane 7. To a chilled solution of tetraaldehyde 627 (3.579 g, 7.6
mmol) in THF (300 mL) and absolute ethanol (90 mL) was added
sodium borohydride (0.145 g, 0.214 mmol). After 1 h of stirring at
0 °C, sodium hydrogencarbonate (5% aqueous solution, 90 mL)
was added. The reaction mixture was diluted with water (250 mL)
and extracted with dichloromethane (250 mL). The organic layer
was dried (MgSO4), filtered, and evaporated. Gradient column
chromatography (silica, 1:1 dichloromethane/pentane, 0.5% metha-
nol in dichloromethane gradient) afforded 1.790 g of 7 in 49.6%
yield as a colorless solid, mp 148.5-150.5 °C; 1H NMR (500 MHz,
CDCl3): δ 1.35 (s, 18H; t-Bu-H), 2.13 (br s, 2H; OH), 2.86 (s,
Macrocycle 10. To a suspension of cesium carbonate (9.05 g,
27.8 mmol) in DMF (270 mL) at 35 °C was slowly added (80 min)
a mixture of dibromide 8 (2.823 g, 4.70 mmol) and N,N′-di-p-tosyl-
1,3-diaminopropane (2.1 g, 5.5 mmol) in DMF (90 mL). The
reaction was further stirred for 30 min, and the solvent was removed
in vacuo. The residue was taken up in dichloromethane (250 mL)
and water (150 mL). The aqueous layer was extracted with
dichloromethane (3 × 30 mL). The organic layer was finally washed
with brine (3 × 50 mL), dried (MgSO4), and filtered, and the solvent
was evaporated. Column chromatography (silica, 1:1 dichlo-
romethane/heptane, dichloromethane gradient) afforded 2.79 g (72%
yield) of 10 as a pale-yellow solid, mp 193 °C; 1H NMR (300 MHz,
CDCl3): δ 1.23 (s, 18H; t-Bu-H), 1.67 (br m, 2H; δ-H), 2.43 (s,
3
6H; CH3), 2.92 (s, 4H; ꢀ-H), 3.09 (t, J ) 7.7 Hz, 4H; γ-H), 4.61
(s, 4H; â-H), 7.31 (d, 3J ) 8.3 Hz, 4H; c-H), 7.61 (d, 4J ) 2.4 Hz,
3
4
2H; 5-H), 7.68 (d, J ) 8.3 Hz, 4H; b-H), 7.83 (d, J ) 2.4 Hz,
2H; 3-H), 10.60 ppm (s, 2H; CHO); 13C NMR (75 MHz, CDCl3):
δ 21.9 (CH3), 25.8 (δ-C), 31.1 (C(CH3)3), 35.2 (C(CH3)3), 39.4
(ꢀ-H), 45.1 (γ-C), 48.4 (â-C), 126.5 (3-C), 127.4 (b-C), 130.3 (c-
C), 132.0 (5-C), 133.1 (1-C), 137.3 (2-C), 137.7 (a-C), 141.2 (6-
C), 144.0 (d-C), 153.5 (4-C), 192.7 ppm (CHO); IR (neat): ν 1688
(vs, CO), 2868 and 2960 cm-1 (s, C(O)-H); HRMS (ESI): calcd
for C43H52N2NaO6S4 [M + Na+], 843.26004; found 843.25736.
Macrocycle 11. A solution of hydroxylamine‚HCl (0.168 g, 2.41
mmol) in 5% aqueous sodium hydroxide (2.5 mL) was added to a
solution of macrocycle 10 (0.200 g, 0.24 mmol) in absolute ethanol
(5 mL). After 3 h reflux, the reaction mixture was diluted with
dichloromethane (100 mL) and water (50 mL). The organic layer
was washed with water (2 × 25 mL), dried (MgSO4), and filtered,
and the solvents were evaporated. Column chromatography (silica,
dichloromethane, 5% methanol in dichloromethane gradient) af-
forded 0.160 g (77% yield) of 11 as a colorless solid, mp 255-
4
4H; ꢀ-H), 4.89 (s, 4H; â-H), 7.78 (d, J ) 2.4 Hz, 2H; 5-H), 7.88
(d, 4J ) 2.4 Hz, 2H; 3-H), 10.68 ppm (s, 2H; CHO); 13C NMR (75
MHz, CDCl3): δ 31.3 (C(CH3)3), 35.3 (C(CH3)3), 38.0 (ꢀ-C), 63.5
(â-C), 125.7 (3-C), 131.8 (5-C), 132.8 (1-C), 138.0 (2-C), 145.9
(6-C), 153.5 (4-C), 193.3 ppm (CHO); IR (neat): ν 1046 (s, CH2-
O), 1685 (vs, CO), 2868 and 2962 (s, C(O)-H), 3377 cm-1 (m, br,
OH); elemental analysis calcd (%) for C26H34O4S2‚0.5CH3OH
(490.71): C 64.86, H 7.39, S 13.07; found: C 64.95, H 7.44, S
13.06.
1,2-Bis(4-tert-butyl-2-formyl-6-bromomethylphenylsulfanyl)-
ethane 8. Thionyl bromide (0.10 mL, 0.71 mmol) was added to a
solution of diol 7 (0.150 g, 0.31 mmol) and pyridine (0.05 mL,
0.62 mmol) in dichloromethane (4 mL) at 0 °C. After stirring for
4.5 h under gentle reflux, the reaction mixture was diluted with
dichloromethane (40 mL) and washed with water (3 × 40 mL).
The combined organic phases were dried (MgSO4) and filtered,
and the solvent was evaporated to dryness. Column chromatography
(silica, 7:1 dichloromethane/pentane) of the crude product combined
from two identical runs afforded 0.255 g (67% yield) of 8 as a
1
256 °C; H NMR (300 MHz, CDCl3): δ 1.21 (s, 18H; C(CH3)3),
1.62 (br m, 2H; δ-H), 2.44 (s, 6H; CH3), 2.78 (s, 4H; ꢀ-H), 3.09 (t,
3
3J ) 7.7 Hz, 4H; γ-H), 4.56 (s, 4H; â-H), 7.32 (d, J ) 8.3 Hz,
4
4
4H; c-H), 7.40 (d, J ) 2.1 Hz, 2H; 5-H), 7.68 (d, J ) 2.1 Hz,
3
1
2H; 3-H), 7.69 (d, J ) 8.3 Hz, 4H; b-H), 8.27 (br s, 2H, NOH),
brown solid, mp 144-147 °C; H NMR (300 MHz, CDCl3): δ
8.70 ppm (s, 2H; R-H); 13C NMR (75 MHz, CDCl3): δ 21.7 (CH3),
26.1 (δ-H), 31.1 (C(CH3)3), 34.9 (C(CH3)3), 37.7 (ꢀ-C), 45.3 (γ-
H), 49.2 (â-H), 123.9 (3-C), 127.3 (b-C), 127.8 (5-C), 129.1 (1-
C), 130.1 (c-C), 135.6 (2-C), 137.1 (a-C), 140.3 (6-C), 143.7 (d-
C), 150.2 (R-C), 152.8 ppm (4-C); IR (neat): ν 970 (s, N-OH),
2958 (m, NC-H), 3299 cm-1 (w, O-H); HRMS (ESI): calcd for
C43H54N4NaO6S4 [M + Na+], 873.28184; found 873.28376.
Macrocycle 12. Sodium borohydride (0.14 g, 0.37 mmol) was
added to a solution of dialdehyde 10 (0.500 g, 0.61 mmol) in
methanol (80 mL) at 0 °C. After 1 h of stirring, sodium hydro-
gencarbonate (5% aqueous solution, 20 mL) was added to the
reaction mixture, which was subsequently taken up in dichlo-
romethane (200 mL) and water (100 mL). The organic layer was
washed with water (2 × 100 mL), dried (MgSO4), and filtered,
and the solvents were evaporated, affording macrocycle 12 (0.500
1.35 (s, 18H; t-Bu-H), 2.96 (s, 4H; ꢀ-H), 4.82 (s, 4H; â-H), 7.73
4
4
(d, J ) 2.4 Hz, 2H; 5-H), 7.90 (d, J ) 2.4 Hz, 2H; 3-H), 10.67
ppm (s, 2H; CHO); 13C NMR (75 MHz, CDCl3): δ 31.3 (C(CH3)3),
31.8 (â-C), 35.3 (C(CH3)3), 37.9 (ꢀ-C), 126.9 (3-C), 133.9 (5-C),
134.1 (1-C), 138.6 (2-C), 143.5 (6-C), 153.8 (4-C), 192.9 ppm
(CHO); IR (neat): ν 1681 (vs, CO), 2856 and 2955 (s, C(O)-H),
3068 cm-1 (w, ArH); HRMS (ESI): calcd for C26H32Br2NaO2S2
[M + Na+], 621.01027; found 621.00855.
1,2-Bis(4-tert-butyl-2-formyl-6-chloromethylphenylsulfanyl)-
ethane 9. Thionyl chloride (0.10 mL, 1.3 mmol) was added to a
solution of diol 7 (0.300 g, 0.63 mmol) and pyridine (0.11 mL, 1.3
mmol) in dichloromethane (8 mL) at 0 °C. After stirring for 2 h at
0 °C and 3 h at room temperature, the reaction mixture was diluted
with dichloromethane (40 mL) and washed with water (2 × 40
mL). The water layer was extracted back with dichloromethane (2
× 20 mL). The combined organic phases were dried (MgSO4),
1
g) quantitatively as a colorless solid, mp 180-184 °C; H NMR
(300 MHz, CDCl3): δ 1.21 (s, 18H; C(CH3)3), 1.62 (br m, 2H;
3
δ-H), 2.17 (t, J ) 6.1 Hz, 2H; OH), 2.43 (s, 6H; CH3), 2.93 (s,
(46) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837-838.
(47) (a) Bax, A.; Davis, D. G. J. Magn. Reson. 1985, 63, 207-213. (b)
Desvaux, H.; Berthault, P.; Birlirakis, N.; Goldman, M.; Piotto, M. J. Magn.
Reson. A 1995, 113, 47-52.
3
4H; ꢀ-H), 3.03 (t, J ) 7.8 Hz, 4H; γ-H), 4.61 (s, 4H; â-H), 4.83
(d, 3J ) 6.1 Hz, 4H; R-H), 7.24 (d, 4J ) 2.4 Hz, 2H; 5-H), 7.30 (d,
4
3J ) 8.3 Hz, 4H; c-H), 7.38 (d, J ) 2.4 Hz, 2H; 3-H), 7.69 ppm
J. Org. Chem, Vol. 73, No. 3, 2008 879

Bonnot et al.
3
(d, J ) 8.3 Hz, 4H; b-H); 13C NMR (75 MHz, CDCl3): δ 21.9
(C(CH3)3), 37.2 (ꢀ-C), 44.9 (γ-C), 46.1 (R-C), 49.5 (â-C), 126.6
(5-C), 127.4 (b-C), 127.7 (3-C), 128.9 (1-C), 130.3 (c-C), 137.6
(a-C), 141.1 (6-C), 142.2 (2-C), 143.8 (d-C), 153.5 ppm (4-C);
HRMS (ESI): calcd for C43H54Cl2N2NaO4S4 [M + Na+], 883.22357;
found 883.22799.
(CH3), 26.1 (δ-C), 31.3 (C(CH3)3), 35.1 (C(CH3)3), 37.4 (ꢀ-C), 45.0
(γ-C), 49.7 (â-C), 65.0 (R-C), 125.9 and 126.0 (3-C and 5-C), 127.5
(b-C), 127.8 (1-C), 130.3 (c-C), 137.5 (a-C), 140.6 (6-C), 143.8
(d-C), 145.1 (2-C), 153.4 ppm (4-C); HRMS (ESI): calcd for
C43H56N2NaO6S4 [M + Na+], 847.29134; found 847.29411.
Macrocycle 13. DIAD (4.10 mL, 20.72 mmol) was slowly added
to a solution of macrocycle 12 (5.7 g, 6.9 mmol), phthalimide (3.05
g, 20.72 mmol), and triphenylphosphine (5.44 g, 20.72 mmol) in
THF (235 mL) at 0 °C. After stirring the reaction mixture for 3 h
at 0 °C, the solvent was evaporated and the residue was dissolved
in dichloromethane (300 mL). The organic layer was washed with
5% aqueous sodium hydroxide (3 × 150 mL). The aqueous layer
was extracted back with dichloromethane (2 × 100 mL). The
combined organic extracts were washed with water (3 × 250 mL)
until neutrality, dried (MgSO4), and filtered, and the solvent was
evaporated. Column chromatography (silica, 20% heptane in
dichloromethane, dichloromethane gradient) afforded a first crop
of pure 13 (4.31 g). Further amounts (2.72 g) were obtained by
crystallization from 1:2 dichloromethane/ethanol. Total yield : 94%.
13, mp 171-173 °C; 1H NMR (300 MHz, CDCl3): δ 1.11 (s, 18H;
C(CH3)3), 1.66 (br m, 2H; δ-H), 2.42 (s, 6H; CH3), 3.06 (s, 4H;
Macrocycle 16. Diiodine (0.612 g, 2.41 mmol), imidazole (0.067
g, 0.96 mmol), and finally a solution of macrocycle 12 (0.398 g,
0.48 mmol) in dichloromethane (20 mL) were sequentially added
to a stirred solution of triphenylphosphine (0.634 g, 2.41 mmol) in
dichloromethane (25 mL) at 0 °C, allowing 10 min periods between
each addition. After 2 h stirring the reaction was quenched by
addition of water (40 mL) and dichloromethane (50 mL). The
organic layer was washed with sodium hydrogencarbonate (5%
aqueous solution, 2 × 45 mL) and sodium hydrogensulfite (0.1%
aqueous solution, 2 × 45 mL), dried (MgSO4), and filtered, and
the solvent was evaporated. Macrocycle 16 crystallized from 1:10
dichloromethane/ethanol (22 mL) as colorless aggregates (0.405
1
g) in 80% yield, mp 202-204 °C; H NMR (300 MHz, CDCl3):
δ 1.20 (s, 18H; C(CH3)3), 1.65 (br m, 2H; δ-H), 2.43 (s, 6H; CH3),
3
3.05 (t, J ) 7.7 Hz, 4H; γ-H), 3.06 (s, 4H; ꢀ-H), 4.62 (s, 4H;
4
â-H), 4.76 (s, 4H; R-H), 7.23 (d, J ) 2.3 Hz, 2H; 5-H), 7.30 (d,
4
3J ) 8.1 Hz, 4H; c-H), 7.37 (d, J ) 2.3 Hz, 2H; 3-H), 7.69 ppm
3
3
ꢀ-H), 3.08 (t, J ) 8.1 Hz, 4H; γ-H), 4.67 (s, 4H; â-H), 5.21 (s,
(d, J ) 8.1 Hz, 4H; b-H); 13C NMR (75 MHz, CDCl3): δ 6.5
4
4
4H; R-H), 7.15 (d, J ) 2.4 Hz, 2H; 3-H), 7.26 (d, J ) 2.4 Hz,
(R-C), 21.9 (CH3), 25.4 (δ-C), 31.2 (C(CH3)3), 35.0 (C(CH3)3), 36.0
(ꢀ-H), 44.7 (γ-C), 49.3 (â-H), 126.0 (5-C), 127.4 (b-C), 127.6 (3-
C), 128.0 (1-C), 130.3 (c-C), 137.6 (a-C), 141.3 (6-C), 143.8 (2-
C), 144.0 (d-C), 153.5 ppm (4-C); elemental analysis calcd (%)
for C43H54I2N2O4S4 (1044.98): C 49.43, H 5.21, N 2.68; found: C
49.34, H 5.19, N 2.68. HRMS (ESI): calcd for C43H54I2N2NaO4S4
[M + Na+], 1067.09480; found 1067.09825.
3
3
2H; 5-H), 7.30 (d, J ) 8.3 Hz, 4H; c-H), 7.70 (d, J ) 8.3 Hz,
4H; b-H), 7.74 (dd, 3J ) 3.2 Hz, 4J ) 5.6 Hz, 4H; δ′-H), 7.88 ppm
(dd, J ) 3.2 Hz, J ) 5.6 Hz, 4H; γ′-H); 13C NMR (75 MHz,
CDCl3): δ 21.9 (CH3), 25.5 (δ-C), 31.2 (C(CH3)3), 35.0 (C(CH3)3),
37.0 (ꢀ-C), 40.7 (R-C), 44.9 (γ-C), 49.5 (â-C), 123.8 (γ′-C), 124.6
(3-C), 125.3 (5-C), 127.5 (b-C), 127.7 (1-C), 130.3 (c-C), 132.4
(â′-C), 134.5 (δ′-C), 137.7 (a-C), 140.8 (6-C and 2-C), 143.7 (d-
C), 153.1 (4-C), 168.6 ppm (R′-C); MS (LSI-MS): m/z (%): 1083
(100) [M+], 927 (81) [M+ - Ts]; elemental analysis calcd (%) for
C59H62N4O8S4 (1083.43): C 65.41, H 5.77, N 5.17; found: C 65.37,
H 5.70, N 5.16.
3
4
Macrotricycle 17. Separate solutions of macrocycle 10 (2.50 g,
3.04 mmol) and macrocycle 14 (2.51 g, 3.04 mmol) each in
dichloromethane (100 mL) were added simultaneously over 15 h
to a suspension of 3 Å molecular sieves in dichloromethane (175
mL) at 30 °C. After stirring for a week, the solvent was evaporated
and the residue was taken up in THF (250 mL) and methanol (250
mL). The brown suspension was chilled to 0 °C and treated with
sodium borohydride (0.115 g, 3.04 mmol). After 3 h stirring, sodium
hydrogen-carbonate was added (5% aqueous solution, 250 mL).
The mixture was then diluted with dichloromethane (400 mL) and
water (200 mL). The aqueous layer was extracted with dichlo-
romethane (2 × 250 mL). The organic layer was washed with water
(2 × 300 mL), dried (MgSO4), filtered and the solvent evaporated.
The resulting tan solid was crystallized from 2:5 dichloromethane/
ethanol (70 mL). Macrotricycle 17 was obtained as colorless crystals
(3.502 g) in 71% yield. Crystals of [17‚2H](CF3CO2)2 suitable for
X-ray diffraction were obtained by layering with cyclohexane a
solution of macrotricycle 17 (0.020 g, 0.0124 mol) and trifluoro-
acetic acid (0.002 mL, 0.0273 mmol) in dichloromethane (3 mL).
17, mp 238-239 °C; 1H NMR (500 MHz, CDCl3): δ 1.20 (s, 36H;
C(CH3)3), 1.55 (br m, 6H; δ-H and NH), 2.44 (s, 12H; CH3), 2.97
(s, 8H; ꢀ-H), 3.00 (br t, 8H; γ-H) 4.00 (s, 8H; R-H), 4.62 (s, 8H;
Macrocycle 14. Hydrazine hydrate (3.15 mL, 64.8 mmol) was
added to a suspension of macrocycle 13 (7.03 g, 6.48 mmol) in
refluxing ethanol (800 mL). After 4 h of reaction, the solvent was
evaporated and the residue was taken up in dichloromethane (600
mL). The organic layer was washed with 5% aqueous sodium
hydroxide (2 × 250 mL) and then water (2 × 250 mL), dried
(MgSO4), and filtered, and the solvent was evaporated, leaving
macrocycle 14 as a colorless solid (5.32 g) quantitatively, mp 167-
1
169 °C; H NMR (300 MHz, CDCl3): δ 1.20 (s, 18H; C(CH3)3),
1.62 (br m, 2H; δ-H), 1.75 (br s, 4H; NH2), 2.43 (s, 6H; CH3),
3
2.87 (s, 4H; ꢀ-H), 3.04 (t, J ) 7.7 Hz, 4H; γ-H), 4.00 (s, 4H;
4
R-H), 4.62 (s, 4H; â-H), 7.19 (d, J ) 2.3 Hz, 2H; 5-H), 7.30 (d,
3J ) 8.1 Hz, 4H; c-H), 7.30 (d, J ) 2.3 Hz, 4H; 3-H), 7.69 ppm
4
3
(d, J ) 8.1 Hz, 4H; b-H); 13C NMR (75 MHz, CDCl3): δ 21.9
(CH3), 25.9 (δ-H), 31.3 (C(CH3)3), 35.1 (C(CH3)3), 37.2 (ꢀ-H), 44.9
(γ-H), 46.2 (R-H), 49.6 (â-H), 124.9 (5-C), 125.5 (3-C), 127.4 (b-
C), 127.7 (1-C), 130.2 (c-C), 137.6 (a-C), 140.6 (6-C), 143.7 (d-
C), 147.6 (2-C), 153.3 ppm (4-C); HRMS (ESI): calcd for
C43H59N4O4S4 [M + H+], 823.34137; found 823.34258.
4
3
â-H), 7.23 (d, J ) 2.0 Hz, 4H; 5-H), 7.32 (d, J ) 8.5 Hz, 8H;
4
3
c-H), 7.42 (d, J ) 2.0 Hz, 4H; 3-H), 7.72 ppm (d, J ) 8.5 Hz,
8H; b-H); 13C NMR (75 MHz, CDCl3): δ 21.9 (CH3), 25.8 (δ-C),
31.4 (C(CH3)3), 35.1 (C(CH3)3), 37.3 (ꢀ-C), 45.0 (γ-C), 49.9 (â-
C), 53.8 (R-C), 124.9 (5-C), 125.9 (3-C), 127.4 (b-C), 128.5 (1-
C), 130.3 (c-C), 137.5 (a-C), 140.5 (6-C), 143.8 (d-C), 144.6 (2-
C), 153.1 ppm (4-C); MS (MALDI-TOF): m/z (%): 1612.4 [M+],
1456.7 [M+ - Ts]; elemental analysis calcd (%) for C86H110N6O8S8
(1612.38): C 64.06, H 6.88, N 5.21; found: C 64.16, H 7.01, N
5.01.
Macrocycle 15. Thionyl chloride (0.02 mL, 0.27 mmol) was
added to a solution of macrocycle 12 (0.101 g, 0.12 mmol) and
pyridine (0.03 mL, 0.36 mmol) in dichloromethane (5 mL) at
0 °C. After stirring for 21 h at room temperature, the reaction
mixture was diluted with dichloromethane (25 mL) and washed
with water (3 × 20 mL). The combined organic phases were dried
(MgSO4), filtered, and evaporated to dryness. Column chromatog-
raphy (silica, 1:1 dichloromethane/heptane) afforded macrocycle
15 (0.085 g) as a colorless solid in 81% yield, mp 129-130 °C;
1H NMR (300 MHz, CDCl3): δ 1.22 (s, 18H; C(CH3)3), 1.66 (br
Macropentacycle 5 and Macrononacycle 18. A solution of
macrotricycle 17 (2.315 g, 1.43 mmol) and macrocycle 16 (1.50 g,
1.43 mmol) in 1:1 toluene/acetonitrile (86 mL) was added, over
24 h, to a suspension of cesium carbonate (4.685 g, 14.35 mmol)
in 1:1 toluene/acetonitrile (430 mL) at 50 °C. After 5 days of
stirring, the solvents were evaporated and the residue was taken
up in dichloromethane (300 mL). The organic layer was washed
3
m, 2H; δ-H), 2.43 (s, 6H; CH3), 2.97 (s, 4H; ꢀ-H), 3.06 (t, J )
8.0 Hz, 4H; γ-H), 4.62 (s, 4H; â-H), 4.88 (s, 4H; R-H), 7.30 (d, 3J
) 8.6 Hz, 4H; c-H), 7.32 (d, 4J ) 2.4 Hz, 2H; 5-H), 7.40 (d, 4J )
2.4 Hz, 2H; 3-H), 7.69 ppm (d, J ) 8.6 Hz, 4H; b-H); 13C NMR
3
(125 MHz, CDCl3): δ 21.8 (CH3), 25.5 (δ-C), 31.2 (C(CH3)3), 35.1
880 J. Org. Chem., Vol. 73, No. 3, 2008

In, out Pseudohelix of a Diaza-Macropentacycle
2
2
with water (3 × 150 mL), dried (MgSO4), filtered, and concentrated
to 40 mL. The resulting solution was treated with a solution of
trifluoromethanesulfonic acid (0.500 g, 3.3 mmol) in dichlo-
romethane (10 mL) and refluxed for 36 h. The residue obtained
after evaporation of the solvent was dissolved in the minimum
amount of dichloromethane (10 mL), and the resulting solution
layered with 1:1 dichloromethane/ethylacetate (10 mL) and ethyl
acetate (40 mL). Slow evaporation (48 h) afforded colorless crystals
(in fact a mixture of [5‚H](OTf)22 and 18) which were collected
and rinsed with ethyl acetate (3 × 30 mL). [5‚H](OTf) and 18 were
separated by column chromatography on silica eluting with 20%
heptane/dichloromethane, 10% methanol/dichloromethane gradient.
Monoprotonated macropentacycle [5‚H](OTf) was obtained as a
colorless solid (1.95 g) in 53% yield and macrononacycle 18 was
obtained as a colorless solid (0.512 g) in 7% yield.
4.39 (d, J ) 15.0 Hz, 1H; â′B-H), 4.60 (d, J ) 17.0 Hz, 1H;
â′D-H), 4.64-4.77 (br m, 4H; â′F-H, RE-H, RF-H and âD-H), 4.82
2
2
(d, J ) 15.0 Hz, 1H; âB-H), 4.86 (d, J ) 18.3 Hz, 1H; âE-H),
5.16-5.25 (br m, 2H; âA-H and âF-H), 5.27 (br d, 2J ) 8 Hz, 1H;
2
2
âC-H), 5.38 (d, J ) 16.3 Hz, 1H; RA-H), 5.45 (d, J ) 16.5 Hz,
1H; RC-H), 6.09 (d, 3J ) 7.5 Hz, 2H; cD-H), 6.43 (br s, 2H; cF-H),
3
6.80 (s, 1H; 5C-H), 6.88 (s, 1H; 5A-H), 7.19 (d, J ) 7.5 Hz, 2H;
cE-H), 7.25-7.40 (m, 12H; cA, 5E, cB, 3D, cC, bF and bD), 7.44 (s,
3
1H; 3E-H), 7.48 (br s, 3H; bE-H and 3F-H), 7.53 (d, J ) 7.5 Hz,
2H; bA-H), 7.56 (d, 3J ) 8.0 Hz, 2H; bC-H), 7.64 (s, 1H; 5B-H, and
3
d, J ) 8.5 Hz, 2H; bB-H), 7.69 (s, 1H; 5D-H), 7.82 (br s, 1H;
5F-H), 7.92 (s, 1H; 3C-H), 8.19 (s, 1H; 3B-H), 8.22 ppm (s, 1H;
3A-H); MS (MALDI-TOF): m/z (%): 2401.1 [M+], 2245.0 [M+
- Ts]; elemental analysis calcd (%) for C129H162N8O12S12‚0.5CH2-
Cl2 (2444.01): C 63.64, H 6.72, N 4.58, S 15.74; found: C 63.73,
H 7.09, N 4.99, S 15.78.
Free base macropentacycle 5 was obtained as follows: a solution
of sodium methoxide (10 mL, 0.172 M, 1.7 mmol) in methanol
was added to a solution of [5‚H](OTf) (0.217 g, 0.085 mmol) in
methanol (20 mL). After 24 h stirring the solvent was evaporated.
The residue was taken up in dichloromethane (20 mL) and the
organic layer washed with water (2 × 20 mL), dried (MgSO4),
filtered, and evaporated to dryness, leaving macropentacycle 5 as
a colorless solid (0.200 g) in 98% yield. Crystals suitable for X-ray
diffraction were obtained by slow evaporation of a 1:1 acetonitrile/
dichloromethane solution.
18, mp 257-260 °C; 1H NMR (500 MHz, C2D2Cl4, 340 K): δ
1.24 (two s, 36H; t-Bu′-H, and 72H; t-Bu-H), 1.53 (br m, 4H; δ-H),
1.61 (br m, 4H; δ-H), 1.95 (br m, 4H; δ′-H), 2.40 (s, 12H; e′-H),
2.46 (s, 24H; e-H), 2.77 (s, 8H; ꢀ′-H), 2.96 (s, 16H; γ-H), 3.06 (br
q, 16H; ꢀ-H), 3.28 (br t, 8H; γ′-H), 3.88 (br s, 8H; R′-H), 3.89 (dd,
ABJ ) 13.9 Hz, ∆νAB ) 21.9 Hz, 16H; R-H), 4.57 (s, 8H; â′-H),
4.72 (dd, ABJ ) 17.0 Hz, ∆νAB ) 49.3 Hz, 16H; â-H), 7.16 (s, 4H;
3
5′-H), 7.24 (br s, 8H; 5-H), 7.28 (d, J ) 8.2 Hz, 8H; c′-H), 7.35
3
3
(d, J ) 8.2 Hz, 16H; c-H), 7.66 (s, 4H; 3′-H), 7.67 (d, J ) 8.1
Hz, 8H; b′-H), 7.72 (d, 3J ) 8.1 Hz, 16H; b-H), 7.77 ppm (s, 8H;
3-H); 13C NMR (151 MHz, C2D2Cl4, 350 K): δ 21.2 (CH3′), 21.3
(CH3), 24.8 (δ-C), 26.0 (δ′-C), 31.0 (C(CH3)3′), 31.0 (C(CH3)3),
34.5 (C(CH3)3′ and C(CH3)3), 37.0 (ꢀ′-C), 37.2 (ꢀ-C), 44.0 (γ-C),
44.7 (γ′-C), 48.6 (â-C), 49.7 (â′-C), 55.4 (R′-C), 57.1 (R-C), 124.1
(5′-C), 124.4 (5-C), 125.8 (3 and 3′-C), 126.9 (b and b′-C), 128.4
(1-C), 128.5 (1′-C), 129.7 (c′-C), 129.8 (c-C), 137.3 (a′-C), 137.7
(a-C), 139.3 (6′-C), 139.8 (6-C), 143.2, 143.3 (2×), 143.6 (2, 2′,
d, d′-C), 152.3 (4′-C), 152.6 (4-C); MS (TOF-ESI): m/z (%):
4802.9 [M+]; elemental analysis calcd (%) for C258H324N16O24S24
(4803.09): C 64.52, H 6.80, N 4.67, S 16.02; found: C 64.55, H
6.93, N 4.72, S 16.21.
1
5, mp 240-244 °C. H NMR (500 MHz, C2D2Cl4, 380 K): δ
1.28 (s, 54H; t-Bu-H), 1.65 (br m, 6H; δ-H), 2.41 (s, 18H; e-H),
2.92 (s, 12H; ꢀ-H), 3.14 (br t, 12H; γ-H), 4.19 (s, 12H; R-H), 4.67
(s, 12H; â-H), 7.24 (d, 3J ) 7.8 Hz, 12H; c-H), 7.47 (s, 6H; 5-H),
7.67 (d, 3J ) 7.8 Hz, 12H; b-H), 7.76 ppm (s, 6H; 3-H); 13C NMR
(151 MHz, C2D2Cl4, 350 K): δ 21.2 (CH3), 25.6 (δ-C), 30.8
(C(CH3)3), 34.4 (C(CH3)3), 38.8 (ꢀ-C), 45.5 (γ-C), 50.4 (â-C), 58.1
(R-C), 126.2 (5-C), 126.6 (3-C), 127.1 (b-C), 129.6 (c-C), 130.6
(1-C), 137.4 (a-C), 140.4 (6-C), 143.0 (2-C), 143.2 (d-C), 152.2
1
(4-C); H NMR (500 MHz, CD2Cl2, 200 K): δ -0.47 (br s, 2H;
δ′AD-H and δ′CF-H), 0.54 (br s, 1H; δCF-H), 0.65 (br s, 1H; δAD
-
H), 0.92 (s, 9H; t-BuC-H), 1.07 (s, 9H; t-BuA-H), 1.19 (s, 9H; t-BuE-
H), 1.21 (s, 9H; t-BuB-H), 1.26 (s, 9H; t-BuD-H), 1.30 (s, 9H; t-BuF-
H), 1.43 (br s, 1H; δ′BE-H), 1.54 (br t, 1H; ꢀ′D-H), 1.96 (br s, 6H;
eF and eD), 2.00 (br m, 2H; ꢀD-H and ꢀE-H), 2.10 (br s, 2H; δBE-H
and γ′C-H), 2.22 (d, 2J ) 12.5 Hz, 1H; γ′A-H), 2.35 (s, 3H; eE-H),
2.38 (s, 3H; eA-H), 2.39 (s, 3H; eC-H), 2.42 (s, 4H; ꢀF-H and eB-
H), 2.54 (br m, 2H; γ′B-H and ꢀ′F-H), 2.63-2.76 (br m, 3H; ꢀ′B-H,
Acknowledgment. We thank Dr. Jean-Michel Barbe and Ms.
Marie-Jose´ Penouilh (ICMUB) for the EI and ESI mass spectra
and Ms. Evelyne Pousson (ICMUB) for the elemental analyses.
The referees are acknowledged for helpful comments.
2
ꢀA-H and γ′E-H), 2.78 (d, J ) 12.0 Hz, 1H; R′D-H), 2.87 (br t,
Supporting Information Available: ORTEP views of 5, 10,
and 18, VT 1H NMR spectra of 18, full range 1H NMR spectra of
5 in various solvents and/or at VT, low-temperature COSY and
ROESY 1H and 1H/13C HSQC NMR spectra of 5, 1H and 13C NMR
spectra of compounds 7-17, and high-temperature 13C NMR spectra
of 5 and 18. This material is available free of charge via the Internet
at http://pubs.acs.org.
2
1H; γD-H), 2.91 (d, J ) 11.0 Hz, 2H; R′E-H and γF-H), 2.95-
2
3.10 (br m, 4H; γC-H, γA-H, ꢀ′C-H, ꢀB-H), 3.12 (d, J ) 11 Hz,
2
2
1H; â′A-H), 3.18 (br d, J ) 8 Hz, 1H; â′C-H), 3.27 (d, J ) 10.5
Hz, 1H; R′F-H), 3.39 (br t, 1H; γB-H), 3.45-3.63 (br m, 3H; γ′F-
H, γ′D-H and ꢀC-H), 3.67 (d, 2J ) 16.5 Hz, 1H; R′C-H), 3.70 (br d,
2J ) 12.0 Hz, 1H; ꢀ′A-H), 3.77 (d, 2J ) 12.0 Hz, 1H; RD-H), 3.86
2
(br s, 1H; γE-H), 3.88 (br s, 2H; RB-H and R′B-H), 4.02 (d, J )
16.3 Hz, 2H; R′A-H and ꢀ′E-H), 4.12 (d, 2J ) 18.3 Hz, 1H; â′E-H),
JO701984Z
J. Org. Chem, Vol. 73, No. 3, 2008 881