Chiral pyridine-based macrobicyclic clefts: Synthesis and enantiomeric recognition of ammonium salts

Article abstract of DOI:10.1021/jo960890u

An achiral (3) and two chiral pyridine-based macrobicyclic clefts (4 and 5) have been prepared by treating 2,6-bis[[2′,6′-bis(bromomethyl)-4′-methylphenoxy]methyl] pyridine (2) with the appropriate achiral and chiral glycols. Starting 2 was prepared by fi

Full text of DOI:10.1021/jo960890u

7270
J . Org. Chem. 1996, 61, 7270-7275
Ch ir a l P yr id in e-Ba sed Ma cr obicyclic Clefts: Syn th esis a n d
En a n tiom er ic Recogn ition of Am m on iu m Sa lts
Paul C. Hellier, J erald S. Bradshaw,* J . J olene Young, Xian Xin Zhang, and Reed M. Izatt
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602
Received May 14, 1996X
An achiral (3) and two chiral pyridine-based macrobicyclic clefts (4 and 5) have been prepared by
treating 2,6-bis[[2′,6′-bis(bromomethyl)-4′-methylphenoxy]methyl]pyridine (2) with the appropriate
achiral and chiral glycols. Starting 2 was prepared by first treating 2,6-bis(hydroxymethyl)-4-
methylphenol with 2,6-[(tosyloxy)methyl]pyridine followed by phosphorus tribromide. Achiral
macrobicyclic cleft 3 formed a complex at 25 °C in 50% CH3OH/50% CHCl3 (v/v) with a primary
ammonium salt (log K ) 3.15) as evidenced by a significant change in the 1H NMR spectrum.
Highly organized (S,S,S,S)-4, prepared by treating 2 with (1S,5S)-3-oxapentane-1,5-diol, exhibited
recognition at 25 °C in 20% C2H5OH/80% 1,2-C2H4Cl2 (v/v) for the (S)-enantiomer of R-(1-naphthyl)-
ethylammonium perchlorate (NapEt) over its (R)-form (∆ log K ) 0.85). This high recognition
factor probably reflects an increase in molecular rigidity by the introduction of a second macro
ring on the monocyclic pyridinocrown ligand.
In tr od u ction
based on the pyridine-18-crown-6 structure.3a This host-
guest pairing is particularly suited to such studies
because of the strong intermolecular binding observed,
arising from 3-point hydrogen bonding of the ammonium
hydrogen atoms to the pyridine nitrogen atom and two
of the oxygen atoms within the ring.6 A further contribu-
tion to the overall stability of the supramolecular complex
comes from the charge-dipole electrostatic interactions.
The systematic introduction of various substituents
around the macrocyclic ring has shed much light on the
effect that such structural modifications have upon the
differential binding of a pair of enantiomers. These
studies have been guided by the characterisation of the
host-guest interactions using a variety of physical
techniques including 1H NMR spectroscopy,7-11 calori-
metric titration,7 X-ray crystallography,7,10 and molecular
mechanics calculations.10,11 Crown ethers of this type,
when bound to silica gel, have been shown to successfully
effect the separation of the (R) and (S) forms of R-(1-
naphthyl)ethylammonium perchlorate.12
The study of chirality at the molecular level has
emerged as a central theme in contemporary chemistry.
Much of the stimulus for this interest originated from
the chiral nature of many biomolecules and their interac-
tion with other molecules. Chiral molecules find use in
pharmaceuticals and agrochemicals. While the field of
asymmetric synthesis has progressed at a tremendous
rate in recent years,1 there are still many instances where
these methods do not provide a practical means for the
preparation of pure homochiral compounds. Thus, there
is a continuing interest in the chromatographic separa-
tion of racemic mixtures using chiral stationary phases.2
Fundamental to the development of such materials is a
thorough understanding of the factors affecting chiral
recognition at the molecular level.3 The knowledge
gained through the study of this aspect of supramolecular
chemistry is also of importance because of the insight it
may give us into the forces driving biological recognition
phenomena such as enzyme-substrate and antibody-
antigen interactions.
The seminal work of Cram and co-workers4 on the
host-guest chemistry of primary ammonium salts and
1,1-binaphthol-derived chiral crown ethers illustrates
clearly the validity of this approach. Enantiomeric
recognition was optimized using a rational approach to
host design. The subsequent covalent attachment of such
compounds to an inert support resulted in systems
capable of effecting the enantiomeric separation of race-
mic amino acid and ester salts.5
As a result of their complexity, the synthesis of chiral
macrobicyclic hosts has been left relatively unexplored.13
Even less attention has been given to their use in
enantiomeric recognition studies, even though they offer
a number of potentially advantageous properties in
comparison to macromonocyclic structures. Macrobi-
(6) Izatt, R. M.; Zhu, C.-Y.; Dalley, N. K.; Curtis, J . C.; Kou, X.;
Bradshaw, J . S. J . Phys. Org. Chem. 1992, 5, 656.
(7) Davidson, R. B.; Bradshaw, J . S.; J ones, B. A.; Dalley, N. K.;
Christensen, J . J .; Izatt, R. M.; Morin, F. G.; Grant, D. M. J . Org. Chem.
1984, 49, 353.
(8) Bradshaw, J . S.; Thompson, P. K.; Izatt, R. M.; Morin, F. G.;
Grant, D. M. J . Heterocycl. Chem. 1984, 21, 897.
(9) Bradshaw, J . S.; Colter, M. L.; Nakatsuji, Y.; Spencer, N. O.;
Brown, M. F.; Izatt, R. M.; Arena, G.; Morin, F. G.; Grant, D. M. J .
Org. Chem. 1985, 50, 4865.
(10) Bradshaw, J . S.; Huszthy, P.; McDaniel, C. W.; Zhu, C. Y.;
Dalley, N. K.; Izatt, R. M.; Lifson, S. J . Org. Chem. 1990, 55, 3129.
(11) Huszthy, P.; Bradshaw, J . S.; Zhu, C. Y.; Izatt, R. M.; Lifson,
S. J . Org. Chem. 1991, 56, 3330.
(12) (a) Bradshaw, J . S.; Huszthy, P.; Wang, T.-M.; Zhu, C.-Y.;
Nazarenko, A. Y.; Izatt, R. M. Supramol. Chem. 1993, 1, 267. (b)
Huszthy, P.; Bradshaw, J . S.; Bordunov, A. V.; Izatt, R. M. Acta Chim.
Hung. 1994, 131, 445.
Our work has focused on the enantiomeric recognition
of chiral organic ammonium salts by chiral crown ethers
X Abstract published in Advance ACS Abstracts, October 1, 1996.
(1) Rahman, A.; Shah, Z. Stereoselective Synthesis in Organic
Chemistry; Springer-Verlag: New York, 1993.
(2) Pirkle, W. H.; Pochapsky, T. C. Chem. Rev. 1989, 89, 347.
(3) (a) Izatt, R. M.; Wang, T.-M.; Hathaway, J . K.; Zhang, X. X.;
Curtis, J . C.; Bradshaw, J . S.; Zhu, C.-Y.; Huszthy, P. J . Incl. Phenom.
Mol. Recognit. Chem. 1994, 17, 157. (b) Webb, T. H.; Wilcox, C. S.;
Chem. Soc. Rev. 1993, 22, 383.
(4) (a) Kyba, E. P.; Koga, K.; Sousa, L. R.; Siegel, M. G.; Cram, D.
J . J . Am. Chem. Soc. 1973, 95, 2692. (b) Hegelson, R. C.; Timko, J . M.;
Moreau, P.; Peacock, S. C.; Mayer, J . M.; Cram, D. J . J . Am. Chem.
Soc. 1974, 96, 6762.
(13) (a) Stoddart, J . F. Chiral Crown Ethers. In Topics In Stereo-
chemistry, Vol.17; Eliel, E. L., Wilen, S. H., Eds.; Wiley Interscience:
New York, 1988; pp 207-208. (b) Fyles, T. M.; Suresh, V. V.; Fronczek,
F. R.; Gandour, R. D. Tetrahedron Lett. 1990, 31, 1101. (c) Bako, P.;
Fenichel. L.; Toke. L. Liebigs. Ann. Chem. 1990, 1161.
(5) Sogah, D. G. Y.; Cram, D. J . J . Am. Chem. Soc. 1975, 97, 1259.
S0022-3263(96)00890-0 CCC: $12.00 © 1996 American Chemical Society

Chiral Pyridine-Based Macrobicyclic Clefts
J . Org. Chem., Vol. 61, No. 21, 1996 7271
Sch em e 1
nature of the cavity through the use of the appropriate
(e.g. chiral) diol in the final macrobicyclization step. An
analagous pyridine-based macrobicycle was recently
descibed by Lu¨ning and co-workers,19 although the
potential to render their macrobicycle chiral has yet to
be realized.
Resu lts a n d Discu ssion
The key precursor in the planned syntheses of the
chiral macrobicycles was the pyridine-bridged tetra-
bromide 2. This material was prepared according to the
route depicted in Scheme 1. 2,6-[(Tosyloxy)methyl]-
pyridine was treated with 2 equiv of 4-methyl-2,6-bis-
(hydroxymethyl)phenol in acetone using potassium car-
bonate as a base. Regioselective alkylation of the more
acidic phenolic oxygen atoms occurred to give tetraalcohol
1 in an 83% yield. This gave access to 2 via bromination
with phosphorus tribromide.
We decided to begin our studies by preparing the
achiral pyridine-containing macrobicycle 3. This would
allow us to demonstrate the feasibility of the cyclization
strategy and verify that successful complexation of
organic ammonium salts would occur, before embarking
on more lengthy syntheses of chiral hosts. Thus, 2 was
treated with 2 equiv of diethylene glycol (Scheme 1) in
THF using NaH as a base. The desired compound 3 was
isolated as a white crystalline solid in a 13% yield. This
represents a reasonable yield for such a reaction, prob-
ably the result of a convergent nature of the bromomethyl
groups and the rigidity of precursor 2. The 1H NMR
spectrum of this compound gave clear evidence that the
expected cleftlike structure was maintained in solution.
The bulk and rigidity of the pyridine group prevents the
macrobicycle from inverting on itself. Thus, the two
hydrogens of the benzylic methylene groups on the
aromatic bridgeheads are magnetically inequivalent,
giving rise to two doublets of an AB system in contrast
to the singlet observed for the corresponding protons of
acyclic precursor 2.
cycles possess a three-dimensional cavity in which the
recognition event may take place, thus, possibly leading
to improved discrimination. In addition, recognition can
be encouraged by the large degree of preorganization that
is typically found in such molecules. The chiral recogni-
tion of amides and carboxylic acids has been demon-
strated in macrobicyclic hosts by Still and co-workers14
and Kilburn and co-workers,15 respectively. The great
potential of polycyclic structures in such studies is well
illustrated in a recent publication of Yoon and Still,16
where a macrotricyclic receptor showed binding of L-
amino acid derivatives with enantioselectivites as high
as 99% ee. Chiral cage-type cyclophanes of a similar
topology have also been investigated by Murakami and
co-workers.17
1H NMR spectroscopy gave clear evidence that achiral
macrobicycle 3 could function as a host for primary
ammonium salts. The addition of 1 equiv of (R)-(+)-(R-
phenylethyl)ammonium perchlorate (PhEt) to a solution
of the macrobicycle in a mixture of CDCl3 and CD3OD
(1:1, v:v) resulted in substantial spectral changes. For
instance, the doublet arising from the protons in the
3-position of the pyridine ring was shifted upfield from
δ 7.538 to δ 7.381. More complex changes were observed
in the spectrum reflecting the overall decrease in sym-
metry of the host-guest complex compared to the free
host arising from the chiral nature of the ammonium salt.
This could be seen clearly in the region δ 4.05 to δ 4.40
where the AB system, originating from the benzylic
methylene protons adjacent to the benzene rings, was
split into two distinctly separate AB patterns upon
complexation. A log K value of 3.15 (See Table 1) for the
complexation of (R)-(+)-PhEt was determined from the
chemical shift changes induced by the incremental ad-
dition of the salt, according to the technique described
by Zhu et al.20 In a similar manner, the association
constants for the binding of (R)-(-)-phenylglycinol hy-
drogen perchlorate (PhEtOH) and (R)-(+)-R-(1-naphthyl)-
The present work is concerned with the synthesis of
one achiral and two chiral macrobicylic hosts containing
pyridine rings (3-5) (Schemes 1 and 2). This topology
was chosen as previous studies on similar achiral com-
pounds had shown that the 1,2,3-substitution pattern on
the aromatic bridgeheads would result in the formation
of a cleftlike structure.18 This would allow ready access
into the cavity for a guest organic ammonium salt. The
incorporation of the rigid pyridine unit would impart a
good deal of preorganization to the molecule resulting in
a fixed conformation with the basic pyridine nitrogen
atom directed toward the base of the cleft. The opening
of the cleft is defined by the two polyether chains. Our
synthesis of the achiral pyridine-containing cleft (Scheme
1) was flexible, thus allowing us to readily control the
(14) Sanderson, P. E. J .; Kilburn, J . D.; Still, W. C. J . Am. Chem.
Soc. 1989, 111, 8314.
(15) Waymark, C. P.; Kilburn, J . D.; Gilles, I. Tetrahedron Lett. 1995,
36, 3051.
(16) Yoon, S. S.; Still, W. C. Tetrahedron Lett. 1994, 35, 2117.
(17) (a) Murakami, Y.; Hayashida, O. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 1140. (b) Murakami, Y.; Ohno, T.; Hayashida, O.; Hisaeda,
Y. J . Chem. Soc., Chem. Commun. 1991, 950.
(18) (a) Alston, D. R.; Slawin, A. M. Z.; Stoddart, J . F.; Williams, D.
J . Angew. Chem., Int. Ed. Engl. 1984, 23, 821. (b) Alston, D. R.; Slawin,
A. M. Z.; Stoddart, J . F.; Williams, D. J .; Zarzycki, R. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 693.(c) Richards, T. I.; Layden, K.; Warminski,
E. E.; Milburn, P. J .; Haslam, E. J . Chem. Soc., Perkin Trans. 1987,
2765.
(19) Lu¨ning, U.; Baumstark, R.; Schyja, W. Tetrahedron Lett. 1993,
34, 5063.
(20) Zhu, C. Y.; Bradshaw, J . S.; Oscarson, J . L.; Izatt, R. M. J . Incl.
Phenom. Mol. Recognit. Chem. 1992, 12, 275.

7272 J . Org. Chem., Vol. 61, No. 21, 1996
Hellier et al.
Ta ble 1. Log K, ∆H (k J /m ol), a n d T∆S (k J /m ol) Va lu esa Deter m in ed by 1H NMR a n d Ca lor im etr ic Titr a tion s for
In ter a ction s of Ch ir a l Ma cr ocyclic Liga n d s w ith En a n tiom er s of Th r ee P r im a r y Am m on iu m Ca tion sb in Va r iou s
Solven ts a t 25 °C
ligand
cation
log K
∆H
T∆S
∆log Kc
solventd
3
(R)-NapEt
(R)-PhEt
(R)-PhEtOH
(R)-NapEt
(S)-NapEt
(R)-PhEt
2.32 ( 0.05
3.15 ( 0.05
2.95 ( 0.04
ND
ND
ND
1 M/1 C
1 M/1 C
1 M/1 C
M
M
M
(S,S,S,S)-4
(S)-PhEt
ND
M
(R)-NapEt
(S)-NapEt
(R)-NapEt
(S)-NapEt
(R)-PhEt
(S)-PhEt
(R)-PhEt
(S)-PhEt
(R)-PhEt
2.49 ( 0.05
3.34 ( 0.04
2.26 ( 0.03
2.71 ( 0.03
2.47 ( 0.04
2.85 ( 0.02
2.48 ( 0.05
2.65 ( 0.05
1.77 ( 0.06
2.10 ( 0.04
2.47 ( 0.02
2.06 ( 0.02
3.88 ( 0.03
3.42 ( 0.04
2.96 ( 0.02
2.43 ( 0.04
2.33 ( 0.05
2.11 ( 0.05
-13.6 ( 0.8
-15.7 ( 0.7
0.61
3.36
2Et/8DCE
2Et/8DCE
2M/8C
2M/8C
5M/95C
5M/95C
1M/9C
1M/9C
1M/1C
1M/1C
M
0.85
0.45
0.38
0.17
0.33
0.41
0.46
0.53
0.22
(S)-PhEt
(S,S)-6
(S,S)-6
(R)-NapEte
(S)-NapEte
(R)-NapEt
(S)-NapEt
(R)-NapEtf
(S)-NapEtf
(R)-PhEtg
(S)-PhEtg
-27.6 ( 0.1
-26.4 ( 0.1
-29.2 ( 0.4
-23.5 ( 0.7
-18.9
-18.5
-7.00
-3.98
M
2Et/8DCE
2Et/8DCE
1M/1C
1M/1C
M
M
a
Log K values without ∆H and T∆S values were determined using the 1H NMR mehod. ND means not determined because no significant
b
chemical shift change was observed. Perchlorate salts of the ammonium cations were used. The notations of ammonium cations are
defined in Figure 2. c The ∆log K value is the difference between log K values for enantiomer interactions with a given chiral macrocyclic
d
ligand. M ) methanol; C ) chloroform; DCE ) 1,2-dichloroethane; Et ) ethanol. Solvent mixtures are indicated by volumetric ratios
of their components. For example, 1M/1C ) 50% methanol-50% chloroform (v/v). For NMR measurements, 100% deuterated solvents
were used. e Reference 7. f Reference 23. Reference 3a.
g
Sch em e 2
ethylammonium perchlorate (NapEt) were found to be
2.95 and 2.32, respectively. The lower value in the latter
case probably reflects the bulkier nature of the guest.
Having established that achiral pyridine-containing
macrobicycle 3 would effectively complex primary am-
monium salts, we prepared the chiral analogues. For this
purpose the homochiral methyl-substituted diethylene
glycol, (1S,5S)-3-oxapentane-1,5-diol, was prepared in
four steps from ethyl (S)-lactate according to the reported
procedure.21,22 Chiral tetramethyl-substituted macrobi-
cycle 4 was synthesized in a 14% yield by treating the
previously mentioned tetrabromide 2 with 2 equiv of the
dianion derived from the chiral diol (Scheme 2). In a
similar fashion a related chiral macrocycle (5), with a
smaller cavity, was prepared from (2R,4R)-pentanediol
which is commercially available. The analogous reaction
using (2R,3R)-butanediol was unsuccessful, possibly re-
flecting the increased strain in the still smaller cavity
size.
1
The H NMR spectrum of highly organized chiral host
4 is beautifully resolved (Figure 1), and clearly reflects
the C2 symmetry of the molecule that results from the
introduction of chirality, in contrast to the C2v symmetry
of its achiral analogue (3). Thus the benzylic methylene
groups of the aromatic bridgeheads now give rise to two
separate AB systems, resulting in a pair of doublets at δ
5.02 and 4.44; and δ 4.25 and 3.98. Similarly the protons
of the methylene group adjacent to the pyridine ring are
characterized by another AB system with signals at δ
5.33 and 4.97 instead of the usual singlet. The two
distinct environments of the polyether ring methyl groups
are identified by two doublets at δ 1.22 and 1.04. The
1H NMR spectrum when recorded at 500 MHz shows, in
the region δ 3.19 to 3.81, clear resolution of the remaining
six inequivalent protons on a single dimethyl-substituted
polyether section. Together with the two previously
(21) Huszthy, P.; Oue, M.; Bradshaw, J . S.; Zhu, C. Y.; Wang, T.
M.; Dalley, N. K.; Curtis, J . C.; Izatt, R. M. J . Org. Chem. 1992, 57,
5383.
(22) Dyer, R. B.; Metcalf, D. H.; Ghirardelli, R. G.; Palmer, R. A.;
Holt, E. M.; J . Am. Chem. Soc. 1986, 108, 3621.

Chiral Pyridine-Based Macrobicyclic Clefts
J . Org. Chem., Vol. 61, No. 21, 1996 7273
F igu r e 1. Proton NMR spectrum of 4.
mentioned methyl groups these constitute two inde-
pendent spin systems, the coupling interconnectivities of
1
which have been clearly established by a 2D-COSY H
1
NMR experiment. An NOE H NMR experiment aimed
at unambiguously assigning the relative spatial positions
of the ring methyl groups with respect to the pyridine
ring was not successful. A similar logic to that detailed
above allowed the interpretation of the 1H NMR spectrum
of the smaller macrobicyclic cleft (5).
On complexing with (R)- and (S)-NapEt, the host
pyridine proton signal at δ ) 7.49 ppm undergoes an
upfield shift indicating an overlap between the naphtha-
lene group of the guest ammonium salt and the pyridine
group of host 4. The benzene proton signals of 4 shift
downfield in the NapEt complex. This downfield shift is
believed to be a result of hydrogen bonding between the
guest ammonium salt and the oxygen atoms adjacent to
the benzene groups of 4. Thus, the NMR data suggest
that the ammonium guest interacts with the macrocyclic
cleft through hydrogen bonding and that the naphthalene
group of NapEt and the pyridine part of host 4 are close
together.
Thermodynamic quantities for interactions of macro-
bicyclic compounds 3, (S,S,S,S)-4 and dimethylpyridino-
18-crown-6 ligand (S,S)-6 with three primary organic
ammonium salts are listed in Table 1. The ligands and
ammonium salts are shown in Figure 2. Compared with
(S,S)-6, macrobicyclic (S,S,S,S)-4 shows improved enan-
tiomeric recognition toward NapEt. A large difference
in stabilities between the complexes of (R)- and (S)-NapEt
with (S,S,S,S)-4 (∆log K ) 0.85) is observed in a 2:8 (v/
v) EtOH/ClC2H4Cl (2Et/8DCE) solvent mixture, while the
∆log K value for (R)- and (S)-NapEt interactions with
F igu r e 2. Macrocylic ligands and chiral organic ammonium
perchlorates used in this study.
(S,S)-6 is 0.46 in the same solvent mixture. The ∆log K
value of 0.85 indicates an excellent enantiomeric recogni-
tion. This high degree of enantiomeric recognition by
(S,S,S,S)-4 is probably due to an increase in molecular
rigidity by introducing a second macro ring and two
phenyl groups. Thermodynamic data provide evidence
for this point. Positive values of entropy changes for
4-NapEt interactions, as compared with 6-NapEt in-
teractions which show negative values of entropy changes,
suggest a smaller conformational change of ligand 4
during complexation, indicating that 4 is more rigid than
6.

7274 J . Org. Chem., Vol. 61, No. 21, 1996
Hellier et al.
white crystals on standing at 4 °C to give 53.7 g (83%) of 1;
It is interesting to note that (S,S,S,S)-4 recognizes the
(S) forms of NapEt and PhEt over their (R) forms, a
reverse sequence of recognition as compared to (S,S)-6
which recognizes the (R) forms of NapEt and PhEt over
their (S) forms (see Table 1). Both enthalpic and entropic
effects make contributions to the enantiomeric recogni-
tion of NapEt by (S,S,S,S)-4. The ∆H and T∆S values
for (S)-NapEt-(S,S,S,S)-4 interaction are 2.1 and 2.75
(kJ /mol), respectively, more favorable than those for (R)-
NapEt-(S,S,S,S)-4 interaction. On the other hand, only
the enthalpy change contributes to enantiomeric recogni-
tion of NapEt by (S,S)-6. In methanol for example, the
∆H value for (R)-NapEt-(S,S)-6 interaction is 1.2 (kJ /
mol) more favorable but the T∆S value is 0.4 (kJ /mol)
more unfavorable than those for (S)-NapEt-(S,S)-6
interaction.
As has been observed in other chiral recognition
systems,3,22-25 solvent has an effect on enantiomeric
recognition with (S,S,S,S)-4. In MeOH/CHCl3 solvent
mixtures, the degree of enantiomeric recognition is lower
than that in the 2Et/8DCE binary solvent. A high degree
of enantiomeric recognition toward NapEt by (S,S,S,S)-4
is observed in 2Et/8DCE while in 2:8 (v/v) CD3OD/CDCl3
(2M/8C) the ∆log K value decreases to 0.45 and it further
decreases to 0.38 with an increase in the CDCl3 compo-
nent of the solvent mixture (5M/95C). The recognition
of (S,S,S,S)-4 for PhEt enantiomers is not directly
comparable with that of (S,S,)-6 due to the different
solvents used. As seen in Table 1, however, (S,S,S,S)-4
does not show a significant improvement in enantiomeric
recognition toward PhEt.
In MeOH, the interaction of macrobicycles 3 and 4 with
NapEt and PhEt is very weak. No complexation could
be detected by the 1H NMR spectral method. In the
solvent mixtures used, 1M/1C and 2Et/8DCE, 3 and 4,
form complexes with NapEt, PhEt, and PhEtOH but the
complex stabilities are lower than those with 6. This
observation indicates that the second macro ring attached
through the two phenyl groups and an enlargement of
the pyridine-containing macro ring (from 18 members of
6 to 20 members for 3 and 4) may result in a macrocyclic
conformation which weakens tripod hydrogen bonding
formed with the ammonium cations. The smaller -∆H
values for (R)- and (S)-NapEt interactions with (S,S,S,S)-4
than those for (R)- and (S)-NapEt interactions with
(S,S)-6 support this explanation.
mp 180 °C; IR (KBr) 3407, 2917, 1599, 1481, 1203, 1155, 1039,
1
1017, 995 cm-1; H NMR (DMSO-d6) δ: 2.30 (s, 6H), 4.55 (d,
8H, J ) 4.5 Hz), 4.95 (s, 4H), 5.13 (t, 4H, J ) 4.5 Hz), 7.17 (s,
4H), 7.65 (d, 2H, J ) 8.2 Hz), 8.00 (t, 1H, J ) 8.2 Hz); 13C
NMR (DMSO-d6) δ 20.7, 58.1, 76.1, 120.6, 127.9, 132.7, 134.7,
138.1, 151.2, 156.7; MS (CI) m/ z 440 (M+ + 1). Anal. Calcd.
for C25H29NO6: C, 68.32; H, 7.47; N, 3.19. Found: C, 68.13;
H, 7.34; N, 3.12.
2,6-Bis[2′,6′-b is(b r om om e t h yl)-4′-m e t h ylp h e n oxy]-
m eth yl]p yr id in e (2) (Sch em e 1). A 1.0 M solution of PBr3
in CH2Cl2 (90 mL) was added to a solution of 1 (9 g, 0.02 mol)
in THF (700 mL) under a nitrogen atmosphere at 0 °C over a
period of 30 min. Stirring was continued at 0 °C for 3 h. The
reaction mixture was evaporated under vacuum. The residue
was added to a mixture of ice-water (300 mL) and CH2Cl2 (250
mL). The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 250 mL). The combined organic
layers were washed with saturated aqueous NaHCO3, dried
(Mg2SO4), filtered, and evaporated under vacuum. The crude
product was recrystallized from ClCH2CH2Cl/MeOH (2:3.5) to
give 7.06 g (54%) of 2 as a white solid; mp 155-156 °C; IR
(KBr) 2920, 1595, 1480, 1365, 1236, 1210, 1160, 972, 792 cm-1
;
1H NMR (CDCl3) δ: 2.31 (s, 6H), 4.60 (s, 8H), 5.29 (s, 4H),
7.21 (s, 4H), 7.69 (d, 2H, J ) 8.1 Hz), 7.91 (t, 1H, J ) 8.1 Hz);
13C NMR (CDCl3) δ 21.2, 28.4, 77.0, 121.4, 132.3, 133.4, 135.6,
139.6, 153.5, 156.9; MS (CI) m/ z 691 (M+). Anal. Calcd. for
C25H25Br4NO2: C, 43.44; H, 3.64; N, 2.03. Found: C, 43.66;
H, 3.81; N, 1.88.
13,27-Dim e t h yl-3,6,9,17,20,23,30,38-oct a oxa -40-a za -
h exa cyclo[23.3.1.929,39.311,15.111,15.132,36]t et r a con t a -1(29),
11,13,15(39),25,27,32,34,36(40)-n on a en e (3) (Sch em e 1). A
solution of diethylene glycol (0.95 mL, 10 mmol) in THF (90
mL) was added to a suspension of 95% NaH (0.76 g, 30 mmol)
in THF (90 mL) under N2 over 10 min. The reaction mixture
was heated at reflux for 1 h. After cooling to rt, a solution of
2 (3.45 g, 5 mmol) in THF (190 mL) was added with vigorous
stirring over a period of 3 h. The reaction mixture was stirred
at rt for a further 16 h. After cooling to 0 °C, H2O (20 mL)
was added. The reaction mixture was evaporated under
vacuum. The residue was dissolved in a mixture of H2O (100
mL) and CH2Cl2 (200 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (2 × 100 mL).
The combined organic layers were dried (Mg2SO4), filtered, and
evaporated under vacuum. The residue was chromatographed
on silica gel eluting with first MePh/MeCO2Et (20:1) and then
MePh/MeOH (100:1). The crude product was isolated by
evaporation of the second eluant under vacuum. The isolated
product was further purified by chromatography on silica gel
eluting with MeOH/30% aqueous NH3 (20:1) to give 0.37 g
(13%) of 3 as a white crystalline solid; mp 57 °C; IR(KBr) 2919,
1596, 1452,1242, 1097, 697 cm-1; 1H NMR (CDCl3) δ: 2.27 (s,
6H), 3.23-3.60 (m, 16H), 4.19 (d, 4H, J ) 11.5 Hz), 4.61 (d,
4H, J ) 11.0 Hz), 5.25 (s, 4H), 7.07 (s, 4H), 7.54 (d, 2H, J )
8.0 Hz), 7.80 (t, 1H, J ) 8.0 Hz); 13C NMR (CDCl3) δ: 20.6,
68.6, 68.7, 69.9, 78.5, 121.4, 130.6, 131.1, 132.7, 136.8, 154.1,
Exp er im en ta l Section
1H NMR spectra were recorded at 200 and 500 MHz.
Solvents and starting materials were puchased from com-
mercial sources where available.
156.9; MS (CI) m/ z 578 (M+ + 1). Anal. Calcd. for C33H41
-
NO8: C, 68.37; H, 7.13; N, 2.42. Found: C, 68.05; H, 7.22; N,
2.27.
2,6-Bis[[2′,6′-b is(h yd r oxym et h yl)-4′-m et h ylp h en oxy]-
m eth yl]p yr id in e (1) (Sch em e 1). A solution of 4-methyl-
2,6-bis(hydroxymethyl)phenol (50.9 g, 0.30 mol) and K2CO3
(45.4 g, 0.33 mol) in 1.5 L of acetone was refluxed for 30 min.
2,6-[(Tosyloxy)methyl]pyridine (67.82 g) was added to the
reaction mixture and rinsed in with 0.5 L of acetone. The
reaction mixture was heated at reflux for 16 h. H2O (680 mL)
was added, and the reaction mixture was filtered hot. The
( 4 S , 8 S , 1 8 S , 2 2 S ) -4 , 8 , 1 3 , 1 8 , 2 2 , 2 7 -H e x a m e t h y l -
3 , 6 , 9 , 1 7 , 2 0 , 2 3 , 3 0 , 3 8 -o c t a o x a -4 0 -a z a h e x a c y c l o -
[23.3.1.92 9 ,3 9 .31 1 ,1 5 .11 1 ,1 5 .13 2 ,3 6 ]t e t r a c o n t a -1(29),11,13,
15(39),25,27,32,34,36(40)-n on a en e (4) (Sch em e 2). (2S,6S)-
4-Oxaheptane-2,6-diol21,22 (1.34 g, 10 mmol) was treated with
2 (3.45 g, 5 mmol) according to the procedure described above
for the synthesis of 3. The crude product was purifed by
chromatography on silica gel eluting with MePh/MeCO2Et (20:
1) to give 0.454 g (14.2%) of 4 as a white crystalline solid; mp
volume of the filtrate was reduced to 1 L on
a rotary
evaporator. The analytically pure product precipitated as
131-2 °C; [R]25 ) +11.2 (c ) 1.70, CH2Cl2); IR(KBr) 2922,
D
1592, 1453, 1372, 1207, 1108 cm-1; H NMR (CDCl3) δ: 1.04
1
(23) Zhang, X. X.; Izatt, R. M.; Zhu, C. Y.; Bradshaw, J . S. Supramol.
Chem. 1996, 6, 267.
(24) Wang, T.-M.; Bradshaw, J . S.; Huszthy, P.; Izatt, R. M.
Supramol. Chem. 1996, 6, 251.
(25) Izatt, R. M.; Zhang, X. X.; Huszthy, P.; Zhu, C. Y.; Hathaway,
J . K.; Wang, T.-M.; Bradshaw, J . S. J . Inclusion Phenom. Mol. Recognit.
Chem. 1994, 18, 353.
(d, 6H, J ) 5.9 Hz), 1.22 (d, 6H, J ) 6.2 Hz), 2.27 (s, 6H),
3.18-3.23 (m, 2H), 3.25-3.36 (m, 4H), 3.37-3.42 (m, 2H),
3.47-3.52 (m, 2H), 3.75-3.82 (m, 2H), 3.98 (d, 2H, J ) 11.6
Hz), 4.25 (d, 2H, J ) 11.6 Hz), 4.44 (d, 2H, J ) 12.5 Hz), 4.97
(d, 2H, J ) 12.5 Hz), 5.02 (d, 2H, J ) 12.5 Hz), 5.37 (d, 2H, J
) 12.5 Hz), 7.04 (s, 2H), 7.10 (s, 2H), 7.49 (d, 2H, J ) 7.6 Hz),

Chiral Pyridine-Based Macrobicyclic Clefts
J . Org. Chem., Vol. 61, No. 21, 1996 7275
7.79 (t, 1H, J ) 7.6 Hz); 13C NMR (CDCl3) δ: 16.5, 17.2, 20.9,
65.5, 66.1, 70.0, 74.3, 74.6, 75.8, 77.2, 120.9, 129.8, 129.9, 131.3,
132.5, 132.9, 137.1, 153.3, 156.9; MS (CI) m/ z 636 (M+). Anal.
Calcd. for C37H49NO8: C, 69.89; H, 7.77; N, 2.20. Found: C,
70.02; H, 7.94; N, 2.35.
Deter m in a tion of Th er m od yn a m ic Qu a n tities. The log
K values in Table 1 were determined at 25.0 ( 0.1 °C by either
a direct 1H NMR titration procedure at 200 MHz or titration
calorimetry using a Tronac Model 450 calorimeter. The
experimental techniques for direct 1H NMR3a,20,24 and
calorimetric3a,23 titrations have been described in detail. The
calorimetric method determined ∆H and ∆S values besides
the log K values and these values are also reported in Table
1. The calorimeter was calibrated according to the procedures
described in the literature.26 Concentrations of ammonium
salt solutions were 0.11-0.13 M and those of chiral macro-
cycles were (2.4-3.8) × 10-3 M. The ammonium solutions
were titrated continuously at a rate of 1.75 × 10-3 mL/s into
the macrocycle solutions. The correction for heat of dilution
was performed by a separate experiment in which the pure
ammonium salt solution was titrated into pure solvent. The
method used to process the calorimetric data and to calculate
the log K and ∆H values has been described.26
(4R,6R,16R,18R)-4,6,11,16,18,23-Hexa m eth yl-3,7,15,19,-
26,34-h exa oxa -36-a za h exa cyclo[19.3.1.925,35.39,13.19,13.128,32]-
h exa t r icon t a -1(25),9,11,13(35),28,30,32(36)-n on a en e (5)
(Sch em e 2). (2R,4R)-Pentanediol (0.99 g, 9.5 mmol) was
reacted with 2 (3.28 g, 4.75 mmol) according to the procedure
described above for the synthesis of 3. The crude product was
purifed by chromatography on silica gel eluting with MePh/
MeCO2Et (40:1) to give 0.191 g (7.0%) of 5 as a white
crystalline solid; mp 62-65 °C; [R]25 ) -307.8 (c ) 3.84,
D
CH2Cl2); IR(KBr) 2928, 1591, 1458, 1372, 1287, 1204, 1153,
1093, 1029 cm-1; 1H NMR (CDCl3) δ: 0.92 (d, 6H, J ) 6.2 Hz),
1.32 (d, 6H, J ) 5.9 Hz), 2.25 (s, 6H), 3.56 (2H, m), 3.95 (d,
2H, J ) 13.8 Hz), 4.18 (2H, m), 4.27 (d, 2H, J ) 13.8 Hz), 4.44
(d, 2H, J ) 12.8 Hz), 4.92 (d, 2H, J ) 12.8 Hz), 5.25 (d, 2H, J
) 12.4 Hz), 5.67 (d, 2H, J ) 12.4 Hz), 6.78 (s, 2H), 6.84 (s,
2H), 7.24 (d, 2H, J ) 7.7 Hz), 7.71 (t, 1H, J ) 7.7 Hz); 13C
NMR (CDCl3) δ: 18.6, 20.3, 21.2, 46.3, 63.6, 64,9, 67.0, 73.2,
77.5, 121.3, 126.2, 126.9, 131.2, 133.3, 137.2, 154.3, 158.1; MS
(CI) m/ z 576 (M+). Anal. Calcd. for C35H45NO6: C, 73.01;
H, 7.88; N, 2.43. Found: C, 73.17; H, 8.00; N, 2.27.
Ack n ow led gm en t. This work was supported by the
Office of Naval Research.
J O960890U
(26) Eatough, D. J .; Christensen, J . J .; Izatt, R. M. Thermochim.
Acta 1972, 3, 219,233.