Syntheses, conformations, and basicities of bicyclic triamines

Article abstract of DOI:10.1021/ja030236d

The multistep syntheses of several bicyclic triamines are described, all of which have an imbedded 1,5,9-triazacyclododecane ring. In 1,5,9-triazabicyclo[7.3.3]pentadecanes 12, 13, 15, and 16, two nitrogens are bridged by three carbons. The monoprotonated forms of these triamines are highly stabilized by a hydrogen-bonded network involving the bridge and both bridgehead nitrogens, producing a difference of more than 8 pK_a units in acidities of their monoprotonated and diprotonated forms. The one- and zero-carbon bridges in 1,5,9-triazabicyclo[9.1.1]tridecane (23) and 7-methyl-1,5,9-triazabicyclo[5.5.0]dodecane (39) do not enhance the stabilities of their monoprotonated forms. X-ray crystal structures and computational studies of 12·HI and 16·HI reveal similar, but somewhat weaker, hydrogen-bonded networks, relative to 15·HI. The activation free energies for conformational inversion of 13·HI (14.4 ± 0.2 kcal/mol), 16·HI (15.0 ± 0.1 kcal/mol) and 16 (8.8 ± 0.3 kcal/mol) were measured by variable-temperature ¹H and ¹³C NMR spectroscopy. These experimental barriers give an estimate of 6.2 kcal/mol for the strength of the bifurcated hydrogen bond between the bridge nitrogen and cavity proton in 16·HI. Computational studies support the hypothesis that N-inversion occurs in an open conformation, leading to an estimate of 10.32 kcal/mol for the enthalpy of the bifurcated hydrogen bond in 16·HI in the gas phase.

Full text of DOI:10.1021/ja030236d

Published on Web 09/11/2003
Syntheses, Conformations, and Basicities of Bicyclic
Triamines
Thomas W. Bell,*,† Heung-Jin Choi,‡,§ William Harte,‡ and Michael G. B. Drew*,|
Contribution from the Departments of Chemistry, UniVersity of NeVada,
Reno, NeVada 89557-0020, State UniVersity of New York, Stony Brook, New York 11794-3400,
and The UniVersity, Whiteknights, Reading RG6 2AD, U.K.
Received April 16, 2003; E-mail: twb@unr.edu; m.g.b.drew@reading.ac.uk
Abstract: The multistep syntheses of several bicyclic triamines are described, all of which have an imbedded
1,5,9-triazacyclododecane ring. In 1,5,9-triazabicyclo[7.3.3]pentadecanes 12, 13, 15, and 16, two nitrogens
are bridged by three carbons. The monoprotonated forms of these triamines are highly stabilized by a
hydrogen-bonded network involving the bridge and both bridgehead nitrogens, producing a difference of
more than 8 pKa units in acidities of their monoprotonated and diprotonated forms. The one- and zero-
carbon bridges in 1,5,9-triazabicyclo[9.1.1]tridecane (23) and 7-methyl-1,5,9-triazabicyclo[5.5.0]dodecane
(39) do not enhance the stabilities of their monoprotonated forms. X-ray crystal structures and computational
studies of 12‚HI and 16‚HI reveal similar, but somewhat weaker, hydrogen-bonded networks, relative to
15‚HI. The activation free energies for conformational inversion of 13‚HI (14.4 ( 0.2 kcal/mol), 16‚HI (15.0
( 0.1 kcal/mol) and 16 (8.8 ( 0.3 kcal/mol) were measured by variable-temperature 1H and 13C NMR
spectroscopy. These experimental barriers give an estimate of 6.2 kcal/mol for the strength of the bifurcated
hydrogen bond between the bridge nitrogen and cavity proton in 16‚HI. Computational studies support the
hypothesis that N-inversion occurs in an open conformation, leading to an estimate of 10.32 kcal/mol for
the enthalpy of the bifurcated hydrogen bond in 16‚HI in the gas phase.
Introduction
well potential, inside-protonated form cannot be formed by
proton transfer in acidic media.5,6 Such findings may seem
Polyamines in which two or more nitrogen atoms lie in close
proximity are of interest from both theoretical and practical
points of view. The enhanced basicities of proton sponges,1 such
as 1,2 2,1a and 3,3 have stimulated numerous experimental and
theoretical studies.4 Proton sponge 1 (X ) H),2a,d in particular,
is useful in synthetic organic chemistry because it is quite basic
(pKa ) 12.1), but it is not nucleophilic. Nitrogen bridgehead
bicyclic diamines (4)1b,5 are another structural class of molecules
in which interaction between lone-pair electrons is dictated by
the carbon framework. Of particular interest is 1,6-diazabicyclo-
[4.4.4]tetradecane (4, k ) l ) m ) 4), for which the single-
esoteric, but proton sponges and bicyclic diamines have made
available a series of [N-H‚‚‚N]+ cations of various hydrogen
bond strengths, stabilities and barriers. These species may be
useful, for example, as models for evaluating the role of low-
barrier hydrogen bonds in enzyme catalysis.7
This article concerns the synthesis, basicities, and protonated
structures of bicyclic triamines of type 5, which are similar to
4, but contain an additional basic site in one of the three bridges.
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Staab, H. A. Angew. Chem., Int. Ed. Engl. 1989, 28, 84-86. (c) Staab, H.
A.; Zirnstein, M. A.; Krieger, C. Angew. Chem., Int. Ed. Engl. 1989, 28,
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† University of Nevada, Reno.
‡ SUNY, Stony Brook.
§ Current address: Department of Industrial Chemistry, Kyungpook
National University, 1370, Sankyuk-Dong, Puk-ku, Taegu, Korea.
| The University, Reading.
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12196
J. AM. CHEM. SOC. 2003, 125, 12196-12210
10.1021/ja030236d CCC: $25.00 © 2003 American Chemical Society

Syntheses and Conformations of Bicyclic Triamines
A R T I C L E S
Scheme 1 a
The key molecular framework of interest (5, k ) l ) m ) n )
3), is a bicyclic analogue of 1,5,9-triazacyclododecane (6),8
which is relatively basic (pKa ) 12-13) and forms complexes
with various transition metals. Linking two nitrogens of 6 with
a three-carbon bridge has been reported to significantly enhance
basicity but retain rapid proton-transfer kinetics.9 Other rapidly
protonating bicyclic polyamines contain two10 or three11 nitrogen
atoms in the bridges, but 5 may represent the simplest molecular
architecture exhibiting such properties. Interestingly, [1.1.1]-
cryptand is extremely basic, but protonates very slowly.12 The
present studies were originally aimed at the synthesis of tricyclic
triamine 7, which is a substructure of a previously targeted
tetrahedrally symmetric tetramine.13 Triamine 7 was viewed as
a potential ionophore for lithium, and several known azacages
are known to bind this cation.14 The current results on basicities
of triamines of type 5 are relevant to the question of cation
selectivity (H+ vs Li+) for 7 and related hypothetical structures.
Many of the compounds reported here might also be of use in
future syntheses of more elaborate cage polyamines.
a (a) NaH, DMF, 100 °C (50%); (b) H2SO4, 100 °C (55%); (c) KHCO3,
2-butanol, reflux; KOH, H2O, CHCl3 (31%); (d) CH2O, NaCNBH3, CH3CN,
HOAc; KOH, H2O, CHCl3 (50%); (e) K2CO3, 2-propanol, reflux; NaOH,
H2O, CHCl3 (70%); (f) HCO2H, CH2O (43%); (g) 9-BBN, THF; H2O2,
NaOH, THF, H2O, EtOH (97%, 4:1 mixture of diastereomers).
and obtained as a crystalline solid in 90% yield (Scheme 1).
Cyclization by treatment of 8 with NaH, followed by slow
addition of ditosylate 9,16 gave tritosyl macrocycle 10.8a,e,16b,17
A 50% yield of pure 10 was obtained after precipitation of
higher-molecular weight material by addition of hexane to a
hot toluene solution of the crude product, evaporation of the
supernatant solution and recrystallization. Removal of the tosyl
groups in hot sulfuric acid, followed by vacuum distillation from
KOH, gave macrocycle 6,8a-e,17 the key intermediate for
synthesis of all bicyclic triamines discussed in this article.
Reaction of macrocyclic triamine 6 with 1,3-diiodopropane
(11) was carried out by simultaneous, slow addition of these
reactants to a pot of hot solvent to minimize the formation of
higher-molecular weight byproducts. A low yield of bicyclic
triamine 12 was obtained when boiling 2-propanol was used,
indicating that the rate of cyclization was too slow at this
temperature. Substitution of boiling 2-butanol resulted in a 50%
yield of 12‚HI after removal of impurities by trituration,
followed by recrystallization. Treatment of this salt with 5 M
aqueous KOH gave free base 12 in 61% yield after distillation.
Results
Synthesis. Following the Atkins-Richman method for mac-
rocyclic polyamine synthesis,15 N,N′,N′′-tritosylbis(3-amino-
propyl)amine 88a,e was prepared from commercial bis(3-
aminopropyl)amine, tosyl chloride and aqueous NaOH/CH2Cl2,
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Vogel, E. Angew. Chem., Int. Ed. 2001, 40, 431-434. (j) Mock, W. L.;
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9
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A R T I C L E S
Bell et al.
Scheme 2 a
Scheme 3 a
a (a) BnCl, NaHCO3, H2O, reflux (68%); (b) H2, Ni, NaOH, EtOH (81%);
(c) TsCl, NaOH, CH2Cl2, H2O (95%); (d) NaH, 18, DMF, 100 °C (55%);
(e) 1. ACE-Cl, ClCH2CH2Cl, reflux; 2. CH3OH (78%); (f) 1. thexylborane,
THF, reflux; 2. H2O2, NaOH, THF, EtOH, H2O; (g) PPh3, CCl4, DMF; (h)
H2, Pd/C, 2-propanol (25%); (i) K2CO3, 2-propanol, reflux (100%).
a (a) NaH, DMF, 100 °C (59%); (b) thexylborane, THF, reflux; H2O2,
NaOH, THF, H2O, EtOH (66%); (c) PPh3, CCl4, DMF (64%); (d) H2SO4,
100 °C; (e) K2CO3, 2-propanol, reflux (58%, two steps).
Methylation of 12 to 13 could be carried out in ca. 60% yield
by means of the Eschweiler-Clarke reaction (formaldehyde/
formic acid),18 but a higher yield was obtained when the HI
salt was treated with formaldehyde and sodium cyanoborohy-
dride19 (Scheme 1).
As previously communicated,9 simultaneous addition of
macrocycle 6 and 2-iodomethyl-3-iodo-1-propene (14)20 to
boiling 2-propanol gave bicyclic triamine 15, which could be
isolated from the reaction mixture in good yield as the free
amine. Eschweiler-Clarke methylation of 15 gave 16 in
moderate yield. Reaction of 15 with various organoboranes was
also investigated in order to produce potential intermediates for
the synthesis of tricyclic triamine 7. Best results were obtained
with 9-BBN in THF, which gave a 4:1 mixture of stereoisomeric
primary alcohols (17). The relative configurations of these two
products (17a and 17b) were not determined.
Atkins-Richman method.15 Hydroboration of the exocyclic
methylene group of the product (19) with BH3‚THF and
oxidation with alkaline hydrogen peroxide gave a 1:1 mixture
of primary alcohol 20 and the corresponding tertiary alcohol.
Use of thexylborane cleanly gave 20, which was used in the
next step without purification. The planned bicyclization
required that the hydroxyl group of 20 be transformed into a
leaving group that would be stable to the conditions of
21
detosylation. Reaction of 20 with triphenylphosphine and CCl4
gave chloromethyl derivative 21, which was detosylated in hot
sulfuric acid to give chloromethyl triamine 22 as an oil. In an
attempt to effect displacement of chloride by N9, a solution of
crude 22 in 2-propanol was heated with K2CO3. Distillation of
the crude product of this reaction from KOH gave a pure sample
of bicyclic triamine 23, rather than the desired product (25). In
the presence of potassium hydroxide, a small amount of alkene
24 was formed in addition to bicycle 23. Bicyclic target 25 was
not detected under any reaction conditions, indicating the
following order of decreasing reactivity for 22: four-membered
ring formation > elimination . eight-membered ring formation.
An alternate approach to triamine 25 involved protection of
N9 by a group that could be removed in the presence of
tosylamide substituents at N1 and N5. The benzyl protection
group was chosen, and various transformations were carried out
(Scheme 3). N,N-Bis(2-cyanopropyl)benzylamine (27) was
prepared previously22 by conjugate addition of benzylamine to
acrylonitrile at 140 °C. We employed a two-step procedure that
was more amenable to larger-scale preparations involving
reaction of acrylonitrile with ammonia at room temperature,23
In an approach to bicyclic triamine 25, a series of 3-substi-
tuted 1,5,9-triazacyclododecanes were synthesized (Scheme 2).
Entry to this series was provided by cyclization of tritosyltri-
amine 8 with 2-chloromethyl-3-chloro-1-propene (18) by the
M.; Dapporto, P.; Micheloni, M.; Nardi, N.; Paoli, P.; Valtancoli, B. J.
Am. Chem. Soc. 1990, 29, 3282-3286. (d) Bencini, A.; Bianchi, A.;
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M.; Nardi, N.; Paoli, P.; Valtancoli, B. J. Am. Chem. Soc. 1991, 30, 3687-
3691.
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Chem. Soc. 1957, 79, 3467-3469. (b) Smith, W. L.; Ekstrand, J. D.;
Raymond, K. N. J. Am. Chem. Soc. 1978, 100, 3539-3544.
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15, 1499-1502. (c) Chavez, F.; Sherry, A. D. J. Org. Chem. 1989, 54,
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36, 829-832.
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Jentoft, N.; Dearborn, D. G. J. Biol. Chem. 1979, 254, 4359-4365.
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319, 463-474.
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4364. (b) Baldwin, J. J.; Raab, A. W.; Mensler, K.; Arison, B. H.; McClure,
D. E. J. Org. Chem. 1978, 43, 4876-4878.
(22) (a) Bergeron, R. J.; Garlich, J. R. Synthesis 1984, 782-784. (b) Bergeron,
R. J.; Kline, S. J.; Stolowich, N. J.; McGovern, K. A.; Burton, P. S. J.
Org. Chem. 1981, 46, 4524-4529. (c) Bergeron, R. J.; Burton, P. S.;
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9
12198 J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003

Syntheses and Conformations of Bicyclic Triamines
A R T I C L E S
Scheme 4 a
Table 1. Basicities of Triamines 6, 12, 13, 15, 16, 23, and 40; pH
Values of Aqueous solutions (5 mM, 25 °C) and pKa Values
Measured by Titration with 0.1 M HCl, 25 °C
pH
pK
a1
pK
a2
pK
a3
6a
12.8
12.6 ( 0.1
(12.2)f
7.49 ( 0.02
2.07 ( 0.07
6b
11.8
(11.4)f
7.41 ( 0.01
7.57 ( 0.02
7.97 ( 0.02
7.3 ( 0.1
4.50 ( 0.01
4.89 ( 0.01
4.36 ( 0.06
4.29 ( 0.08
4.16 ( 0.08
4.88 ( 0.07
6.24 ( 0.01
7.16 ( 0.01
5.7 ( 0.1
2.17 ( 0.02
2.41 ( 0.03
6c
12.60 ( 0.05
13.15 ( 0.05
12.3 ( 0.1
(11.1)f
6d
6e
2.4 ( 0.1
(2.8)g
12
13
15
15a
15b
16
23
39
40e
11.4
11.4
11.8
13.1
11.7
11.8
11.7
10.6
(11.0)f
(2.9)g
(11.3)f
(2.7)g
(12.6)f
(1.8)g
(11.2)f
(2.6)g
(11.3)f
(2.7)g
(11.3)f
(2.6)g
a (a) m-CPBA, K2CO3, CH2Cl2; (b) 1. Hg(OAc)2, EtOAc; 2. NaBH4; 3.
NaOH, H2O; (c) H2SO4, 100 °C (46%).
9.7 ( 0.1
12.8 ( 0.1
1.71 ( 0.02
2.9 ( 0.1
a Concentration 0.1 M (25 °C). b Concentration 5 mM (20 °C). c Ref-
erence 8c, potentiometric titration of 6‚3HCl in 0.1 M aq KNO3 (25 °C).
followed by alkylation with benzyl chloride. Raney nickel
catalyzed hydrogenation of 27 gave N,N-bis(2-aminopropyl)-
benzylamine 2822 in good yield. Other protecting groups,
including t-BOC, acetyl, benzoyl, and p-anisoyl, were investi-
gated but were either too labile under the alkaline hydrogenation
conditions (step b) or were too stable toward deprotection in
step e (cf. Scheme 3).
1
d Reference 8d, H NMR titration of 6‚3HCl in 0.05 M aq KNO3 (25 °C).
e Reference 8f, 1H NMR titration of free base in D2O, corrected for isotope
effect (25 °C). f Estimated from pH at 0.5 equiv point. g Estimated from
pH at 2.5 equiv point.
Tosylation of triamine 28, macrocyclization of 29 with
3-chloro-2-chloromethyl-1-propene (18), hydroboration/oxida-
tion of alkene 30, and conversion of alcohol 32 to chloride 33
were carried out as described for synthesis of tritosyl analogue
21 (cf. Scheme 2). The benzyl protecting group in 33 was
cleaved by means of catalytic hydrogenolysis.24 Removal of the
benzyl group in alkene 30 was accomplished in good yield by
means of R-chloroethyl chloroformate (ACE-Cl).25 Both of the
resulting ditosyl macrocycles (31 and 34) were considered
potential precursors to triamine 25. Attempted conversion of
34 to 25 by reaction with K2CO3 in hot 2-propanol resulted in
quantitative formation of alkene 31. These same conditions gave
the least amount of alkene 24 in the cyclization of 22 to 23,
again indicating that elimination is much faster than bicyclization
via eight-membered ring formation in the 1,5,9-triazacyclodode-
cane ring system.
Several attempts were made to cyclize 31 by intramolecular
attack of N9 on the exocyclic methylene carbon atom (Scheme
4). The general strategy was to produce an electrophilic three-
membered ring intermediate (e.g., an epoxide or mercurinium
ion), which might undergo nucleophilic displacement at the less
hindered position. Alternately, attack by nitrogen at the tertiary
position would afford bicyclic isomers containing seven-
membered, rather than eight-membered rings. An attempt to
epoxidize the double bond of 31 with m-CPBA instead gave
tricyclic isoxazolidine 36, apparently via intramolecular 1,3-
dipolar cycloaddition of nitrone 35, produced by oxidation of
the corresponding hydroxylamine intermediate.26 Bromination
of 31 was also investigated, but a complex mixture of products
was obtained. Several attempts were made to produce the
bicyclic skeleton of amine 25 by intramolecular aminomercu-
ration27 of 31, followed by reduction of the organomercury
product with sodium borohydride. Regardless of the Hg2+
counterion (CF3CO2-, CH3CO2-, Br-, Cl-, NO2-, or O2-) or
solvent (acetonitrile, benzene, ether, ethyl acetate, DME, diox-
ane, or THF), borane complex28 31‚BH3, bicyclic alcohol 37,
and bridgehead methyl analogue 38 were the only isolable
products. Product 38 was anticipated from nucleophilic attack
at the tertiary carbon of the mercurinium intermediate, but 37
likely arises from solvolysis of a tricyclic aziridinium intermedi-
ate.29 To compare the basicity of bicyclic amine 39 with those
of 12, 13, 15, and 16, the tosylamide groups of 38 were cleaved
in hot sulfuric acid.
Basicities. The basicities of the six bicyclic triamines 12, 13,
15, 16, 23, and 39 were compared to that of the parent
monocyclic triamine 6 in two ways. First, the pH values of
aqueous solutions were measured (Table 1). At concentrations
of 5 mM, all pH values fell in the range of 11.4-11.8, except
for that of triamine 39 (10.6). More concentrated solutions (0.1
M) of 6 and 15 gave pH values of 12.8 and 13.1, respectively,
indicating that 15 is a significantly stronger base than 6. A
second comparison was made by potentiometric titration of the
free amines (5 mM) with 0.1 N HCl. By this procedure, the pH
remained below 12, avoiding alkaline error in the glass pH
electrode measurements. The titration curves showed that the
ionization constants of the monoprotonated and triprotonated
forms (pKa1 and pKa3, respectively) could not be measured
potentiometrically for triamines 12, 13, 15, 16, and 23 because
(27) (a) Barluenga, J.; Fan˜ana´s, F. J.; Villaman˜a, J.; Yus, M. J. Org. Chem.
1982, 47, 1560-1564. (b) Tong, M. K.; Blumenthal, E. M.; Ganem, B.
Tetrahedron Lett. 1990, 31, 1683-1684.
(28) Schaeffer, G. W.; Anderson, E. R. J. Am. Chem. Soc. 1949, 71, 2143-
2145.
(29) (a) Ebno¨ther, A.; Jucker, E. HelV. Chim. Acta 1964, 47, 745-756. (b)
Hammer, C. F.; Heller, S. R. J. Chem. Soc., Chem. Commun. 1966, 919-
920.
(24) ElAmin, B.; Anantharamaiah, G. A.; Royer, G. P.; Means, G. E. J. Org.
Chem. 1979, 44, 3442-3444.
(25) (a) Olofsen, R. A.; Martz, J. T.; Senet, J.-P.; Piteau, M.; Malfroot, T. J.
Org. Chem. 1984, 49, 2081-2082. (b) Olofsen, R. A.; Abbott, D. E. J.
Org. Chem. 1984, 49, 2795-2799.
(26) Hamer, J.; Macaluso, A. Chem. ReV. 1964, 473-495.
9
J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003 12199

A R T I C L E S
Bell et al.
Figure 1. Conformations of HI salts of 12, 15, and 16 observed in the
X-ray crystal structures. Cavity hydrogen atoms not located crystallographi-
cally are shown in parentheses in the skeletal diagrams. Crystal structure
diagrams of 16‚H+ and 12‚H+ (one of two equivalent cations in the
asymmetric unit) are shown with ellipsoids at 25% probability.
Figure 2. Scale diagram showing N-N distances observed in X-ray crystal
structures of HI salts of 12, 15, and 16. Arrangement: N1 (bottom right),
N5 (top), N9 (bottom left).
the pKa1 values were too large and the pKa3 values were too
small. The titration curve of a 0.1 M solution of 15 matches
that of 0.1 M sodium hydroxide. Table 1 lists the pKa2 values
for 12, 13, 15, 16, and 23 and all three values measured for 39
and 6. These thermodynamic pKa’s were calculated from
protonation curves with correction for the activities of all ions
in solution. The pKa’s calculated for macrocycle 6 are consistent
with previously reported pKa values8c,d,f when the latter are
corrected for ionic strength.
Crystallography. The HI salts of triamines 12 and 16 were
crystallized and their structures were determined by X-ray
diffraction at the University of Reading. The conformations of
the triamines in the crystal structures are compared in Figure 1
with that of 15‚HI, the crystal structure of which was previously
reported.9 There are two conformationally equivalent molecules
of 12‚HI in the asymmetric unit and one is represented in Figure
1 as 12‚H+. The structure of 12‚HI is not very accurate because
the crystal diffracted weakly, but the essential features are clear.
The conformations of the two cations in the asymmetric unit
are almost identical, but they differ from those of 15‚HI and
16‚HI in one major way. One of the three-carbon bridges of
12‚HI is bent away from the other, while both bridges are bent
toward each other in the HI salts of 15 and 16.
Table 2. Torsion Angles (deg) in the Crystal Structures of the HI
Salts of Bicyclic Triamines 12, 15, and 16
torsion
16‚HI
57.7
-71.8
154.9
15‚HI
59.5
-71.7
12‚HI(A)
12‚HI(B)
N(1)-C(2)-C(3)-C(4)
C(2)-C(3)-C(4)-N(5)
C(3)-C(4)-N(5)-C(6)
C(4)-N(5)-C(6)-C(7)
N(5)-C(6)-C(7)-C(8)
C(6)-C(7)-C(8)-N(9)
C(7)-C(8)-N(9)-C(15)
C(8)-N(9)-C(15)-C(14)
N(9)-C(15)-C(14)-C(13)
N(1)-C(13)-C(14)-C(15)
C(12)-N(1)-C(13)-C(14)
C(2)-N(1)-C(13)-C(14)
C(13)-N(1)-C(12)-C(11)
C(13)-N(1)-C(2)-C(3)
C(14)-C(15)-N(9)-C(10)
C(15)-N(9)-C(10)-C(11)
N(9)-C(10)-C(11)-C(12)
C(10)-C(11)-C(12)-N(1)
50.9
-66.7
64.6
-81.1
175.0 -179.4 -178.1
-161.6 -177.8 -176.7 -176.1
77.9
-57.0
-68.9
169.5
-50.8
47.9
71.5
-58.7
-74.7
169.7
-44.2
41.0
67.8
-58.5
-80.4
177.9
-61.8
66.2
62.4
-40.6
-88.9
168.9
-45.3
53.8
63.2
66.4
44.6
52.3
-172.2 -167.9 -175.4 -168.2
-61.6
67.7
-65.3
69.6
44.1
-48.7
-58.2 -110.1 -111.7
75.1
-60.4
57.6
54.6
-53.8
78.5
-48.9
106.5
-65.4
69.9
73.6
-60.9
103.4
-60.8
65.3
opposite side. Only for 16‚HI could a hydrogen atom be located
in the cavity by difference Fourier maps, and it is covalently
bonded to bridgehead nitrogen N1.
Apart from the orientation of one of the small bridges, there
are very minor differences between the crystal conformations
of 12‚HI, 15‚HI, and 16‚HI. The presence of an exocyclic double
bond in 15 and 16 alters bond angles according to the different
requirements of sp2 and sp3 carbon. The four structures are
numbered as shown in Figure 2. This figure also displays the
N-N distances; the torsion angles are compared in Table 2.
Particularly striking is the equivalence of the conformations of
15‚HI and 16‚HI; no torsion angle differs by more than 15°.
An approximate mirror plane bisects each structure, passing
through N5, C14, and C11, which is part of the exocyclic double
bond in 15 and 16. Staggering of all ethylene units produces a
cyclohexane-like conformation in which adjacent atoms of the
long bridge alternate above and below the best plane of the
macrocycle. In 15‚HI the unsaturated bridge is on the same side
as C3 and C7 of the long bridge, whereas in 16‚HI it is on the
NMR Spectroscopy. Bicyclic triamines 12, 13, 15, and 16
have very similar structures, differing only in the presence of
an exocyclic double bond at C11 and a methyl group on the
bridge nitrogen atom (N5, cf. Figure 2 for numbering scheme).
The NMR spectra of these triamines and their HI salts are of
interest for comparing their solution and crystal conformations,
particularly with respect to interaction of the bridge nitrogen
with the protonated cavity. As reported previously,9 the results
1
of two-dimensional H and 13C NMR studies (COSY, CSCM,
and NOESY) indicate that the crystal and solution (CDCl3)
conformations of 15‚HI are very similar. The conformational
bias of the C10-12 bridge bearing the exocyclic double bond
is toward the smaller (C13-15) bridge. This is revealed by a
significant NOE interaction between the vinylic protons and an
axial proton on C14. Moreover, allylic coupling is observed
4
for only one pair of protons on C10/12 (δ 3.88, J ) 1.7 Hz),
9
12200 J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003

Syntheses and Conformations of Bicyclic Triamines
A R T I C L E S
Table 3. 13C and 1H NMR Peak Assignments for Bicyclic Triamines 12, 13, 15, 16, and Their HI Salts
C2
52.7
49.2
2.95
56.3
59.0
59.9
58.5
C3
27.7
23.6
2.05
29.4
22.6
26.3
22.4
C4
61.8
60.5
2.79
58.9
59.4
51.7
48.6
C10
53.3
53.3
2.59, 2.95
54.4
54(br)
60.1
C11
C13
53.3
53.3
2.59, 2.95
54.4
54(br)
55.0
C14
30.3
27.9
1.74
dCH
CH
3
2
12
12‚HI
(13C)a
(13C)b
(1H)b
30.0
27.9
1.74
-
-
-
-
-
114.5
115.5
5.00
-
-
-
13
13‚HI
15
(13C)a
(13C)a
(13C)b
(13C)b
(1H)b
31.4
24(br)
149.5
145.5
-
31.4
44.6
42.8
-
24(br)
29.31
27.2
1.5, 2.1
31.0
15‚HI
60.2
3.05, 3.88
62.0
54.6
2.5-3.5
53.8
-
-
43.8
42.1
2.5-3.5
53.8
57.8
1.9, 2.2
27.1
21.5
2.5-3.5
57.4
55.6(br)
16
16‚HI
(13C)b
(13C)b
150.9
139.6
114.2
115.3
58.3
55.6(br)
21.5
a CD3CN, 25 °C; b CDCl3, 25 °C.
and the other pair of protons on C10/12 (geminal to the first
pair) is shielded (δ 3.05) by the antiperiplanar bridgehead
nitrogen electron pairs.30
Better spectral dispersion was observed in the 1H NMR
spectra of the salts than the neutral forms of these triamines,
suggesting that their conformational rigidity increases upon
protonation. The 1H and 13C NMR peaks of 12‚HI were assigned
to specific nuclei by means of two-dimensional NMR techniques
1
(COSY and CSCM). H and 13C NMR assignments for 12‚HI
and 15‚HI are given in Table 3, along with 13C assignments for
12, 13, 13‚HI, 15, 16, and 16‚HI made by comparison. Broad
peaks were observed in the NMR spectra of N-methylated salts
13‚HI and 16‚HI, suggesting the presence of conformational
exchange processes with coalescence occurring near room
temperature. Variable-temperature (VT) NMR studies were
performed, anticipating that the activation energies for inversion
of the bridge nitrogen could be related to the strength of
interaction between N5 and the proton in the cavity.
Figure 3. Proposed mechanism for conformational inversion of 16‚HI via
hydrogen bond cleavage, followed by nitrogen inversion.
discrete steps in Figure 3, showing “opening” of the hydrogen-
bonded anti-closed conformation to form the syn-open, N5
inversion to the anti-open, and reformation of the hydrogen bond
to the protonated cavity to produce the syn-closed conformation.
1
The H NMR spectrum of 16‚HI in CDCl3 showed broad
VT 1H NMR spectra of 13‚HI were complicated by overlap-
ping multiplets, but clean two-site exchange was observed in
peaks at room temperature, but they resolved to two sets of
sharp resonances at -30 °C. Integration of the vinylic proton
signals at δ 5.088 and 5.183 ppm gave a ratio of 47:53,
respectively. Complete line shape analysis of 12 spectra recorded
in the range of 6-40 °C (Tc 20 °C) gave 15.1 ( 0.1 kcal/mol
as the activation free energy for interconversion of the syn-
closed and anti-closed conformations. The resonances of the
two sp2 carbon atoms (C11 and CH2) were also used to measure
this activation energy. At -60 °C in CDCl3, these singlets
occurred at δ 113.6 and 115.2 ppm for the CH2 carbon, and at
138.3 and 139.8 ppm for C11. Curve-fitting of seven spectra
recorded in the range of 10-50 °C gave ∆Gq ) 14.9 ( 0.2
kcal/mol from the CH2 line shapes and 14.8 ( 0.3 kcal/mol
from C11. A coalescence temperature of 38 °C was observed
in both cases. Slight temperature dependence of the chemical
shifts was observed. This was corrected by adjusting the slow-
exchange chemical shifts, but not the chemical shift separation,
used for the two sites in calculating the curves.
the temperature range of -20 to +60 °C in CD3CN for the 13
C
resonances C10, 12, 13, and 15, the R-carbons of the smaller
bridges. At -20 °C two peaks of equal intensity occur at 51.6
and 54.4 ppm, which coalesce into a single peak at 38 °C.
Complete bandshape analysis of the 13C NMR spectra obtained
at 10, 20, 30, 35, 38, 40, and 50 °C by iteratively fitting curves
calculated for a system of two uncoupled nuclei in exchanging
magnetic environments gave a series of rate constants that were
used to calculate a free energy of 14.4 ( 0.2 kcal/mol. No
significant variation of the calculated energy was seen over a
40 °C temperature range, so the enthalpic and entropic contribu-
tions could not be measured.
The observation of two-site exchange for atoms of the smaller
bridges of 13‚HI is consistent with a solution conformation
similar to that observed in the solid-state structure of 12‚HI (cf.
Figure 1), with the exception that the axial hydrogen on N5 in
the large bridge is replaced by a methyl group. The different
magnetic environments of the two smaller bridges interchange
upon inversion of both N5 and the gauche conformations about
the C-C and C-N bonds in the large bridge. In 16‚HI, the
two three-carbon bridges are differentiated by the exocyclic
methylene group; the N5 methyl group is either syn or anti to
the bridge bearing the double bond. Interconversion of these
nonequivalent conformations requires both cleavage of the N5
hydrogen bond and nitrogen inversion. These are postulated as
The mechanism for conformational exchange shown in Figure
3 is strictly unimolecular, so experiments were performed at
different concentrations to test whether intermolecular proton-
transfer processes might be involved. For example, VT-NMR
studies of 16‚HI were performed in CDCl3 at different concen-
trations in the range of 12-55 mM, but no variation of the
20 °C coalescence temperature was observed. Moreover, a 1:1
mixture of 13 and 13‚HI (both 0.13 M in CDCl3 at 25 °C)
produces a slow-exchange 13C NMR spectrum showing separate
signals for the syn and anti forms of 13‚HI.31 This indicates
that even if low concentrations of the free base forms of 13
(30) Weisman, G. R.; Johnson, V.; Fiala, R. E. Tetrahedron Lett. 1980, 21,
3635-3638.
9
J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003 12201

A R T I C L E S
Bell et al.
and 16 are present in solutions of their HI salts, this would not
significantly affect the rate of conformational exchange.
Dynamic NMR studies were also performed on free base 16
to observe the effect of cavity protonation on the activation
energy for nitrogen inversion. At -120 °C in CD2Cl2/CDCl3
(2:1, v/v) two sets of 13C NMR resonances were observed
corresponding to a population ratio of 35:65. A coalescence
temperature of -93 ( 3 °C was measured for the C11 carbon
resonating at δ values of 148.9 and 149.6 ppm at -120 °C.
Line-shape analysis at six temperatures in the range of -100
to -85 °C gave an activation free energy of 8.8 ( 0.3 kcal/
mol for nitrogen inversion. This value is similar to that observed
for medium ring amines, e.g., N-methylhomopiperidine (6.8
kcal/mol).32
Modeling. To address the hydrogen bonding pattern in 15‚
HI, for which the position of the hydrogen atom in the cavity
was not crystallographically determined, ab initio calculations
at the HF/6-31+G* level using Gaussian98 were first used to
model 16‚HI. The structure of the salt was minimized starting
with the geometry observed in the crystal structure, including
the identified location of the hydrogen atom bonded to
bridgehead nitrogen atom N1 but omitting the iodine atom (cf.
Figs. 1, 2). The calculated structure differed little from the crystal
structure; N1-N9, and N1-N5 distances increased by only 0.06
and 0.03 Å, respectively, whereas the N5-N9 distance increased
by 0.09 Å. This result is consistent with the presence of a strong
hydrogen bond between N1 and N9 (2.72 Å) and a weaker
hydrogen bond to the bridge nitrogen (N5). When the geometry
was minimized after moving the hydrogen atom in the crystal
structure from N1 to N5, the resulting distances were: N1-
N5, 2.93 Å; N5-N9, 2.93 Å; and N1-N9, 2.85 Å. The
calculated energy also increased by 4.5 kcal/mol. When the
proton was removed from 16‚H+ the distances were calculated
as follows: N1-N5, 3.27 Å; N5-N9, 3.27 Å; and N1-N9,
2.85 Å.
These quantum mechanics calculations were then repeated
on the crystal geometry of 15‚H+, placing the second hydrogen
atom first on N5, then on N1. In both cases the N-N distances
increased, but the deviation was less with the hydrogen atom
on N5. Relative to the crystal geometry in 15‚HI, the N-N
distances increased by the following increments with the
hydrogen on N5: N1-N5, 0.09 Å; N5-N9, 0.06 Å; N1-N9,
0.06 Å. With the hydrogen on N1, the increases were: N1-
N5, -0.05 Å; N5-N9, 0.32 Å; N1-N9, 0.13 Å. The results of
these calculations are thus in better agreement with a structure
of 15‚H+ in which the internal hydrogen atom is covalently
bonded to the bridge nitrogen (N5), rather than to a bridgehead
nitrogen (N1 or N9), although the calculated energy of the latter
is lower by 3.8 kcal/mol.
Figure 4. Conformational models of inversion in 16. Relative energies
determined at the HF/6-31+G* level (kcal/mole): A (syn-open, -6.34); B
(planar TS, 00.0); C (anti-open, -1.31). Color scheme: C, green; H, yellow;
N, blue.
bridge. We were also unable to generate a transition state based
on the crystal conformation in which N5 had a trigonal
environment.
It therefore seems likely that N5 inversion will occur within
a different conformation. One major conformation in which N5
inversion can occur easily in 16 is shown in Figure 4. This
conformation has mirror symmetry and differs from that in 16‚
HI mainly at the C3-C4 and C6-C7 bonds, which are anti
rather than gauche. Planar transition state B was obtained using
the QST2 method in Gaussion98 using structures A and C as
input structures. The obtained structure was confirmed as a
transition state by the presence of one negative frequency. The
structures of A, B, and C had energies of -709.13655,
-709.12644, and -709.12853 au at the HF/6-31+G* level. In
all of these structures N5 is 4.2-4.3 Å from either bridgehead
atom, indicating that there could be no direct interaction between
N5 and a proton located on N1 or N9 in the inversion transition
state.
We then repeated this calculation with N1 protonated using
the three structures in the same conformations as shown in
Figure 4. We obtained a significantly different result. The
structures of B and C were geometry optimized at the HF/6-
31+G* level with converged energies of -709.53805 and
-709.53815 au, respectively. Structure B was confirmed as
being a transition state by the presence of one negative
frequency. The negligible difference between the energies of B
and C can readily be explained by examining the two structures.
In B the nitrogen atom is trigonal, in C it becomes tetrahedral
but with very little movement of other atoms. This is because
the presence of the proton on N1 holds the bridge in a chairlike
conformation, and pseudoaxial â-hydrogens prevent the methyl
group on N5 from approaching the cavity of the macrocycle.
Geometry optimization of A proved more difficult. The input
structure almost converged to a structure close to the input
structure with an energy of -709.52960 au, but only three of
The inversion process observed in 16 and 16‚HI by dynamic
NMR spectroscopy was then modeled using Gaussian98.
Attempts to invert N5 followed by geometry optimization with
Gaussian98 gave extended conformations in which one or both
of the C3-C4 and C6-C7 torsions went from gauche (<120°)
to trans (>120°). Both results suggest that inversion of N5 in
conformations similar to that of 16‚HI is prohibited by steric
interaction between the bridge methyl group and the C13-C15
(31) At equal concentrations in CDCl3 12 and 12‚HI give a rapid-exchange 13
NMR spectrum, even down to -40 °C.
C
(32) Lambert, J. B. In Topics in Stereochemistry; Allinger, N. E., Eliel, E. L.,
Eds.; Wiley-Interscience: NY, 1975; Vol. 6, pp 19-105.
9
12202 J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003

Syntheses and Conformations of Bicyclic Triamines
A R T I C L E S
the four default convergence criteria in Gaussian98 were
satisfied. After continued geometry optimization the structure
converged to the anti-closed structure of Figure 3 with an energy
of -709.55854 au. The closeness of the energies of C and B
indicates that the barrier to inversion from C to A is negligible
in 16‚HI, but that the syn-open structure of A is unstable to
ring closure to form the anti-closed structure, which is stabilized
by hydrogen bond formation.
tions present in 6 and 40. Triamine 39 has a smaller pKa1 (9.7)
and a ∆pKa of only 1.4 units. Thus, the bicyclo[5.5.0] skeleton
of 39 does not facilitate interaction between the three nitrogens;
the bridgehead nitrogen may even prefer “out” pyramidalization,5b
with the electron pair oriented away from the two bridge
nitrogens.
Previous NMR and crystallographic studies established
similarity between the solution- and solid-state conformations
of 15‚HI.9 The crystal structures of 12‚HI and 16‚HI reflect
weaker observed stabilization of the monoprotonated form. The
cavity proton of 15‚HI was not located crystallographically, but
the nearly perfect equilateral triangle formed by the three
nitrogens (cf. Figure 2) suggests that they are participating
almost equally in a hydrogen-bonded network. In 12‚HI, the
N1-N9 distance is lengthened by ca. 0.15 Å. Another difference
is that in 12‚HI one of the three-carbon bridges is oriented away
from the other, while in 15‚HI they are oriented together,
possibly because of less steric hindrance between the sp2 carbon
at C11 and the “axial” hydrogen on C14. This conformation
may permit more effective hydrogen bonding between the bridge
nitrogen (N5) and both bridgehead nitrogens (N1 and N9). In
16‚HI, weaker stabilization of the monocation is manifested by
lengthening of both bridge-bridgehead nitrogen distances (N1-
N5 and N5-N9) by 0.2-0.3 Å. In 16‚HI, the cavity proton
was crystallographically localized on one bridgehead nitrogen
(N1); thus, bifurcation of the hydrogen bond occurs unequally
between N5 and N9.
Discussion
Strong N-N interaction in proton sponges not only enhances
the basicity of the neutral form, it also decreases the basicity of
the monocation.1a,b Cooperation between all three nitrogens of
a triamine in stabilizing a single proton should accordingly
increase the pKa of the monoprotonated form (pKa1) and decrease
the pKa of the dication (pKa2).1c An example is 12,17-dioxa-
1,5,9-triazabicyclo[7.5.5]nonadecane (41), with pKa1 > 13 and
pKa2 ) 6.20.33 The resulting pKa difference (∆pKa ) pKa1
-
pKa2) of more than 6.8 log units results from the necessity of
breaking a strong N‚‚‚H+ hydrogen bond during the second
protonation. For comparison, the pKa1 and pKa2 values for 1,3-
diaminopropane are 10.56 and 8.76, respectively (∆pKa ) 1.8).1c
The Gaussian calculations at the HF/6-31+G* level carried
out on 12‚H+, 13‚H+, 15‚H+, and 16‚H+ all show that the
structure with the internal hydrogen atom bonded to the
bridgehead nitrogen atom N1 (or N9) has a lower energy by
3.35, 4.32, 4.69, and 3.95 kcal/mol, respectively, relative to the
structure with the internal hydrogen atom bonded to N5.
However, the correlation between these results and the crystal
structures of 12‚H+, 15‚H+, and 16‚H+ is not straightforward.
In the crystal structure of 16‚H+ the extra hydrogen atom was
located on the bridgehead N1, and the internal N-N distances
obtained from the cation optimized in Gaussian98 are compa-
rable with those obtained experimentally. The shortest distance,
and apparently the strongest hydrogen bond, is between N1 and
the other bridgehead (N9). The longer N1-N5 distance implies
unequal bifurcation of the hydrogen bond between bridge and
bridgehead positions. However, in 15‚HI the experimental
structure and, in particular, the N-N distances are more
comparable with the theoretical structure obtained when the
hydrogen is located on the bridge (N5). This equally bifurcated
hydrogen-bonded structure is supported by shorter distances for
both N1-N5 and N5-N9 (see Figure 2), and the expansion of
the N1-N9 distance is apparently a consequence of H-
localization on N5. The resulting N3 triangle in 15‚HI is nearly
equilateral, permitting rapid migration of the proton between
the three basic sites in solution. Steric hindrance caused by the
methyl group in 16‚HI apparently reduces stabilizing interaction
between the bridge and bridgehead sites, and this is reflected
by the smaller ∆pKa for 16‚HI than for 15‚HI. The experimental
dimensions in 12‚HI are similar to those obtained in 15‚HI, and
the N-N distances are compatible with the theoretical structure
in which N5 is protonated rather than N1.
All six triamines studied here (12, 13, 15, 16, 23, and 39)
have the 1,5,9-triazacyclododecane ring embedded in their
bicyclic structures; thus the pKa’s of these systems reflect the
consequences of bridging and substitution on the stability of
the monoprotonated form. The average ∆pKa value for 1,5,9-
triazacyclododecane (6) calculated from the pKa’s listed in Table
1 is 5.1, indicating that the macrocyclic framework conforma-
tionally stabilizes interaction between the nitrogen atoms. The
tri-N-methyl derivative 40 has a similar pKa1 value (ca. 12.8),
but the monoprotonated form is a weaker base (pKa2 5.7 vs ca.
7.5). This suggests that at least one of the three nitrogens is
responsible for greater stabilization in 40‚HI+ than in 6‚HI+.
Bicyclic triamines 12, 13, 15, and 16 all contain a three-carbon
bridge across two nitrogens of 1,5,9-triazacyclododecane. Their
pKa1 values could not be measured accurately by potentiometric
titration in water, but the pH of a 0.1 M aqueous solution of 15
(13.1) is greater than that of a 0.1 M aqueous solution of 6
(12.8). The pKa1 of 15 must be at least 13, while the pKa2 (4.4)
is lower than that of 6. The ∆pKa of 15 is thus at least 3.5 units
greater than that of 6, showing that the three-carbon bridge
considerably stabilizes the monocation. The ∆pKa values for
12, 13, and 16 are slightly smaller than that for 15, indicating
a somewhat lower degree of stabilization of the monoprotonated
form.
Bicyclic triamines 23 and 39 are isomeric structures contain-
ing a one-carbon bridge from N1 to C3 (in 23) or a zero-atom
bridge from N1 to C7 (in 39). The pKa values of 23 are similar
to those of 6 and 40, indicating that the incorporation of an
azetidine ring in 23 does not strongly affect the N-N interac-
The results of dynamic NMR studies on the HI salts of
N-methylated triamines 13 and 16 gave 14.4 ( 0.2 and an
(33) Bianchi, A.; Ciampolini, M.; Micheloni, M.; Chimichi, S.; Zanobini, F.
Gazz. Chim. Ital. 1987, 117, 499-502.
9
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A R T I C L E S
Bell et al.
Figure 5. Energy profile for conformational inversion of 16‚HI, assuming
equivalent inversion barriers of free amine 16 and the open conformations
of 16‚HI (see Figure 3), based on experimental (VT NMR) inversion barriers
(∆Gq).
Figure 6. Structures of the anti-closed, anti-open, and syn-closed confor-
mations of 16‚H+ as calculated at the HF/6-31+G* level. The syn-open
structure proved unstable to geometry optimization and reverted to the anti-
closed conformation. Color scheme: C, green; H, yellow; N, blue.
average of 15.0 ( 0.1 kcal/mol for the activation free energies
for ring inversion of 13‚HI and 16‚HI, respectively. These
experiments were performed in different solvents, but the smaller
value for 13‚HI is consistent with weaker bridge nitrogen
stabilization, as revealed by basicity, crystallography, and
computational studies. The latter, which have neglected solvent,
have also established that bridge nitrogen inversion must occur
via an open conformation (cf. Figure 3), even for free base 16,
for which an inversion barrier of 8.8 ( 0.3 kcal/mol was
measured. Protonation of 16 clearly increases the inversion
barrier by about 6 kcal/mol, a value which indicates the strength
of the hydrogen bond between N5 and the proton covalently
bonded to N1.
Figure 5 displays the energy profile for conformational
inversion of 16‚HI, assuming that the barrier for N-inversion
of the open forms (cf. Figure 3) is equal to that for free amine
16. The actual barrier for interconversion of the syn-open and
anti-open forms of 16‚HI may be smaller or larger than that of
free base 16. For example, conformational rigidity caused by
interbridgehead hydrogen bonding might increase or decrease
bond angle strain in the nitrogen inversion transition state. If
we assume that these barriers are equal, as indicated in Figure
5, then the 6.2 kcal/mol free energy difference between the open
and closed forms of 16‚HI is still only an estimate of the strength
of the hydrogen bond between the bridge nitrogen and the cavity
proton. This is because the open and closed forms should have
different solvation and conformational energies. Moreover,
removal of hydrogen bond bifurcation is likely to be partially
compensated by an increase in the strength of the primary
hydrogen bond between the bridgehead nitrogen atoms.
We investigated the proposed mechanism for the conforma-
tional inversion of 16‚HI via hydrogen bond cleavage followed
by nitrogen inversion, as exactly shown in Figure 3. We first
built the four conformations shown in the figure, which have
different exo-methylene bridge conformations relative to Figure
4, and used Gaussian98 at the HF/6-31G* level to optimize their
geometries. However, the syn-open conformation failed to
converge but instead reverted to the anti-closed conformation.
The relative energies of the other conformations, shown in
Figure 6, were the following: anti-closed -709.55854, anti-
open -709.53554, and syn-closed -709.55039 au. To under-
stand the mechanism more fully we repeated the calculations
using the unprotonated 16. Here by contrast, but not unexpect-
edly, the anti-closed conformation now proved unstable and
Figure 7. Structures of the syn-open, anti-open and syn-closed conforma-
tions of 16 as calculated at the HF/6-31+G* level. The anti-closed structure
proved unstable to geometry optimization and reverted to the syn-open
conformation. Color scheme: C, green; H, yellow; N, blue.
reverted to the syn-open conformation. The energies of the three
structures, shown in Figure 7, were syn-open -709.12520, anti-
open -709.11666, and syn-closed -709.11710 au. From these
calculations we can compare the difference in energies between
anti-open and syn-closed, which is 10.57 kcal/mol for 16‚H+,
but 0.25 kcal/mol for 16. These values clearly show the
importance of hydrogen bond formation to the stabilization of
16‚H+ in the closed form. This calculation provides an estimate
of 10.32 kcal/mol for the enthalpy of the hydrogen bond between
the bridge nitrogen and the cavity proton in 16‚H+ in the gas
phase.
Conclusions
Effective routes have been developed for synthesis of three
types of bicyclic triamines having the 1,5,9-triazacyclododecane
ring embedded in their structures. Bridging two nitrogens with
three carbons gives proton sponges 12, 13, 14, and 15 having
greatly stabilized monoprotonated forms, with pKa values more
than 8 units larger than those of their diprotonated forms. The
one-carbon bridge in 23 and the zero-atom bridge in 39 do not
9
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Syntheses and Conformations of Bicyclic Triamines
A R T I C L E S
1.74 (m, 4 H). IR (film): 3325 (s), 3075 (s), 2975 (s), 2900 (m), 1619
enhance the stability of the monoprotonated form. Structural
studies involving X-ray crystallography and computational
modeling reveal hydrogen-bonded networks that are apparently
responsible for the stabilities of 12‚H+, 13‚H+, 15‚H+, and 16‚
H+. The cavity proton is covalently bonded to the bridge
nitrogen in 15‚HI, and the bridge nitrogens form equally
bifurcated hydrogen bonding contacts. The bridge methyl group
in 16‚HI decreases interaction of the bridge nitrogen with the
cavity proton, which is covalently bonded to one of the
bridgehead nitrogens. Dynamic (VT) 1H and 13C NMR studies,
as well as molecular modeling, indicate that conformational
inversion of 16‚HI (∆Gq ) 15.0 kcal/mol) occurs after cleavage
of the hydrogen bond between the bridge nitrogen and the cavity
proton. Comparison with the 8.8 ( 0.3 kcal/mol activation
energy for inversion of free base 16 leads to an estimate of 6.2
kcal/mol for the strength of this hydrogen bond. Computational
results lead to an estimate of 10.32 kcal/mol for the enthalpy
of the bifurcated hydrogen bond in the gas phase. These
conclusions should be useful in the design of other highly basic
compounds and for understanding hydrogen-bonded networks
in biological systems.
(s), 1450 (br, s), 1350 (br, s), 1175 (s) cm-1
.
1,3-Propanediol bis(4-methylbenzenesulfonate) (9).16 A solution
of 38.5 g (0.5 mol) of 1,3-propanediol in 100 mL of pyridine was added
dropwise over 2 h to a solution of 228 g (1.2 mol) of tosyl chloride in
400 mL of anhydrous pyridine, which was cooled in an ice-salt bath
at 0-10 °C. The reaction mixture was stirred for 4 h, then poured into
1 L of ice water. The solid product was collected by filtration, washed
with water, dilute sulfuric acid, dilute sodium carbonate, and again with
water. The wet product was recrystallized from acetone. The resulting
white, crystalline product was filtered and dried under vacuum at room
1
temperature, yielding 190 g (98%), mp 90-91 °C (lit.16b 94 °C). H
NMR (80 MHz, CDCl3): δ 7.75 (d, J ) 8 Hz, 4 H), 7.33 (d, J ) 8 Hz,
4 H), 4.07 (m, 4 H), 2.45 (s, 6 H), 2.01 (m, 2 H).
1,5,9-Tris(4-methylbenzenesulfonyl)-1,5,9-triazacyclododecane
(10).8a,c,e,16b,17 NaH (6 g, 0.25 mol) was added under nitrogen to a
solution of 59.4 g (0.1 mol) of N,N′,N′′-tris(4-methylbenzenesulfonyl)-
bis(3-aminopropyl)amine (8) in 750 mL of anhydrous DMF. The
resulting mixture was stirred at 80-100 °C for 1 h; it was then cooled
to room temperature and filtered under nitrogen through a glass fiber
filter into a 2-L three-necked round-bottomed flask equipped with a
rubber septum and a thermometer. The insoluble material was washed
with 250 mL of anhydrous DMF, which was also added to the 2 L
reaction flask. The resulting solution was stirred at 100 °C under
nitrogen as a solution of 39.4 g (0.1 mol) of 1,3-propanediol bis(4-
methylbenzenesulfonate) (9) in 500 mL of anhydrous DMF was added
slowly over 6 h. The reaction mixture was heated for an additional 6
h. The solvent was removed completely under vacuum on a rotary
evaporator using a hot water bath. A solution of the viscous crude
product in 300 mL of CHCl3 was washed with an equal amount of
water. The organic layer was separated, dried over MgSO4, filtered to
remove insoluble material, and concentrated by rotary evaporation. A
solution of the residue in hot toluene was diluted with hexane and the
clear supernatant liquid was decanted from the white precipitate. The
residue was redissolved in toluene and the process was repeated until
precipitation no longer occurred upon addition of hexane. The combined
supernatant solutions were concentrated and the crude product was
recrystallized from CHCl3/EtOH, yielding 31.5 g (50%) of 10 as a white
solid, mp 170-171 °C (lit.8e 171 °C); Rf 0.41 (silica gel, ethyl acetate/
Experimental Section
General Methods. All commercial solvents and reagents were used
without purification, unless noted otherwise. Anhydrous tetrahydrofuran
(THF) was obtained by distillation from sodium benzophenone ketyl
immediately prior to use. Dichloromethane was either distilled from
CaH2 or passed through Woelm neutral alumina (activity I). Anhydrous,
acid-free CDCl3 was obtained by the latter method. Anhydrous benzene
and dimethyl sulfoxide (DMSO) were obtained by distillation from
CaH2 (in vacuo for DMSO). Pyridine was dried over KOH, distilled
from barium oxide and stored over 4Å molecular sieves. Tosyl (4-
methylbenzenesulfonyl) chloride was purified by recrystallization from
petroleum ether. 3,3′-Diaminodipropylamine (Eastman) was purified
by vacuum distillation. Sodium hydride was obtained as a 60%
dispersion in mineral oil and was washed with hexanes under N2 prior
to use. All reactions were conducted under dry nitrogen, unless noted
otherwise. Thin-layer chromatography (TLC) was performed with
Machery-Nagel plastic sheets coated with alumina or silica gel (0.25
mm). Spots were visualized under UV light or by heating after dipping
in solutions of vanillin (9 g in 300 mL of ethanol and 1.5 mL of H2-
SO4) or phosphomolybdic acid (10% (w/w) in ethanol). Flash column
chromatography was conducted with Merck Silica Gel 60 (230-400
mesh), and silica gel used for purification by filtration was ICN Silica
TSC (activity III). Melting points are uncorrected and mass spectra
(MS) were obtained by electron impact (70 eV).
1
hexane (1:1, v/v)). H NMR (80 MHz, CHCl3): δ 7.64 (d, J ) 8 Hz,
6 H), 7.29 (d, J ) 8 Hz, 6 H), 3.17 (t, J ) 6 Hz, 12 H), 2.40 (s, 9 H),
1.78 (m, 6 H). MS m/z (rel intens): 478 (100), 223 (43), 155 (78), 91
(98).
1,5,9-Triazacyclododecane (6).8a-e,17 A solution of 31.7 g (50 mmol)
of 10 in 100 mL of 98% H2SO4 was heated at 100 °C for 54 h under
nitrogen. The solution was cooled in an ice bath and 200 mL of absolute
ethanol was added slowly from an addition funnel, followed by 500
mL of anhydrous ether. The precipitate was collected by filtration and
dried under nitrogen. It was dissolved in a minimum amount of water,
and the pH was adjusted to >13 by addition of 10 M aqueous NaOH
solution. The resulting solution was extracted with chloroform (2 ×
200 mL). The combined extracts were dried over MgSO4 and
concentrated by rotary evaporation. After residual chloroform was
completely removed under high vacuum overnight, the crude product
was distilled under vacuum from powdered KOH to afford 4.70 g (55%)
of a colorless liquid, bp 107 °C (1.0 mm), mp 8-9 °C. 1H NMR (300
MHz, CDCl3): δ 2.70 (t, J ) 5.4 Hz, 12 H), 2.22 (br, 3 H), 1.59 (p,
J ) 5.4 Hz, 6 H). 13C NMR (75 MHz, CDCl3): δ 48.8, 27.5. IR
(film): 3500-3200 (br, s), 2950 (s), 2830 (br) cm-1. MS m/z (rel
intens): 171 (M+, 30), 143 (50), 84 (72), 70 (100).
N,N′,N′′-Tris(4-methylbenzenesulfonyl)bis(3-aminopropyl)-
amine (8).8a,e A solution of 65.6 g (0.5 mol) of 3,3′-diaminodipropy-
lamine and 72 g (1.8 mol) of NaOH in 400 mL of water was added to
a 2-L three-necked flask equipped with a mechanical stirrer, a condenser
and a 1 L addition funnel. The reaction flask was placed in a water
bath at room temperature. A solution of 292 g (1.53 mol) of
p-toluenesulfonyl chloride in 750 mL of CH2Cl2 was added dropwise
with vigorous stirring over 1 h. The mixture was then stirred for 2 h
until it became clear. The CH2Cl2 layer was separated from the water
layer and washed with water (3 × 400 mL), adding some MgSO4 to
aid separation of the layers. After the CH2Cl2 layer was dried with
MgSO4, it was concentrated to a volume of 450 mL, then 350 mL of
Et2O was added. The resulting solution was concentrated by slow
evaporation. The crystalline product was collected by filtration, washed
with a small portion of cold Et2O, and dried under vacuum at room
temperature, yielding 266 g (90%), mp 112.5-113.5 °C (lit.8e 114 °C);
1,5,9-Triazabicyclo[7.3.3]pentadecane hydriodide (12‚HI). Sepa-
rate solutions of 1.71 g (10 mmol) of 1,5,9-triazacyclododecane (6) in
50 mL of 2-butanol and 2.96 g (10 mmol) of 1,3-diiodopropane in 50
mL of 2-butanol were added over 8 h by syringe pump to a mixture of
3.3 g (33 mmol) of KHCO3 and 900 mL of 2-butanol that was heated
at reflux under N2. The reaction mixture was then heated under reflux
1
Rf 0.57 (alumina, CH2Cl2). H NMR (80 MHz, CDCl3): δ 7.72 (d, J
) 8 Hz, 6 H), 7.30 (d, J ) 8 Hz, 6 H), 3.00 (m, 8 H), 2.41 (s, 9 H),
9
J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003 12205

A R T I C L E S
Bell et al.
for 15 h. The solvent was removed completely by rotary evaporation.
A solution of the residue in 30 mL of 3 M aqueous NaOH solution
was extracted with CHCl3 (3 × 60 mL). The combined organic extracts
were concentrated by rotary evaporation. A solution of the resulting
oil was partially neutralized with dilute aqueous HI to pH ≈ 10 and
extracted with CHCl3 (3 × 50 mL). The combined CHCl3 solutions
were dried over MgSO4 and concentrated by rotary evaporation. The
product was purified by adding hexane to a hot solution of the residue
in toluene and decanting the supernatant solution. The product (12‚
HI) crystallized from the supernatant at room temperature, yielding
1.68 g (50%) in two crops. Recrystallization from toluene/chloroform
gave analytically pure material, mp 227-229 °C. 1H NMR (300 MHz,
CDCl3): δ 10.4 (br s, 2 H), 2.95 (m, 8 H), 2.79 (t, J ) 5.7 Hz, 4 H),
2.59 (m, 4 H), 2.05 (p, J ) 5.7 Hz, 4 H), 1.74 (m, 4 H). 13C NMR (75
MHz, CDCl3): δ 60.5, 53.3, 49.2, 27.9, 23.6. IR (KBr): 3330-3600,
2950, 2860, 2810, 2560, 2450, 1895, 1635, 1470, 1460, 1425, 1380,
1355, 1195, 1105 cm-1. Anal. Calcd for C12H26N3I: C, 42.48; H, 7.72;
N, 12.38. Found: C, 42.67; H, 7.96; N, 12.27.
(m), 1175 (w), 1120 (w), 1050 (w) cm-1. Anal. Calcd for C13H27N3:
C, 69.28; H, 12.08; N, 18.64. Found: C, 69.24; H, 12.32; N, 18.88.
11-Methylene-1,5,9-triazabicyclo[7.3.3]pentadecane (15). Separate
solutions of 0.86 g (5 mmol) of 1,5,9-triazacyclododecane (6) in 50
mL of 2-propanol and 1.54 g (5 mmol) of 2-iodo-3-iodomethyl-1-
propene20 in 50 mL of 2-propanol were added over 3 h by syringe
pump to a mixture of 1.66 g (12 mmol) of K2CO3, and 150 mL of
2-propanol that was heated at reflux under N2. The reaction mixture
was then heated under reflux for 3 h. The solvent was removed by
rotary evaporation. A solution of the residue in 50 mL of CHCl3 was
washed with 5 M aqueous NaOH solution (3 × 30 mL). The combined
organic layers were dried over MgSO4, concentrated by rotary evapora-
tion, and dried completely under vacuum. The crude product was
distilled under vacuum from powdered KOH, yielding 0.78 g (70%)
of colorless oil, bp 110 °C (1.0 mm). 1H NMR (300 MHz, CDCl3): δ
6.3 (br s, 1 H), 4.84 (t, J ) 13 Hz, 2 H), 3.63 (dt, J ) 1.8, 13 Hz, 2
H), 2.84 (d, J ) 13 Hz, 2 H), 2.4-2.7 (m, 12 H), 1.7 (m, 3 H), 1.4 (m,
3 H). 13C NMR (75 MHz, CDCl3): δ 149.5, 114.5, 60.1, 59.9, 55.0,
51.7, 29.3, 26.3. IR (CCl4): 3220, 2950, 2940, 2890, 2800, 1645, 1490,
1190, 1150, 925 cm-1. MS m/z (rel intens): 223 (M+, 50), 110 (60),
96 (100), 82 (70), 70 (80), 56 (70), 42 (50). Anal. Calcd for C13H25N3:
C, 69.90; H, 11.28; N, 18.81. Found: C, 69.96; H, 11.14; N, 18.90.
11-Methylene-1,5,9-triazabicyclo[7.3.3]pentadecane Hydriodide
(15‚HI). 11-Methylene-1,5,9-triazabicyclo[7.3.3]pentadecane (15) was
dissolved in 0.1 M aqueous HI, and the pH of the solution was adjusted
to 9-10. The monoprotonated product was extracted with CHCl3. The
extract was dried over MgSO4 and concentrated by rotary evaporation.
The crude HI salt was dissolved in boiling toluene/chloroform (1:1,
v/v). Colorless crystals were obtained at room temperature, mp 199-
1,5,9-Triazabicyclo[7.3.3]pentadecane (12). A mixture of 0.66 g
(1.9 mmol) of 12‚HI and 5 M aqueous KOH solution was stirred
vigorously, and then the free amine was extracted with chloroform.
The chloroform layer was dried over MgSO4 and then concentrated by
rotary evaporation. Residual solvent was completely removed under
vacuum overnight, and the residue was then distilled under vacuum
from powdered potassium hydroxide. The colorless oil (250 mg, 61%),
which distilled at 110 °C (0.5 mm), was handled carefully under N2.
1H NMR (300 MHz, CD3CN): δ 5.5 (br s, 1 H), 2.56 (m, 8 H), 2.42
(m, 8 H), 1.53 (m, 4 H), 1.45 (m, 4 H). 13C NMR (75 MHz, CD3CN):
δ 61.8, 53.3, 52.7, 30.0, 27.7. IR (film): 3210 (br, s), 3170 (br, s),
2900 (br, s), 2850 (m), 2770 (br, s), 2700 (s), 1470 (s), 1440 (m), 1430
(m), 1345 (m), 1330 (m), 1275 (m), 1230 (m), 1190 (s), 1175 (m),
1125 (m), 1110 (m), 1030 (m), 985 (m), 750 (m) cm-1. MS m/z (rel
intens): 212 (3.2, M + l), 211 (26, M+), 85 (21), 84 (100), 71 (30), 70
(62), 58 (41). Anal. Calcd for C12H25N3: C, 68.20; H, 11.92; N, 19.88.
Found: C, 67.85; H, 12.21; N, 19.96.
1
200 °C. H NMR (300 MHz, CDCl3): δ 11.50 (br s, 1 H), 10.50 (br
s, 1 H), 5.00 (t, J ) 2 Hz, 2 H), 3.88 (d, J ) 14 Hz, 2 H), 3.05 (d, J
) 14 Hz, 2 H), 2.5-3.5 (m, 12 H), 2.2 (m, 2 H), 2.1 (m, 1 H), 1.9 (m,
2 H), 1.5 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ 145.5, 115.5, 60.0,
58.5, 54.6, 48.6, 27.2, 22.4. IR (KBr): 2950, 2800, 2450, 1635, 1460,
1375, 1300, 1100 cm-1
.
5-Methyl-11-methylene-1,5,9-triazabicyclo[7.3.3]pentadecane (16).
A mixture of 0.14 g (0.63 mmol) of 15, 78 µL (1.5 mmol) of 90%
formic acid and 54 µL (0.66 mmol) of 37% aqueous formaldehyde
was heated in an oil bath at 120 °C for 16 h. The reaction mixture was
basified with 10 M aqueous KOH solution and extracted with CHCl3.
The CHCl3 layer was dried over MgSO4 and filtered. The filtrate was
concentrated by rotary evaporation and dried under vacuum. The crude
oily product was distilled from powdered KOH, yielding 65 mg (43%)
of a colorless oil, bp 100-110 °C (0.3 mm). 1H NMR (300 MHz,
CDCl3): δ 4.88 (s, 2 H), 3.39 (d, J ) 13 Hz, 2 H), 3.25 (d, J ) 13 Hz,
2 H), 2.81 (m, 4 H), 2.62 (m, 4 H), 2.48 (m, 4 H), 2.25 (s, 3 H), 1.65
(m, 2 H), 1.53 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ 150.9, 114.2,
62.0, 53.8, 57.4, 43.8, 31.0, 27.1. IR (film): 3075, 2750-2950, 1640,
1450, 1350, 1270, 1200, 1180, 1050, 760 cm-1. MS m/z (rel
intensity): 238 (M + l, 18), 237 (M+, 85), 222 (15), 151 (25), 141
(30), 122 (35), 110 (60), 96 (90), 84 (100), 70 (80), 58 (90), 42 (90).
5-Methyl-11-methylene-1,5,9-triazabicyclo[7.3.3]pentadecane Hy-
driodide (16-HI). The procedure for preparation of (16‚HI) from 16
is the same as for preparation of 15‚HI from 15, giving a white solid,
mp 246.5-247.5 °C (toluene/chloroform). 1H NMR (300 MHz,
CDCl3): δ 12.8 (br s, 1 H), 5.16, 4.72, 4.00, 3.62, 3.42, 3.10, 2.82,
2.46, 2.25 (s, 3 H), 1.92, 1.85 (s), 1.60. All peaks are broad at room
temperature (25 °C). 13C NMR (75 MHz, CDCl3 at 25 °C): δ 139.6,
115.3, 58.3, 57.8, 55.6, 42.1, 21.5. IR (KBr): 3400, 3050, 2950, 2800,
2100-2800, 1640, 1450, 1355, 1300, 1255, 1200, 1180, 1150, 1120,
1080, 1040, 990, 960, 940, 910, 860, 760 cm-1. Anal. Calcd for
C14H28N3I: C, 46.01; H, 7.73; N, 11.50. Found: C, 46.01; H, 7.79; N,
11.48.
5-Methyl-1,5,9-triazabicyclo[7.3.3]pentadecane-HI Salt (13‚
HI). A mixture of 0.34 g (1.0 mmol) of 1,5,9-triazabicyclo[7.3.3]-
pentadecane-HI (12‚HI), 0.77 g (8 mmol) of 30% aqueous formalde-
hyde, 0.1 g (1.6 mmol) of NaCNBH3 and 1 mL of acetonitrile
containing a few drops of acetic acid was stirred for 3 h at room
temperature. The reaction mixture was concentrated by rotary evapora-
tion, basified to pH 13 by addition of aqueous NaOH solution, and
extracted with CHCl3. The CHCl3 layer was concentrated by rotary
evaporation. A solution of the crude product in water was adjusted
exactly to pH 10 with 0.1 M aqueous HI solution and extracted with
CHCl3. The extract was dried over Na2SO4 and concentrated by rotary
evaporation. The crude product was recrystallized from boiling toluene
(note: 13‚HI dissolves in cold toluene and crystallizes from hot toluene),
1
yielding 0.24 g (70%) of white crystals, mp 272-273.5 °C. H NMR
(300 MHz, CDCl3): δ 12.0 (s, 1 H), 2.27 (s, 3 H), plus several broad
peaks at room temperature. 13C NMR (75 MHz, CDC13, 60 °C): δ
58.4, 57.8, 53.8, 42.4, 22.4, 21.8; (20 °C): δ 58.3, 57.8, 54.6, 52.3,
42.2, 22.8, 21.7. IR (KBr): 3330-3600, 2970, 2900, 1465, 1440, 1360,
1250, 1180, 1015, 995 cm-1. Anal. Calcd for C13H28N3: C, 44.19; H,
7.99; N, 11.89. Found: C, 43.82; H, 8.14; N, 11.67.
5-Methyl-1,5,9-triazabicyclo[7.3.3]pentadecane (13). A mixture of
0.71 g (2.0 mmol) of 13‚HI and 10 M aqueous KOH solution was
stirred vigorously under N2. The free amine was extracted with CHCl3,
and the extract was dried over MgSO4. Chloroform was completely
removed under vacuum overnight, and the residue was distilled from
powdered KOH. A colorless oil (0.32 g, 71%) was obtained and handled
1
carefully under N2. H NMR (300 MHz, CD3CN): δ 2.8-3.2 (m, 16
H), 2.24 (s, 3 H), 1.4-1.7 (m, 8 H). 13C NMR (75 MHz, CD3CN): δ
58.9, 56.3, 54.4, 44.6, 31.4, 29.4. IR (film): 2920 (s), 2905 (s), 2880
(s), 2820 (s), 2770 (s), 2740 (s), 1500 (m), 1480 (m), 1350 (m), 1200
11-Hydroxymethyl-1,5,9-triazabicyclo[7.3.3]dodecane (17). A so-
lution of 0.29 g (1.3 mmol) of 11-methylene-1,5,9-triazabicyclo-
[7.3.3]pentadecane (15) in 15 mL of anhydrous THF was cooled to
9
12206 J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003

Syntheses and Conformations of Bicyclic Triamines
A R T I C L E S
-78 °C under N2. A solution of 9-borabicyclo[3.3.1]nonane (9-BBN)
in anhydrous THF (0.5 M, 7.7 mL) was added, and stirring was
continued for 2 h at -78 °C. The reaction solution was allowed to
warm to room temperature and stirred for 5 h; EtOH (3 mL), 3 M
aqueous NaOH (3 mL), and 30% aqueous hydrogen peroxide (3 mL)
were then added, and the resulting mixture was stirred for l h at room
temperature. The mixture was saturated with K2CO3, and the THF layer
was separated. The THF was removed by rotary evaporation, and 10
mL of 2 M aqueous HCl was added to the residue. The resulting solution
was heated under reflux for 1 h to cleave any boramine complex, cooled,
and continuously extracted overnight with methylene chloride. The pH
of the aqueous solution was adjusted to >13 by addition of NaOH,
and then it was extracted with chloroform. The chloroform extract was
dried over anhydrous Na2SO4, and the solvent was removed in vacuo,
yielding 0.30 g (97%) of the crude product as a crystalline, white solid.
(Note: Use of magnesium sulfate as a drying agent gave a complex
that was insoluble in toluene and produced a very broad 1H NMR
spectrum (CDCl3).) This 4:1 mixture of diastereomeric alcohols (17a
and 17b, respectively) was separated by repeated recrystallization from
hexane, yielding small samples that gave the following data. 17a: mp
to quench excess borane. Sodium hydroxide (30 mL of 3 M aqueous
solution) was added, followed by 15 mL of 30% aqueous H2O2, keeping
the temperature in the range of 30-35 °C by means of an ice bath.
The reaction mixture was stirred for 3 h, then the solvent was removed
by rotary evaporation. A solution of the residue in 300 mL of CHCl3
was washed with water (3 × 150 mL), dried over MgSO4, filtered,
and concentrated by rotary evaporation. The residue was dried under
vacuum, yielding 22 g (66%) of crude product, which could be used
in the next step without further purification. For the purpose of
characterization, the product was recrystallized from EtOH/CH2Cl2, mp
201.5-202.5 °C; Rf 0.24 (silica gel, ethyl acetate/hexane (1:1, v/v)).
1H NMR (300 MHz, CDCl3): δ 7.67 (d, J ) 8 Hz, 4 H), 7.59 (d, J )
8 Hz, 2 H), 7.33 (d, J ) 8 Hz, 4 H), 7.31 (d, J ) 8 Hz, 2 H), 3.72 (m,
2 H), 3.47 (m, 4 H), 3.20 (m, 6 H), 2.72 (dt, J ) 5, 14 Hz, 2 H), 2.43
(s, 6 H), 2.43 (s, 3 H), 2.34 (m, 1 H), 2.18 (m, 1 H), 1.98 (m, 2 H),
1.83 (m, 2 H). 13C NMR (75 MHz, CDC13): δ 143.8, 143.5, 135.5,
133.6, 129.8, 127.3, 127.0, 60.8, 47.3, 47.1, 44.2, 37.0, 27.0, 21.5. IR
(CDCl3): 3530 cm-1
.
3-Chloromethyl-1,5,9-tris(4-methylbenzenesulfonyl)-1,5,9-triaza-
cyclododecane (21). Triphenylphosphine (0.7 g, 2.7 mmol) was added
slowly to a solution of 1.33 g (2 mmol) of 20 and CCl4 (0.6 mL) in 5
mL of anhydrous DMF, which was cooled by means of an ice bath.
The reaction mixture was stirred overnight at room temperature. The
solvent was removed by rotary evaporation, and the reaction product
was isolated by flash chromatography (ethyl acetate/hexane (1:1, v/v))
and recrystallized from EtOH/CH2Cl2, yielding 0.85 g (64%) of solid,
mp 156-157 °C; Rf 0.45 (silica gel, ethyl acetate/hexane (1:1, v/v)).
1H NMR (300 MHz, CDCl3): δ 7.67 (d, J ) 8 Hz, 4 H), 7.60 (d, J )
8 Hz, 2 H), 7.33 (d, J ) 8 Hz, 4 H), 7.31 (d, J ) 8 Hz, 2 H), 3.61 (d,
J ) 5 Hz, 2 H), 3.47 (m, 4 H), 3.20 (m, 6 H), 2.72 (dt, J ) 5, 14 Hz,
2 H), 2.41 (m, 10 H), 2.03 (m, 2 H), 1.78 (m, 2 H). 13C NMR (75
MHz, CDCl3): δ 143.8, 143.7, 135.3, 133.4, 129.8, 129.7, 127.4, 127.1,
1
124-125 °C. H NMR (300 MHz, CDCl3): δ 3.73 (d, J ) 6.1 Hz, 2
H), 2.2-3.2 (m, 18 H), 1.4-2.0 (m, 7 H). 13C NMR (75 MHz,
CDCl3): δ 63.6, 60.7, 54.2, 52.6, 50.9, 41.1, 28.4, 25.4. IR (KBr):
3400 (br, s), 3125 (s), 2900 (s), 2875 (s), 1475 (s), 1340 (m), 1180
(m) cm-1. MS m/z (rel intens): 241 (48), 84 (100), 70 (95), 58 (80).
1
17b: mp 184-186 °C. H NMR (300 MHz, CDCl3): δ 3.38 (d, J )
6.1 Hz, 2 H), 2.5-3.2 (m, 18 H), 1.4-2.4 (m, 7 H). 13C NMR (75
MHz, CDCl3): δ 63.6, 60.6, 57.2, 51.7, 49.7, 43.0, 25.5, 24.3. IR
(KBr): 3425 (br, s), 2950 (s), 2800 (s), 1475 (s), 1350 (m), 1200 (m)
cm-1
.
3-Methylene-1,5,9-tris(4-methylbenzenesulfonyl)-1,5,9-triazacy-
clododecane (19). To a solution of 59.4 g (0.1 mol) of 8 in 1 L of
anhydrous DMF, was added 6 g (0.25 mol) of NaH under N2. The
resulting mixture was stirred at 80-100 °C for 1 h and then cooled to
room temperature. It was then filtered under nitrogen through a glass
fiber filter by means of a cannula into a 2-L three-necked round-
bottomed flask equipped with a rubber septum and a thermometer.
Transfer was completed with an additional 400 mL of anhydrous DMF.
The resulting solution was heated at 100 °C, and a solution of 12.5 g
(0.1 mol) of 3-chloro-2-chloromethyl-1-propene in 100 mL of anhy-
drous DMF was added by means of a syringe pump over 5 h. The
reaction mixture was heated for 5 h; the DMF was removed completely
by rotary evaporation using a boiling water bath. The resulting viscous
crude product was dissolved in 150 mL of chloroform. This chloroform
solution was washed with water (3 × 100 mL), dried over MgSO4,
and concentrated in vacuo. The yellow viscous product was purified
in the same way as that described for tris(4-methylbenzenesulfonyl)-
1,5,9-triazacyclododecane (10), yielding 38.3 g (59.3%) of solid, mp
168-169 °C (EtOH-CH2Cl2); Rf 0.42 (silica gel, ethyl acetate/hexane
48.0, 46.7, 44.7, 37.0, 26.3, 21.5. IR (CDCl3): 975 cm-1
.
3-Chloromethyl-1,5,9-triazacyclododecane (22). A solution of 1.37
g (2 mmol) of 21 in 2 mL of 98% H2SO4 was kept at 100 °C for 54 h
under nitrogen. The solution was cooled in an ice bath, and 10 mL of
absolute ethanol was added slowly by means of an addition funnel,
followed by 20 mL of anhydrous ether. The precipitate was collected
by filtration and dried under nitrogen. It was dissolved in the minimum
volume of water, and the pH was adjusted to >13 with 10 M aqueous
NaOH. This solution was extracted with chloroform (3 × 20 mL). The
combined extracts were dried over MgSO4 and concentrated by rotary
evaporation. The crude product was used in the next step without
1
purification. A sample of this oil was completely dried in vacuo. H
NMR (300 MHz, CDCl3): δ 6.4 (br s, 3 H), 3.51 (d, J ) 5 Hz, 2 H),
2.95 (m, 6 H), 2.6 (m, 6 H), 2.4 (m, 1 H), 1.9 (m, 2 H), 1.7 (m, 2 H).
MS m/z (rel intens): 221 (M + 2, 2.5), 220 (M + l, 1.3), 219 (M+,
6.9), 184 (19.9), 70 (100).
1,5,9-Triazabicyclo[9.1.1]tridecane (23). The crude 3-chloromethyl-
1,5,9-triazacyclododecane (22) product obtained from 1.37 g (2 mmol)
of 21, 400 mL of anhydrous 2-propanol and 0.3 g (2 mmol) of K2CO3
was heated under reflux for 10 h. The solvent was removed by rotary
evaporation. A mixture of the residue and 5 M aqueous NaOH solution
was extracted with CHCl3. The CHCl3 extract was dried with MgSO4
and concentrated by rotary evaporation. The crude product was distilled
in vacuo from powdered KOH, yielding 0.22 g (58%), bp 110-
130 °C (0.1 mm). 1H NMR (300 MHz, CDCl3): δ 3.28 (m, 2 H), 2.98
(m, 2 H), 2.86 (t, J ) 5 Hz, 2 H), 2.76 (d, J ) 3 Hz, 2 H), 2.62 (m,
4 H), 2.63 (m, 2 H), 2.61 (m, 2 H), 2.44 (t, J ) 6 Hz, 2 H), 2.15 (tt,
1
(1:1, v/v)). H NMR (300 MHz, CDCl3): δ 7.65 (d, J ) 8 Hz, 4 H),
7.58 (d, J ) 8 Hz, 2 H), 7.31 (d, J ) 8 Hz, 4 H), 7.28 (d, J ) 8 Hz,
2 H), 5.19 (s, 2 H), 3.84 (s, 4 H), 3.23 (t, J ) 7.2 Hz, 4 H), 3.10 (t, J
) 6.3 Hz, 4 H), 2.43 (s, 6 H), 2.41 (s, 3 H), 1.89 (p, J ) 6.8 Hz, 4 H).
13C NMR (75 MHz, CDCl3): δ 143.53, 143.49, 138.2, 135.5, 134.3,
129.7, 129.6, 127.1, 127.0, 117.5, 50.8, 46.6, 44.6, 27.2, 21.4. IR
(CDCl3): 3060, 3030, 2950, 2920, 2860, 1730, 1650, 1595, 1490, 1450,
1330, 1300, 1285, 1150, 1085, 1035, 1015 cm-1
.
3-Hydroxymethyl-1,5,9-tris(4-methylbenzenesulfonyl)-1,5,9-tri-
azacyclododecane (20). A solution of thexylborane (1.0 M, 100 mL,
0.1 mol) in THF was prepared by adding 8.4 g (0.1 mol) of
2,3-dimethyl-2-butene to 100 mL of cold 1.0 M BH3‚THF solution at
0 °C and stirring for an additional hour under nitrogen in an ice bath.
It was added to a solution of 32.3 g (0.05 mol) of 19 in 300 mL of
anhydrous THF at room temperature. The reaction mixture was stirred
at room temperature for 4 h and then heated under reflux for 1 h.
Ethanol (15 mL) was added cautiously to the cooled reaction mixture
J ) 3, 7 Hz, 1 H), 1.61 (p, J ) 5 Hz, 2 H), 1.38 (J ) 6 Hz, 2 H). 13
C
NMR (75 MHz, CDCl3): δ 57.5, 57.1, 52.0, 49.8, 49.0, 48.4, 32.8,
29.3, 25.2. IR (neat): 3600-3000, 2920, 2790, 1640, 1420-1500, 1350,
1290, 1200, 1135, 1040, 1010, 900 cm-1. MS m/z (rel intens): 184
(M + l, 1), 183 (M+, 2), 182 (M - 1, 3), 84 (100), 70 (85), 58 (58),
44 (66). Anal. Calcd for Cl0H2lN3: C, 65.53; H, 11.55; N, 22.92.
Found: C, 64.85; H, 11.72; N, 22.85.
9
J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003 12207

A R T I C L E S
Bell et al.
Bis(2-cyanoethyl)amine (26).23 A mixture of 53.1 g (1.3 mol) of
acrylonitrile and 100 g of 29% aqueous ammonium hydroxide was
stirred vigorously in an open Erlenmeyer flask at room temperature.
After 1 h a homogeneous solution was obtained. Stirring was continued
overnight. Solid NaCl was added, causing separation of two layers.
The product was extracted with chloroform, and the chloroform solution
was dried over MgSO4 and then concentrated in vacuo. Fractional
distillation of the residual oil gave 42.5 g (53%) of the product as a
colorless oil, bp 140-155 °C (0.5 mm). 1H NMR (300 MHz, CDCl3):
induce the formation of a precipitate, which was collected by vacuum
filtration and dried at room temperature (1 mm), yielding 9.65 g (54%)
of 29‚HCl as an off-white solid, mp 150-152 °C. A sample for
microanalysis was prepared by recrystallization from CH2Cl2/ethyl
1
acetate and dried at 78 °C (1 mm, 20 h), mp 160-161 °C. H NMR
(300 MHz, CDCl3): δ 11.06 (br s, 1H), 7.74 (d, J ) 8 Hz, 4H), 7.57
(m, 2 H), 7.39 (m, 3 H), 7.25 (d, J ) 8 Hz, 4 H), 6.78 (t, 2 H), 4.21
(d, 2 H), 3.20 (m, 4 H), 2.94 (m, 4 H), 2.38 (s, 6 H), 2.15 (m, 4H). 13
C
NMR (75 MHz, CDCl3): δ 143.4, 136.5, 131.3, 130.1, 129.7, 129.4,
128.3, 127.1, 57.3, 50.1, 40.2, 23.6, 21.5. IR (KBr): 3154 (br), 2928,
2873, 2620 (br), 1597, 1441, 1335, 1323, 1162, 1093, 813, 694, 659
cm-1. Anal. Calcd for C27H36N3S2O4Cl: C, 57.28; H, 6.41; N, 7.42; S,
11.32; Cl, 6.26. Found: C, 57.34; H, 6.43; N, 7.39; S, 11.33; Cl, 6.41.
δ 2.95 (t, J ) 7 Hz, 4 H), 2.50 (t, J ) 7 Hz, 4 H), 1.5 (br s, 1 H). 13
C
NMR (75 MHz, CDCl3): δ 118.4, 44.4, 18.8. IR (film): 3330 (s), 2920
(s), 2850 (s), 2240 (s), 1440 (s), 1415 (s), 1360 (m), 1130 (s), 750 (br,
m) cm-1
.
Bis(2-cyanoethyl)benzylamine (27). A mixture of 13 g (106 mmol)
of bis(cyanoethyl)amine (26), 12.7 g (0.1 mol) of benzyl chloride, 9.25
g (0.11 mol) of NaHCO3, and 20 mL of water was heated under reflux
for 6 h. The reaction mixture was partitioned between chloroform and
saturated aqueous NaCl solution. The chloroform layer was dried over
MgSO4 and concentrated in vacuo. The crude product was fractionally
distilled, yielding 15.4 g (68%) of a colorless oil, bp 186-187 °C (0.5
9-Benzyl-3-methylene-1,5-bis(4-methylbenzenesulfonyl)-1,5,9-tri-
azacyclododecane (30). NaH (3.6 g, 0.15 mol) was added under N2 to
a solution of 26.5 g (0.05 mol) of 29 in 500 mL of anhydrous DMF.
The mixture was held at 80-100 °C for 1 h then transferred through
a glass fiber filter under N2 by means of a cannula to a 2-L three-
necked, round-bottomed flask equipped with a rubber septum and a
thermometer. An additional 500 mL of anhydrous DMF was used to
ensure complete transfer. A solution of 6.25 g (0.05 mol) of 3-chloro-
2-chloromethyl-1-propene (18) in 50 mL of anhydrous DMF was added
to the 100 °C solution over 9 h by means of a syringe pump. Heating
was continued for an additional 12 h. The solvent was removed
completely by rotary evaporation using a boiling water bath. A solution
of the residue in 150 mL of CHCl3 was washed with water (3 × 100
mL), dried over MgSO4, and concentrated by rotary evaporation. The
product was isolated and purified in the same way as that described
for 10, yielding 16 g (55%) of solid, mp 156-158 °C (ethyl acetate/
1
mm) (lit.22b 190 °C, 0.05 mm). H NMR (300 MHz, CDCl3): δ 7.8
(m, 5 H), 4.18 (s, 2 H), 3.35 (t, J ) 7 Hz, 4 H), 2.93 (t, J ) 7 Hz, 4
H). 13C NMR (75 MHz, CDCl3): δ 137.5, 128.3, 127.4, 118.4, 57.7,
49.1, 16.4. IR (film): 3070 (w), 3050 (m), 3020 (s), 2930 (s), 2830
(s), 2240 (s), 1595 (m), 1575 (w), 1485 (s), 1445 (s), 1415 (s), 1360
(br m), 1250 (br m), 1125 (s), 1070 (s), 1020 (s), 960 (s), 730 (s), 690
(s) cm-1
.
Bis(3-aminopropyl)benzylamine (28). A mixture of 14.5 g (68
mmol) of 27, 3 g of Raney nickel and 55 mL of 1.5 M aqueous NaOH
solution in 95% EtOH was placed in a glass Parr reaction bottle and
shaken under 40 psi of hydrogen. (Caution: explosion hazard; air must
be completely replaced by hydrogen in the Parr apparatus before
reaction is begun.) The catalytic hydrogenation was carried out for 40
h. The catalyst was removed by filtration, and the filtrate was
concentrated in vacuo. Fractional distillation of the residue gave 12.2
g (81%) of a colorless oil, bp 151-155 °C (0.5 mm) (lit.22b 110 °C,
1
hexane); Rf 0.58 (silica gel, ethyl acetate/hexane (1:1, v/v)). H NMR
(300 MHz, CDCl3): δ 7.86 (d, J ) 8 Hz, 4 H), 7.51 (d, J ) 8 Hz, 4
H), 7.4 (m, 5 H), 5.43 (s, 2 H), 4.04 (s, 4 H), 3.59 (s, 4 H), 3.32 (t, J
) 7 Hz, 4 H), 2.63 (s, 6 H), 2.56 (t, J ) 6 Hz, 4 H), 1.85 (m, 4 H). 13
C
NMR (75 MHz, CDCl3): δ 143.4, 139.3, 138.3, 135.5, 129.7, 128.7,
128.1, 127.2, 126.9, 116.2, 59.0, 51.0, 49.5, 44.0, 24.4, 21.5. IR
(CDCl3): 3020, 2940, 2920, 2850, 2800, 1600, 1490, 1450, 1330, 1150,
1080 cm-1. Anal. Calcd for C31H39N3S2O4: C, 64.00; H, 6.76; N, 7.22;
S, 11.02. Found: C, 63.91; H, 6.65; N, 7.13; S, 11.04.
1
0.05 mm). H NMR (300 MHz, CDCl3): δ 7.67 (m, 5 H), 3.89 (s, 2
H), 3.06 (t, J ) 7 Hz, 4 H), 2.82 (t, J ) 7 Hz, 4 H), 1.97 (p, J ) 7 Hz,
4 H), 1.35 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ 139.5, 128.3,
127.7, 126.3, 58.3, 50.9, 40.0, 30.6. IR (film): 3360 (br, m), 3270 (br,
m), 3070 (w), 3050 (w), 3020 (m), 2920 (br, s), 2850 (s), 2800 (s),
1600 (s), 1485 (s), 1450 (s), 1360 (m), 1110 (br, m), 1070 (m), 1020
3-Methylene-1,5-bis(4-methylbenzenesulfonyl)-1,5,9-triazacy-
clododecane (31) and 31-HCl. A solution of 11.6 g (20 mmol) of
thoroughly dried 30 in 100 mL of anhydrous 1,2-dichloroethane
(distilled from P2O5 under N2) was cooled by means of an ice bath,
and then 2.86 g (20 mmol) of R-chloroethyl chloroformate (ACE-Cl)
was added. Stirring was continued at 0 °C for 15 min; the reaction
mixture was then heated under reflux for 50 min. The solvent was
removed in vacuo, and 100 mL of methanol was added to the residue.
The resulting solution was heated under reflux for 30 min. Methanol
was again removed in vacuo, the residue was dissolved in 100 mL of
chloroform, and the chloroform solution was washed with 1 M aqueous
NaOH solution. The chloroform solution was filtered through silica
gel, washing with CH2Cl2 to elute the byproduct, benzyl chloride. The
silica gel was washed with methanol, and this methanol eluate was
concentrated in vacuo to yield 7.7 g (78%) of product 31, mp 143-
145 °C; Rf 0.21 (silica gel, ethyl acetate). 1H NMR (300 MHz,
CDCl3): δ 7.67 (d, J ) 8 Hz, 4 H), 7.32 (d, J ) 8 Hz, 4 H), 4.98 (s,
2 H), 3.80 (s, 4 H), 3.17 (t, J ) 6 Hz, 4 H), 2.60 (t, J ) 6 Hz, 4 H),
2.43 (s, 6 H), 1.65 (p, J ) 6 Hz, 4 H). 13C NMR (75 MHz, CDCl3):
δ 143.2, 135.1, 137.8, 129.5, 127.1, 114.9, 51.5, 44.0, 42.8, 27.7, 21.3.
IR (CDCl3): 3340, 3060, 3030, 2980, 2950, 2920, 2860, 2820, 1660,
1650, 1600, 1490, 1450, 1330, 1160, 1090, 1040, 940, 915, 815, 730,
685, 655 cm-1. The HCl salt was formed by stirring a mixture of 1.75
g of the product, 50 mL of CH2Cl2, 6 mL of 2 N aqueous HCl, and 25
mL of saturated aqueous NaCl solution for 15 min. The organic layer
was separated and washed with saturated aqueous NaCl solution (3 ×
25 mL) and then concentrated in vacuo. The residue was dissolved in
a minimum volume of warm methanol, then 20 mL of ethyl acetate/
(m), 730 (m), 690 (m) cm-1
.
N,N′-Bis(4-methylbenzenesulfonyl)bis(3-aminopropyl)benzy-
lamine (29) and 29-HCl. A solution of 20 g (0.11 mol) of tosyl chloride
in 50 mL of CH2Cl2 was added dropwise with vigorous stirring over 2
h to a solution of 11.1 g (0.05 mol) of 28 and 4.4 g (0.11 mol) of
NaOH in 30 mL of water. The reaction mixture was stirred for 1 h,
and the organic layer was separated, washed with an equal volume of
saturated aqueous NaCl solution, dried over MgSO4, and concentrated
in vacuo. Attempts to crystallize the crude oily product were not
successful. TLC analysis showed only one spot. All remaining solvent
was removed under vacuum, yielding 25 g (95%) of the product, which
was used without further purification (silica gel, ethyl acetate/hexane
1
(1:1, v/v)). H NMR (300 MHz, CDCl3): δ 7.70 (d, J ) 8 Hz, 4 H),
7.28 (d, J ) 8 Hz, 4 H), 7.20 (m, 5 H), 5.80 (br s, 2 H), 3.43 (s, 2 H),
2.92 (t, J ) 6 Hz, 4 H), 2.42 (s, 6 H), 1.64 (p, J ) 6 Hz, 4 H), 1.27
(m, 2 H), 0.89 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ 143.1, 136.9,
129.6, 129.0, 128.4, 127.3, 127.0, 58.6, 51.8, 42.2, 25.9, 21.4. IR
(film): 3280, 3050, 3020, 2940, 2850, 2810, 1595, 1490, 1450, 1320,
1150, 1085, 810, 730, 690, 660 cm-1. The HCl salt was prepared by
washing a solution of 16.9 g of the product in 150 mL of CH2Cl2 with
a mixture of 50 mL of 2 N aqueous HCl and 100 mL of saturated
aqueous NaCl solution. The organic layer was separated and washed
with saturated aqueous NaCl solution (3 × 100 mL), then concentrated
to minimum volume by boiling. Ethyl acetate (50 mL) was added to
9
12208 J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003

Syntheses and Conformations of Bicyclic Triamines
A R T I C L E S
hexane (1:1, v/v) was added slowly to induce precipitation. After the
mixture stood at 0 °C overnight, the white solid (31‚HCl) was collected
by vacuum filtration, washed with hexane, and dried at 78 °C (1 mm,
16 h), yielding 1.44 g, mp 185-186 °C. 1H NMR (300 MHz, DMSO-
d6): δ 9.29 (s, 2 H), 7.69 (d, J ) 8 Hz, 4 H), 7.45 (d, J ) 8 Hz, 4 H),
5.31 (s, 2 H), 3.70 (s, 4 H), 3.15 (m, 4 H), 2.96 (m, 4 H), 2.40 (s, 6 H),
1.82 (m, 4 H). 13C NMR (75 MHz, DMSO-d6): δ 143.7, 140.7, 134.6,
130.0, 127.2, 118.0, 51.5, 47.0, 22.1, 21.0. IR (KBr): 3341 (br, m),
2957, 2767, 2654 (br, m), 1598, 1449, 1341, 1158, 1089, 995, 887,
816, 727, 689, 657 cm-1. Anal. Calcd for C24H34N8S2O4Cl: C, 54.58;
H, 6.49; N, 7.96; S, 12.14; Cl, 6.71. Found: C, 54.58; H, 6.44; N,
7.91; S, 12.13; Cl, 6.58.
5,9-Bis(4-methylbenzenesulfonyl)-13-oxa-1,5,9-triazatricyclo-
[5.5.11,7.17,12]tetradecane (36). A mixture of 0.39 g (0.8 mmol) of 31,
0.17 g (1 mmol) of m-chloroperoxybenzoic acid, 0.14 g (0.9 mmol) of
K2CO3, and 5 mL of CH2Cl2 was stirred for 65 h at room temperature.
The reaction mixture was basified by addition of 3 M aqueous NaOH
solution and then extracted with chloroform. The chloroform layer was
dried over MgSO4 and concentrated in vacuo. The product (82 mg,
20%) was isolated by flash chromatography (ethyl acetate/hexane) and
recrystallized from acetonitrile, mp 234-235 °C. 1H NMR (300 MHz,
CDCl3): δ 7.59 (d, J ) 8 Hz, 2 H), 7.54 (d, J ) 8 Hz, 2 H), 7.25 (d,
J ) 8 Hz, 2 H), 7.21 (d, J ) 8 Hz, 2 H), 3.76 (d, J ) 13 Hz, 1 H),
3.62 (m, 1 H), 3.50 (d, J ) 13 Hz, 1 H), 3.4 (m, 1 H), 3.18 (m, 1 H),
2.92 (m, 2 H), 2.85 (m, 2 H), 2.50 (d, J ) 13 Hz, 1 H), 2.44 (d, J )
13 Hz, 1 H), 2.37 (s, 3 H), 2.34 (s, 3 H), 1.85 (m, 1 H), 1.75 (m, 3 H).
13C NMR (75 MHz, CDCl3): δ 143.5, 143.3, 136.5, 135.9, 129.8, 129.7,
126.8, 87.6, 63.9, 53.6, 53.1, 52.5, 50.3, 44.7, 34.6, 34.4, 25.6, 21.5.
IR (CDCl3): 3040 (w), 3020 (w), 2920 (s), 2860 (m), 1600 (m), 1490
(m), 1470 (m), 1450 (s), 1440 (s), 1330 (s), 1160 (s), 1090 (s), 980
(m), 950 (m), 930 (m), 920 (m), 900 (m), 810 (m), 750 (m), 730 (s),
660 (s) cm-1; MS m/z (rel intens): 505 (M+, 2.6), 506 (0.7), 507 (0.3),
350 (30). Anal. Calcd for C24H31N3O5S2: C, 57.01; H, 6.18; N, 8.31;
S, 12.68. Found: C, 56.64; H, 6.16; N, 8.26; S, 12.01.
9-Benzyl-3-hydroxymethyl-1,5-bis(4-methylbenzenesulfonyl)-1,5,9-
triazacyclododecane (32). A solution of thexylborane in THF (1.0 M,
75 mL, 0.075 mol), prepared by adding 6.32 g (75 mmol) of
2,3-dimethyl-2-butene to 75 mL of 1.0 M BH3‚THF solution in an ice
bath and stirring for 1 h under N2, was added slowly to a solution of
14.6 g (25 mmol) of 30 in 200 mL of anhydrous THF at room
temperature. The reaction mixture was stirred at room temperature for
4 h and heated under reflux for 1 h. Ethanol (10 mL) was added
cautiously to the cooled reaction mixture to quench the excess borane;
25 mL of 3 M aqueous NaOH solution and 10 mL of 30% aqueous
H2O2 solution were then added, controlling the temperature in the range
of 30-35 °C by means of a water bath. The reaction mixture was stirred
for 3 h at room temperature. The solvent was removed completely by
rotary evaporation. A solution of the residue in 200 mL of CHCl3 was
washed with dilute aqueous NaOH solution (3 × 100 mL), dried over
MgSO4, filtered, and concentrated by rotary evaporation. The residue
was dried under vacuum. The crude product was used in the next step
without further purification. A sample of the product was purified by
flash chromatography and dried under vacuum to give a glassy solid;
Rf 0.38 (silica gel, ethyl acetate/hexane (1:1, v/v)). 1H NMR (300 MHz,
CDCl3): δ 7.66 (d, J ) 8 Hz, 4 H), 7.32 (d, J ) 8 Hz, 4 H), 7.2 (m,
5 H), 3.75 (m, 2 H), 3.48 (m, 4 H), 3.42 (s, 2 H), 3.3 (m, 4 H), 3.1 (m,
2 H), 2.5 (m, 2 H), 2.44 (s, 6 H), 2.2 (m, 1 H), 1.9 (m, 2 H), 1.5 (m,
2 H). 13C NMR (75 MHz, CDCl3): δ 143.4, 138.8, 135.5, 129.8, 128.9,
128.3, 127.2, 60.7, 58.3, 49.8, 47.3, 44.2, 36.0, 24.1, 21.5. IR
(CDCl3): 3530, 3050, 3020, 2950, 2920, 1595, 1490, 1450, 1330, 1150,
Aminomercuration of 31. A mixture of 60 mL of cold ethyl acetate,
1.48 g (3 mmol) of 31 and 1 g (3.6 mmol) of mercuric acetate was
stirred for 90 min at 10-20 °C, and then 0.34 g (9 mmol) of NaBH4
was added, followed by 50 mL of 2 M aqueous NaOH solution added
20 min later. Stirring was continued at room temperature for 12 h.
Metallic mercury was removed by decantation, the layers were
separated, and the aqueous layer was extracted with ethyl acetate. The
combined ethyl acetate solutions were washed with 2 M aqueous NaOH
solution and dried over MgSO4. Residual solvent was removed in vacuo,
and the product was purified by flash chromatography (ethyl acetate/
hexane). Three components were isolated, compound 38 (15%, Rf 0.46,
silica, ethyl acetate/hexane (1:1, v/v)), 37 (53%, Rf 0.6), and 31‚BH3
(8%, Rf 0.75), giving the following spectroscopic data. 5,9-Bis(4-
methylbenzenesulfonyl)-7-methyl-1,5,9-triazabicyclo[5.5.0]-
1
dodecane (38): H NMR (300 MHz, CDCl3): δ 7.68 (d, J ) 8 Hz, 4
H), 7.33 (d, J ) 8 Hz, 4 H), 3.36 (d, J ) 15 Hz, 2 H), 3.17 (d, J ) 15
Hz, 2 H), 3.05 (m, 4 H), 2.96 (m, 4 H), 2.43 (s, 6 H), 1.89 (m, 2 H),
1.68 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ 143.3, 134.9, 129.7,
127.2, 59.7, 58.8, 49.7, 49.3, 29.0, 22.8, 21.5. MS m/z (rel intens):
336 (72), 181 (100), 91 (39). IR (CDCl3): 3050 (w), 3020 (w), 2940
(m), 2910 (m), 2850 (m), 1595 (w), 1490 (m), 1450 (m), 1330 (s),
1150 (s), 1080 (s), 990 (m), 900 (m), 810 (m), 740 (m), 720 (m), 650
(m) cm-1. 5,9-Bis(4-methylbenzenesulfonyl)-7-hydroxymethyl-1,5,9-
1080, 720, 650 cm-1
.
9-Benzyl-3-chloromethyl-1,5-bis(4-methylbenzenesulfonyl)-1,5,9-
triazacyclododecane (33). The procedure was the same as that used
for synthesis of 21. The product could not be crystallized but was
obtained as a glassy solid, mp 59-70 °C; Rf 0.57 (silica gel, ethyl
1
acetate/hexane (1:1, v/v)). H NMR (300 MHz, CDCl3): δ 7.65 (d, J
) 8 Hz, 2 H), 7.32 (d, J ) 8 Hz, 2 H), 7.2 (m, 5 H), 3.58 (d, J ) 6
Hz, 2 H), 3.4 (m, 4 H), 3.36 (s, 2 H), 3.3 (m, 4 H), 2.9 (m, 4 H), 2.43
(s, 6 H), 2.2 (m, 1 H), 1.6 (m, 4 H). 13C NMR (75 MHz, CDCl3): δ
143.5, 138.8, 135.3, 129.8, 129.0, 128.3, 127.1, 58.6, 49.7, 48.0, 44.4,
44.2, 36.3, 23.0, 21.4. IR (CDCl3): 3050, 3020, 2950, 2920, 2860,
2800, 1595, 1490, 1445, 1330, 1150, 1105, 1080, 935, 900, 810, 720,
1
triazabicyclo[5.5.l]tridecane (37): H NMR (300 MHz, CDCl3): δ
7.67 (d, J ) 8 Hz, 4 H), 7.32 (d, J ) 8 Hz, 4 H), 3.61 (s, 2 H), 3.58
(d, J ) 15 Hz, 2 H), 3.29 (dd, J ) 8, 15 Hz, 2 H), 3.13 (dd, J ) 6, 15
Hz, 2 H), 3.04 (b, 4 H), 2.85 (dd, J ) 8, 15 Hz, 2 H), 2.43 (s, 6 H),
1.94 (m, 2 H), 1.80 (m, 1 H), 1.60 (m, 2 H). 13C NMR (75 MHz,
CDCl3): δ 143.7, 134.4, 129.8, 127.3, 65.3, 63.5, 55.2, 50.7, 50.1, 29.2,
21.5. MS m/z (rel intens): 476 (12), 352 (19), 334 (6), 321 (58), 197
(21), 166 (18), 91 (100). IR (CDCl3): 3520 (br. m), 3050 (w), 3020
(w), 2940 (s), 2850 (m), 1595 (m), 1490 (w), 1460 (m), 1330 (s), 970
650 cm-1
.
3-Chloromethyl-1,5-bis(4-methylbenzenesulfonyl)-1,5,9-triazacy-
clododecane (34). A mixture of 0.25 g (0.4 mmol) of 33, 0.25 g of
5% Pd/C and 100 mL of 2-propanol was stirred for 7 d under H2. The
catalyst was removed by filtration, and the filtrate was concentrated to
dryness by rotary evaporation. The residue was purified by flash
chromatography (silica gel, ethyl acetate/ethanol), yielding 80 mg (25%)
of a solid, mp 82-84 °C; Rf 0.48 (silica gel, ethyl acetate/methanol
(s), 910 (m), 810 (m), 750 (m), 730 (m), 680 (m), 660 (m) cm-1
.
3-Methylene-1,5-bis(4-methylbenzenesulfonyl)-1,5,9-triazacyclodode-
cane-BH3 complex (31‚BH3): mp 196-198 °C (toluene/CH2Cl2). 1H
NMR (300 MHz, CDCl3): δ 7.66 (d, J ) 8 Hz, 4 H), 7.36 (d, J ) 8
Hz, 4 H), 5.33 (s, 2 H), 3.80 (d, J ) 16 Hz, 2 H), 3.65 (d, J ) 16 Hz,
2 H), 3.08 (m, 6 H), 2.95 (m, 2 H), 2.45 (s, 6 H), 2.04 (m, 2 H), 1.94
(m, 2 H), 1.2-1.7(br, 3 H). 13C NMR (75 MHz, CDCl3): δ 144.3,
133.0, 129.9, 127.6, 141.2, 118.7, 53.1, 50.9, 48.3, 23.5, 21.5. MS m/z
(rel intens): 503 (0.4), 348 (10), 306 (7), 91 (100). IR (KBr): 3240
(s), 3070 (w), 3050 (w), 2960 (w), 2910 (m), 2860 (m), 2350 (s), 2300
(m), 2260 (w), 1600 (m), 1490 (m), 1450 (m), 1330 (s), 1150 (s), 1080
(s), 1010 (m), 910 (s), 810 (s), 720 (s), 680 (s), 650 (s) cm-1. Anal.
1
(9:1, v/v)). H NMR (300 MHz, CDCl3): δ 7.67 (d, J ) 8 Hz, 4 H),
7.33 (d, J ) 8 Hz, 4 H), 3.56 (d, J ) 5 Hz, 2 H), 3.27 (m, 4 H), 3.13
(m, 4 H), 2.67 (m, 2 H), 2.48 (m, 2 H), 2.44 (s, 6 H), 1.81 (m, 2 H),
1.43 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ 143.5, 135.1, 129.7,
127.3, 48.8, 45.1, 44.4, 44.2, 35.5, 26.6, 21.5. IR (CDCl3): 3330, 3050,
3020, 2940, 2905, 2860, 2810, 1605, 1490, 1450, 1330, 1150, 1080,
1020, 950, 900, 810, 720, 705, 650 cm-1. MS m/z (rel intens): 338
(2.9), 337 (6.8), 336 (30), 293 (30), 267 (30), 155 (30), 91 (100).
9
J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003 12209

A R T I C L E S
Bell et al.
Calcd for C24H36BN3O4S2: C, 57.02; H, 7.18; N, 8.31. Found: C, 57.16;
H, 7.31; N, 8.16.
although the methyl hydrogen atoms were refined as rigid groups. In
16‚HI, all non-hydrogen atoms were given anisotropic thermal param-
eters. In 12‚HI, only the iodine atoms were so refined. Both structures
were given a weighting scheme in the form w ) 1/[σ2(F) + 0.003F2].
In 16‚HI, the final R value was 0.073 (Rw ) 0.073). In 12‚HI, the
structure was refined with coordinates (x,y,z) and (-x,-y,-z) and the
set with the lowest R value was chosen (R 0.084, Rw 0.086). Calculations
for both structures were carried out using Shelx7636 and some of our
own programs on an Amdahl 5870 computer at the University of
Reading. In the final cycles of refinement, no shift/error ratio was greater
than 0.1σ. In the final difference Fourier maps, the maximum and
minimum peaks were 1.32, -1.23 e/Å3 in 16‚HI and 1.52, -0.75 e/Å3
in 12‚HI. The largest peaks were ca. 1.0 Å from the iodide ions.
Positional parameters, bond lengths and angles, hydrogen atom posi-
tions, and thermal parameters are given in the Supporting Information.
Computational Chemistry. Calculations were carried out on an
Amdahl 5870 computer at the University of Reading. For molecular
mechanics, we used the MM2 (1987) program37 which incorporates a
treatment of hydrogen bonds that has been described.38 All parameters
in the force field were taken from the program. Quantum mechanical
calculations were carried out with Gaussian98.39
7-Methyl-1,5,9-triazabicyclo[5.5.0]dodecane (39). A solution of
3.17 g (6.4 mmol) of 38 in 10 mL of 98% H2SO4 was heated at
100 °C for 54 h under N2. The resulting solution was cooled in an ice
bath, and 10 mL of absolute ethanol was added slowly from an addition
funnel, followed by 50 mL of anhydrous ether. The precipitate was
collected by filtration and dried under nitrogen. It was dissolved in the
minimum amount of water, and the pH of this solution was adjusted
to >13 by addition of 10 M aqueous NaOH solution. This solution
was extracted with chloroform (5 × 20 mL). The combined organic
layers were dried over MgSO4 and concentrated by rotary evaporation.
The residue was thoroughly dried under vacuum overnight. The
resulting yellow oil was distilled from powdered KOH to afford 0.56
1
g (46%) of the product as a colorless liquid, bp 100 °C (0.3 mm). H
NMR (300 MHz, CDCl3): δ 2.7-2.8 (m, 4 H), 2.64 (d, J ) 14 Hz, 2
H), 2.58-2.68 (m, 2 H), 2.45-2.54 (m, 2 H), 2.30 (d, J ) 14 Hz, 2
H), 1.59 (m, 2 H), 1.54 (m, 2 H), 1.29 (m, 2 H), 0.73 (s, 3 H). 13C
NMR (75 MHz, CDCl3): δ 61.1, 60.6, 50.3, 32.2, 22.3. IR (film):
2000-3700 (br, s), 2920 (br, m), 2840 (br, w), 1550 (br, m), 1460
(m), 1400 (m), 1300 (br, w), 1200 (w), 1170 (w), 805 (m) cm-1. MS
m/z (rel intens): 184 (M+1, 1), 183 (M+, 8), 168 (12), 140 (27), 125
(33), 97 (46), 84 (74), 70 (100), 43 (55). Anal. Calcd for C10H27N3: C,
65.53; H, 11.55; N, 22.92. Found: C, 65.51; H, 11.75; N, 22.87.
Dynamic NMR studies. All spectra were acquired with a Nicolet
1
300 MHz H NMR spectrometer (75.5 MHz for 13C). Temperatures
were stabilized within (1 °C before data acquisition. Curve fitting was
performed by the complete bandshape (CBS) method using the iterative
GENXCH program40 for two-site exchange simulation. The activation
free energy was calculated from exchange rates at various temperatures
by means of the Arrhenius equation, using a value of 4.575 cal/mol.41
Stack-plots of VT 1H NMR data for 16‚HI and 13C NMR data for 13‚
HI are included in the Supporting Information.
Measurement of pKa Values by Potentiometric Titration. Solu-
tions of the freshly distilled triamine in deionized, distilled water (0.1
M or 5.0 mM amine concentration) were titrated with 1.00 M aqueous
HCl solution under nitrogen at 25 ( 0.1 °C in a jacketed glass vessel.
Water from a constant-temperature bath was circulated through the glass
jacket, and the temperature of the titration solution was measured by
means of a thermocouple. A Corning model 150 pH/ion meter with a
semi-micro rugged bulb glass electrode was used to measure pH values.
The pH meter was calibrated at two points by means of Mallinckrodt
buffers (pH 4.01 and 10.00, 25 °C). Thermodynamic pKa values were
calculated from the titration curves, considering the activities of all
ions in the system.34 Data from the titrations of triamines 6, 12, 13,
15, 16, 23, and 39 and equations for pKa calculations are included in
the Supporting Information.
Acknowledgment. We thank the North Atlantic Treaty
Organization for a travel grant to Professors Thomas W. Bell
and Michael G. B. Drew. Also gratefully acknowledged is the
technical assistance of Dr. Andrej Sodoma with the purification
and characterization of compounds 29‚HCl, 30, and 31‚HCl.
Supporting Information Available: Tables of atomic coor-
dinates, bond lengths and angles, and anisotropic and isotropic
thermal parameters for 12‚HI and 16‚HI, stack-plots of VT NMR
data for 13‚HI (13C) and 16‚HI (1H), potentiometric titration
data for triamines 6, 12, 13, 15, 16, 23, and 39, and equations
for thermodynamic pKa calculations (PDF). X-ray crystal-
lographic file in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
Crystallography. HI salts of triamines 12 and 16 were crystallized
by gradually cooling solutions in a mixture of toluene and chloroform.
Crystal data for 12‚HI: N3C12H24I, M ) 339.1, F(000) ) 688,
orthorhomic, a ) 13.867(11) Å, b ) 13.898(13) Å, c ) 15.506(12) Å,
U ) 2988.4 Å3, dc ) 1.51 gcm-3, dm ) 1.49 gcm-3, Z ) 8, 1 ) 0.7107
Å, µ ) 21.5 cm-1, spacegroup Pbc21, (nonstandard setting of No. 29).
Crystal data for 16‚HI: N3C14H28I, M ) 375.1, F(000) ) 760,
monoclinic, a ) 8.145(9) Å, b ) 13.984(12) Å, c ) 15.698(14) Å, â
) 110.0(1)°, U ) 1680.2 Å3, dc ) 1.49 gcm-3, dm ) 1.43 gcm-3, Z )
4, 1 ) 0.7107 Å, µ ) 19.4 cm-1, spacegroup P21/c. Crystals of
approximate size 0.3 × 0.4 × 0.3 mm (12‚HI) and 0.3 mm × 0.3 mm
× 0.3 mm (16‚HI) were set up to rotate about a axes on a Stoe Stadi2
diffractometer, and data were collected via variable width ω scan.
Background counts were for 20 s, and a scan rate of 0.333°/s was
applied to a width of (1.5 + sin µ/tan θ). For 12‚HI, 2370 independent
reflections were measured of which 1329 with I > 2σ(I) were used in
subsequent refinement. For 16‚HI, 2869 independent reflections were
measured of which 1812 with I > 3σ(I) were used in subsequent
refinement. Empirical absorption corrections were applied to both
crystals.35 The structures were determined by the heavy atom method.
In both structures hydrogen atoms were included in calculated positions,
JA030236D
(36) Shelx76 Package for Crystal Stucture Determination, G. M. Sheldrick,
University of Cambridge, 1976.
(37) Allinger, N. L.; Yuh, Y. H., MM2 Q.C.P.E. Program No. 423, Quantum
Chemistry Program Exchange, Indiana University Chemistry Department,
Indiana, U.S.A., Modified Version of 1987.
(38) Allinger, N. L.; Kok, R. A.; Iman, M. R. J. Comput. Chem. 1988, 9, 591.
(39) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montogomery, J. A.; Stratman,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Latham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.;
Replogle E. S.; Pople, J. A. Gaussian98; Gaussian, Inc.: Pittsburgh, PA,
1998.
(34) Albert, A.; Serjeant, E. P. The Determination of Ionization Constants: A
Laboratory Manual; Chapman and Hall: London, 1984.
(35) Walker, N.; Stuart, D. Acta Crystallgr., Sect. A 1983, 39, 158.
(40) General Electric Company, Manual for NMC 300 NMR Spectrometer.
(41) Sandstro¨m, J. Dynamic NMR Spectroscopy; Academic Press: New York,
1982; pp 77-123.
9
12210 J. AM. CHEM. SOC. VOL. 125, NO. 40, 2003