Structural features of neutral and cationic cyclams

Article abstract of DOI:10.1016/j.molstruc.2015.05.037

Dicationic compounds of general formula [1,8-R₂-1,4,8,11-tetraazatricyclo[9.3.1.1^4,8]hexadecane]X₂, where R = H, Me or Bn' and X is a halogen counterion were obtained by reactions of 1,4,8,11-tetraazatricyclo[9.3.1.1^4,8]hexadecane with different electrophiles. The solid-state molecular structures of the compounds reveal that the hydrogen, methyl or benzyl groups are located on the nitrogen atoms that are not only the less sterically hindered but also have the electron lone pair pointing out of the macrocycle backbone. In all compounds it is observed a bond shortening between the N-C_aminal and the two other C-N bonds that may be attributed to an inductive effect. These compounds afford the corresponding trans-N,N'-disubstituted cyclams upon hydrolysis in basic medium.

Full text of DOI:10.1016/j.molstruc.2015.05.037

Journal of Molecular Structure 1098 (2015) 277e288
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Structural features of neutral and cationic cyclams
Luis G. Alves, M. Teresa Duarte, Ana M. Martins*
ꢀ
Centro de Química Estrutural, Instituto Superior Tecnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal
a r t i c l e i n f o
a b s t r a c t
Dicationic compounds of general formula [1,8-R2-1,4,8,11-tetraazatricyclo[9.3.1.14,8]hexadecane]X2,
where R ¼ H, Me or Bn' and X is a halogen counterion were obtained by reactions of 1,4,8,11-
tetraazatricyclo[9.3.1.14,8]hexadecane with different electrophiles. The solid-state molecular structures
of the compounds reveal that the hydrogen, methyl or benzyl groups are located on the nitrogen atoms
that are not only the less sterically hindered but also have the electron lone pair pointing out of the
macrocycle backbone. In all compounds it is observed a bond shortening between the N-Caminal and the
two other CeN bonds that may be attributed to an inductive effect. These compounds afford the cor-
responding trans-N,N'-disubstituted cyclams upon hydrolysis in basic medium.
Article history:
Received 18 March 2015
Received in revised form
27 May 2015
Accepted 29 May 2015
Available online 2 June 2015
Keywords:
Cyclam
Hydrogen bonds
Tetraaza rings
Macrocycles
© 2015 Elsevier B.V. All rights reserved.
Supramolecular structures
1. Introduction
[9.3.1.14,8]hexadecane, 1, by reaction of cyclam with formaldehyde
providing exclusively the trans-disubstituted isomer [6]. This
The growing interest in the design and synthesis of poly-
azamacrocycles during the past years is mainly associated to their
ability to form stable complexes with a plethora of metal ions [1]
and also with a variety of anions [2], if used in their protonated
forms. Several synthetic approaches to prepare sophisticated pol-
yazamacrocycles were recently developed with the focus on the
optimization and widening of their properties. For cyclam, in
particular, numerous methods for the synthesis of poly-N-func-
tionalized derivatives have been used [3]. Tetra- and mono-N-
functionalized cyclams are the most widely described as these
types of compounds may be obtained by straightforward pro-
cedures [4]. Even though, the syntheses of mono-N-functionalized
cyclams are non-efficient procedures concerning atomic economy
requiring a large excess of cyclam. The direct preparation of N,N'-
difunctionalized cyclam rings faces several problems mainly
because the reaction of cyclam with two equivalents of alkyl or aryl
halides yield mixtures of mono-, di-, tri- and even tetrasubstituted
macrocycles [3b,5]. Moreover, disubstituted cyclams display several
isomers depending on the relative positions of the pendant arms,
namely, two different cis-disubstituted and one trans-disubstituted
isomers. Guilard et al. developed a convenient three-step proce-
dure that relies on the formation of 1,4,8,11-tetraazatricyclo
methodology was used by us for the preparation of several trans-
H2(R2Cyclam) compounds whose molecular and supramolecular
structures are discussed here (Scheme 1).
In this work we also explore the solid-state molecular structure
of 1,4,8,11-tetraazatricyclo[9.3.1.14,8]hexadecane either in anhy-
drous and hydrated forms (1.4H2O and 1.6H2O). The role of the
stereochemical conformation on its protonation is addressed.
2. Experimental
2.1. General considerations
Cyclam [7], 3,5-di-tert-butylbenzyl bromide [8], 1,4,8,11-
tetraazatricyclo[9.3.1.14,8]hexadecane,
1 [6], 1,8-benzyl-1,4,8,11-
tetraazacyclotetradecane, 12 [6], 1,8-(4-tert-butylbenzyl)-1,4,8,11-
tetraazacyclotetradecane, 14 [9], 1,8-(4-trifluoromethylbenzyl)-
1,4,8,11-tetraazacyclotetradecane, 16 [9], 1,8-(3,5-di-tert-butylben-
zyl)-1,4,8,11-tetraazacyclotetradecane, 17 [8], 1,8-(3,5-dimethylben
zyl)-1,4,8,11-tetraazacyclotetradecane, 18 [8], and 1,8-methyl-
1,4,8,11-tetraazacyclotetradecane, 20 [6], were prepared according
to general described procedures. All other reagents were com-
mercial grade and used without further purification. The NMR
spectra were recorded in a Bruker AVANCE II 300 or 400 MHz
spectrometers at 296 K. 1H and 13C NMR spectra were referenced
internally to residual solvent resonances and reported relative to
tetramethylsilane (0 ppm). 19F NMR was referenced to external
* Corresponding author.
E-mail address: ana.martins@tecnico.ulisboa.pt (A.M. Martins).
http://dx.doi.org/10.1016/j.molstruc.2015.05.037
0022-2860/© 2015 Elsevier B.V. All rights reserved.

278
L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
Scheme 1. Syntheses of cyclam derivatives.
CF3COOH (ꢀ76.55 ppm). 2D NMR experiments such as 1He13C{1H}
HSQC and 1He1H COSY were performed in order to make all the
assignments. FT-IR spectra were recorded on a Jasco FT/IR-4100
spectrometer at IST. Elemental analyses were obtained from Insti-
then separated by filtration, washed with a small quantity of CH3CN
and dried under reduced pressure. The compound was obtained as
a white powder in 96% yield (7.00 g, 10.3 mmol). Crystalline ma-
terial was obtained from slow evaporation of a H2O/(CH3)2CO so-
tuto Tecnologico e Nuclear or Laboratorio de Analises do IST.
lution. 1H NMR (D2O/(CD3)2CO, 300.1 MHz, 296 K):
d (ppm)
ꢀ
ꢀ
ꢀ
3
7.53e7.46 (overlapping, 8H total, PhCH2N), 5.61 (d, JHeH ¼ 10 Hz,
2
2H, NCH2N), 4.79 (d, JHeH ¼ 13 Hz, 2H, PhCH2N), 4.61e4.47
2.2. Synthesis and characterization of the compounds
(overlapping, 4H total, 2H, [C2]CH2N and 2H, PhCH2N), 3.66e3.61
(overlapping, 4H total, 2H, [C2]CH2N and 2H, NCH2N), 3.42 (m, 2H,
[C3]CH2N), 3.29e3.18 (overlapping, 4H total, 2ꢁ[C3]CH2N),
3.00e2.86 (overlapping, 4H total, 2ꢁ[C2]CH2N), 2.60e2.43 (over-
lapping, 4H total, 2H, [C3]CH2N and 2H, CH2CH2CH2), 1.84 (m, 2H,
CH2CH2CH2), 1.22 (s, 18H, C(CH3)2). 13C{1H} NMR (D2O/(CD3)2CO,
1,8-benzyl-4,11-diazoniatricyclo[9.3.1.14,8]hexadecane-1,8-
diium dibromide (3): The compound was prepared according to a
published procedure [6]. 1,4,8,11-tetraazatricyclo[9.3.1.14,8]hex-
adecane, 1, (5.00 g, 22.3 mmol) was dissolved in acetonitrile and
two equiv. of benzyl bromide (5.80 mL, 48.8 mmol) were rapidly
added. The solution was stirred at room temperature and the white
precipitate formed was then separated by filtration, washed with a
small quantity of CH3CN and dried under reduced pressure. The
compound was obtained as a white powder in 34% yield (4.32 g,
7.63 mmol). Crystalline material was obtained from slow evapo-
75.5 MHz, 296 K):
d (ppm) 154.4 (PhCH2N), 133.5 (PhCH2N), 126.6
(PhCH2N), 124.0 (PhCH2N), 82.4 (C(CH3)2), 77.3 (NCH2N), 63.0
(PhCH2N), 60.1 ([C3]CH2N), 51.8 ([C3]CH2N), 48.2 (2ꢁ[C2]CH2N),
34.9
(C(CH3)2,
20.1
(CH2CH2CH2).
Anal.
calcd
for
C34H54Br2N4.(H2O)4: C, 54.40; H, 8.32; N, 7.46. Found: C, 53.83; H,
H2O/(CH3)2CO solution. 1H NMR (D2O/(CD3)2CO,
(ppm) 7.54e7.45 (overlapping, 10H total,
8.66; N, 7.45.
ration of
300.1 MHz, 296 K):
a
1,8-(4-cyanobenzyl)-4,11-diazoniatricyclo[9.3.1.14,8]hex-
adecane-1,8-diium dibromide (6): Compound 1 (2.86 g, 12.7 mmol)
was dissolved in acetonitrile and two equiv. of 4-cyanobenzyl
bromide (5.00 g, 25.5 mmol) were rapidly added. The solution
was stirred at room temperature and the white precipitate formed
was then separated by filtration, washed with a small quantity of
CH3CN and dried under reduced pressure. The compound was ob-
tained as a white powder in 65% yield (5.09 g, 8.26 mmol). Anal.
calcd for C28H36Br2N6: C, 54.56; H, 5.89; N, 13.63. Found: C, 53.24;
d
PhCH2N), 5.56 (d, 2JHeH ¼ 9 Hz, 2H, NCH2N), 4.76 (d, 2JHeH ¼ 13 Hz,
2H, PhCH2N), 4.59e4.45 (overlapping, 4H total, 2H, [C2]CH2N and
2H, PhCH2N), 3.67e3.59 (overlapping, 4H total, 2H, [C2]CH2N and
2H, NCH2N), 3.40 (m, 2H, [C3]CH2N), 3.28e3.17 (overlapping, 4H
total, 2ꢁ[C3]CH2N), 2.98e2.84 (overlapping, 4H total, 2ꢁ[C2]
CH2N), 2.57e2.44 (overlapping, 4H total, 2H, [C3]CH2N and 2H,
CH2CH2CH2), 1.82 (m, 2H, CH2CH2CH2). 13C{1H} NMR (D2O/
(CD3)2CO, 75.5 MHz, 296 K):
d (ppm) 133.5 (PhCH2N), 131.2 (p-
H, 5.88; N, 13.48. FT-IR (KBr, cmꢀ1): 2230 (
1,8-(4-trifluoromethylbenzyl)-4,11-diazoniatricyclo[9.3.1.14,8
hexadecane-1,8-diium dibromide (7): Compound (2.57 g,
nC]N).
PhCH2N), 129.8 (PhCH2N), 126.6 (i-PhCH2N), 77.2 (NCH2N), 63.3
(PhCH2N), 60.0 ([C3]CH2N), 51.8 ([C3]CH2N), 48.1 (2ꢁ[C2]CH2N),
20.0 (CH2CH2CH2). Anal. calcd for C26H38Br2N4: C, 55.13; H, 6.76; N,
9.89. Found: C, 54.61; H, 6.72; N, 9.98.
]
1
11.5 mmol) was dissolved in acetonitrile and two equiv. of 4-(tri-
fluoromethyl)benzyl bromide (5.77 g, 24.1 mmol) were rapidly
added. The solution was stirred at room temperature and the white
precipitate formed was then separated by filtration, washed with a
small quantity of CH3CN and dried under reduced pressure. The
compound was obtained as a white powder in 35% yield (2.80 g,
3.99 mmol). Crystalline material was obtained from slow evapo-
ration of a H2O/(CH3)2CO solution. 19F NMR (D2O/(CD3)2CO),
1,8-perfluorobenzyl-4,11-diazoniatricyclo[9.3.1.14,8]hex-
adecane-1,8-diium dibromide (4): Compound 1 (2.15 g, 9.58 mmol)
was dissolved in acetonitrile and two equiv. of perfluorobenzyl
bromide (5.00 g, 19.2 mmol) were rapidly added. The solution was
stirred at room temperature and the white precipitate formed was
then separated by filtration, washed with a small quantity of CH3CN
and dried under reduce pressure. The compound was obtained as a
white powder in 14% yield (2.09 g, 2.80 mmol). Anal. calcd for
282.4 MHz, 296 K):
28H36Br2F6N4: C, 47.88; H, 5.17; N, 7.98. Found: C, 47.60; H, 5.18; N,
7.99.
1,8-(3,5-di-tert-butylbenzyl)-4,11-diazoniatricyclo[9.3.1.14,8
hexadecane-1,8-diium dibromide (8): Compound (2.35 g,
d
(ppm) ꢀ62.7 (s, CF3). Anal. calcd for
C
C
26H28Br2F10N4.(H2O)2: C, 41.84; H, 3.78; N, 7.51. Found: C, 39.78; H,
3.68; N, 7.62.
1,8-(4-tert-butylbenzyl)-4,11-diazoniatricyclo[9.3.1.14,8]hex-
adecane-1,8-diium dibromide (5): Compound 1 (2.40 g, 10.7 mmol)
was dissolved in acetonitrile and two equiv. of 4-tert-butylbenzyl
bromide (5.00 g, 22.0 mmol) were rapidly added. The solution was
stirred at room temperature and the white precipitate formed was
]
1
10.5 mmol) was dissolved in acetonitrile and two equiv. of 3,5-di-
tert-butylbenzyl bromide (6.54 g, 23.1 mmol) were rapidly added.
The solution was stirred at room temperature and the white

L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
279
4
precipitate formed was then separated by filtration, washed with a
small quantity of CH3CN and dried under reduced pressure. The
compound was obtained as a white powder in 58% yield (4.82 g,
6.09 mmol). Crystalline material was obtained from slow evapo-
282.4 MHz, 296 K):
d
(ppm) ꢀ139.7 (3JC-F ¼ 21 Hz, JC-F ¼ 6 Hz, o-
3
3
PhCH2N), ꢀ154.5 (t, JC-F ¼ 21 Hz, p-PhCH2N), ꢀ162.0 (td, JC-
¼ 21 Hz, JC-F ¼ 6 Hz, m-PhCH2N). 1H NMR (D2O/(CD3)2CO,
4
F
300.1 MHz, 296 K):
d (ppm) 4.03 (s, 4H, PhCH2N), 3.45 (m, 4H, [C2]
ration of
42H70Br2N4.(H2O): C, 62.37; H, 8.97; N, 6.93. Found: C, 62.81; H,
9.15; N, 7.03.
a
H2O/(CH3)2CO solution. Anal. calcd for
CH2N), 3.40 (m, 4H, [C3]CH2N), 2.84 (m, 4H, [C2]CH2N), 2.76 (m, 4H,
C
[C3]CH2N), 2.11 (m, 4H, CH2CH2CH2). 13C{1H} NMR (D2O/(CD3)2CO,
75.5 MHz, 296 K):
d (ppm) 52.4 ([C3]CH2N), 49.9 ([C2]CH2N), 48.0
1,8-(3,5-dimethylbenzyl)-4,11-diazoniatricyclo[9.3.1.14,8]hex-
adecane-1,8-diium dibromide (9): Compound 1 (5.00 g, 22.3 mmol)
was dissolved in acetonitrile and two equiv. of 3,5-dimethylbenzyl
bromide (9.32 g, 46.8 mmol) were rapidly added. The solution was
stirred at room temperature and the white precipitate formed was
then separated by filtration, washed with a small quantity of CH3CN
and dried under reduced pressure. The compound was obtained as
a white powder in 33% yield (4.59 g, 7.37 mmol). Anal. calcd for
([C3]CH2N), 45.8 ([C2]CH2N), 43.6 (PhCH2N), 23.9 (CH2CH2CH2).
The clear identification of the carbon resonances for the penta-
fluorophenyl groups was not possible due to their weak intensities.
19F NMR (D2O/(CD3)2CO, 282.4 MHz, 296 K):
d
(ppm) ꢀ138.0 (m, 3JC-
3
¼ 18 Hz, o-PhCH2N), ꢀ151.4 (t, JC-F ¼ 21 Hz, p-PhCH2N), ꢀ159.3
F
4
(td,3JC-F ¼ 18 Hz, JC-F ¼ 4 Hz, m-PhCH2N). Anal. calcd for
C
24H26F10N4: C, 51.43; H, 4.68; N, 10.00. Found: C, 51.39; H, 4.88; N,
9.90.FT-IR (KBr, cmꢀ1): 3316 (nN-H).
C
30H46Br2N4.(H2O): C, 56.25; H, 7.55; N, 8.75. Found: C, 55.77; H,
1,8-(4-cyanobenzyl)-1,4,8,11-tetraazacyclotetradecane
(15):
7.46; N, 9.23.
Compound 6 (4.00 g, 6.48 mmol) was hydrolyzed in an aqueous
NaOH solution (3 M) and the product was extracted with small
portions of CHCl3. The organic phases were collected and dried
with MgSO4 anhydrous. The compound was obtained as an off-
white solid after solvent evaporation and successive freeze-
trituration-pump-thaw cycles in 78% yield (2.98 g, 5.05 mmol).
Crystalline material was obtained from slow evaporation of a CHCl3
1,8-(3,5-dinitrobenzyl)-4,11-diazoniatricyclo[9.3.1.14,8]hex-
adecane-1,8-diium dichloride (10): Compound 1 (2.59 g,11.5 mmol)
was dissolved in acetonitrile and two equiv. of 3,5-dinitrobenzyl
chloride (5.00 g, 23.1 mmol) were rapidly added. The solution
was stirred at room temperature and the brown precipitate formed
was then separated by filtration, washed with a small quantity of
CH3CN and dried under reduced pressure. The compound was ob-
tained as a brownish powder in 20% yield (1.49 g, 2.27 mmol). Anal.
calcd for C26H34Cl2N8O8: C, 47.49; H, 5.21; N, 17.04. Found: C, 47.38;
H, 5.28; N, 16.97. FT-IR (KBr, cmꢀ1): 1558, 1533 and 1365, 1346
solution. 1H NMR (CDCl3, 400.1 MHz, 296 K):
d (ppm) 7.56 (d,
3JHeH ¼ 8 Hz, 4H, PhCH2N), 7.40 (d, 3JHeH ¼ 8 Hz, 4H, PhCH2N), 3.70
(s, 4H, PhCH2N), 2.70e2.69 (overlapping, 8H total, 4H, [C3]CH2N
and 4H, [C2]CH2N), 2.55e2.51 (overlapping, 10H total, 4H, [C3]
CH2N, 4H, [C2]CH2N and 2H, NH), 1.80 (m, 4H, CH2CH2CH2). 13C{1H}
(nNO2).
1,8-dimethyl-4,11-diazoniatricyclo[9.3.1.14,8]hexadecane-1,8-
NMR (CDCl3, 100.6 MHz, 296 K):
d (ppm) 143.6 (CN), 132.1 (o-
diium diiodide (11): The compound was prepared according to a
published procedure [6]. Compound 1 (3.50 g, 15.6 mmol) was
dissolved in acetonitrile and two equiv. of methyl iodide (2.14 mL,
34.3 mmol) were rapidly added. The solution was stirred at room
temperature and the white precipitate formed was then filtered,
washed with a small quantity of CH3CN and dried under reduced
pressure. The compound was obtained as a white powder in 86%
yield (6.79 g, 13.4 mmol). Crystalline material was obtained from
PhCH2N or m-PhCH2N), 129.9 (o-PhCH2N or m-PhCH2N), 118.9 (i-
PhCH2N or p-PhCH2N), 111.0 (i-PhCH2N or p-PhCH2N), 57.7
(PhCH2N), 54.5 ([C3]CH2N or [C2]CH2N), 51.2 ([C3]CH2N or [C2]
CH2N), 49.6 ([C3]CH2N or [C2]CH2N), 47.6 ([C3]CH2N or [C2]CH2N),
26.0 (CH2CH2CH2). 1H NMR (D2O/(CD3)2CO, 300.1 MHz, 296 K):
d
(ppm) 7.92 (d, 3JHeH ¼ 8 Hz, 4H, PhCH2N), 7.66 (d, 3JHeH ¼ 8 Hz, 4H,
PhCH2N), 3.93 (s, 4H, PhCH2N), 3.51 (overlapping, 8H total, 4H, [C3]
CH2N and 4H, [C2]CH2N), 2.97 (m, 4H, [C2]CH2N), 2.82 (m, 4H, [C3]
CH2N), 2.17 (m, 4H, CH2CH2CH2). 13C{1H} NMR (D2O/(CD3)2CO,
slow evaporation of a H2O/(CH3)2CO solution. 1H NMR (D2O/
2
(CD3)2CO, 300.1 MHz, 296 K):
d
(ppm) 5.42 (d, JHeH ¼ 10 Hz, 2H,
75.5 MHz, 296 K): d (ppm) 141.2 (CN), 134.1 (o-PhCH2N or m-
NCH2N), 4.55 (m, 2H, [C3]CH2N), 3.68 (m, 2H, [C3]CH2N), 3.55 (m,
2JHeH ¼ 10 Hz, 2H, NCH2N), 3.49e3.40 (overlapping, 4H total, 2H,
[C3]CH2N and 2H, [C2]CH2N), 3.23e3.18 (overlapping, 8H total, 6H,
CH3 and 2H, [C2]CH2N), 3.04 (m, 2H, [C2]CH2N), 2.94 (m, 2H, [C2]
CH2N), 2.70e2.51 (overlapping, 4H total, 2H, [C3]CH2N and 2H,
CH2CH2CH2), 1.93 (m, 2H, CH2CH2CH2). 13C{1H} NMR (D2O/
PhCH2N), 132.6 (o-PhCH2N or m-PhCH2N), 120.4 (i-PhCH2N or p-
PhCH2N), 112.2 (i-PhCH2N or p-PhCH2N), 56.6 (PhCH2N), 52.5 ([C3]
CH2N), 50.9 ([C2]CH2N), 48.5 ([C3]CH2N or [C2]CH2N), 45.8 ([C3]
CH2N or [C2]CH2N), 23.6 (CH2CH2CH2). Anal. calcd for
C
26H34N6.(H2O): C, 69.61; H, 8.09; N, 18.73. Found: C, 69.57; H, 8.10;
N, 18.79. FT-IR (KBr, cmꢀ1): 3314 (nN-H) and 2222 (nC≡N).
(CD3)2CO, 75.5 MHz, 296 K):
d
(ppm) 78.0 (NCH2N), 65.0 ([C3]
1,8-(3,5-dinitrobenzyl)-1,4,8,11-tetraazacyclotetradecane (19):
Compound 10 (1.35 g, 2.05 mmol) was hydrolyzed in an aqueous
NaOH solution (3 M) and the product was extracted with small
portions of CHCl3. The organic phases were collected and dried
with MgSO4 anhydrous. The compound was obtained as a red solid
after solvent evaporation and successive freeze-trituration-pump-
thaw cycles in 63% yield (0.72 g, 1.29 mmol). 1H NMR (CDCl3,
CH2N), 52.0 ([C3]CH2N and [C2]CH2N), 49.2 (CH3), 48.4 ([C2]CH2N),
21.0 (CH2CH2CH2). Anal. calcd for C14H30I2N4(H2O): C, 31.95; H, 6.13;
N, 10.65. Found: C, 31.59; H, 6.07; N, 10.40.
1,8-perfluorobenzyl-1,4,8,11-tetraazacyclotetradecane
(13):
Compound 5 (1.40 g, 1.86 mmol) was hydrolyzed in an aqueous
NaOH solution (3 M) and the product was extracted with small
portions of CHCl3. The organic phases were collected and dried
with MgSO4 anhydrous. The compound was obtained as an off-
white solid after solvent evaporation and successive freeze-
trituration-pump-thaw cycles in 82% yield (0.85 g, 1.52 mmol).
Crystalline material was obtained from slow evaporation of a CHCl3
400.1 MHz, 296 K):
d (ppm) 8.86 (s, 2H, p-PhCH2N), 8.65 (s, 4H, o-
PhCH2N), 3.77 (s, 4H, PhCH2N), 2.83 (m, 4H, [C2]CH2N), 2.76 (m, 4H,
[C3]CH2N), 2.68e2.65 (overlapping, 8H total, 4H, [C3]CH2N and 4H,
[C2]CH2N), 1.88 (m, 4H, CH2CH2CH2). 13C{1H} NMR (CDCl3,
100.6 MHz, 296 K):
d (ppm) 148.6 (m-PhCH2N), 145.3 (i-PhCH2N),
solution. 1H NMR (CDCl3, 300.1 MHz, 296 K):
PhCH2N), 2.71 (m, 4H, [C3]CH2N), 2.66 (m, 4H, [C2]CH2N),
2.57e2.44 (overlapping, 10H total, 4H, [C3]CH2N, 4H, [C2]CH2N and
2H, NH), 1.83 (m, 4H, CH2CH2CH2). 13C{1H} NMR (CDCl3, 75.5 MHz,
d
(ppm) 3.82 (s, 4H,
128.5 (o-PhCH2N),117.5 (p-PhCH2N), 56.3 (PhCH2N), 54.5 ([C3]CH2N
or [C2]CH2N), 49.6 ([C3]CH2N), 47.9 ([C3]CH2N or [C2]CH2N), 47.4
([C2]CH2N), 26.1 (CH2CH2CH2). 1H NMR (D2O/(CD3)2CO, 300.1 MHz,
296 K): d (ppm) 8.94 (s, 2H, p-PhCH2N), 8.58 (s, 4H, o-PhCH2N), 4.03
296 K):
d
(ppm) 144.2 (m, PhCH2N), 141.6 (m, PhCH2N), 139.1 (m,
(s, 4H, PhCH2N), 3.43 (m, 4H, [C2]CH2N), 3.34 (m, 4H, [C3]CH2N),
2.95 (m, 4H, [C2]CH2N), 2.69 (m, 4H, [C3]CH2N), 2.03 (m, 4H,
CH2CH2CH2). 13C{1H} NMR (D2O/(CD3)2CO, 75.5 MHz, 296 K):
PhCH2N), 110.0 (t, JCeF ¼ 20 Hz, i-PhCH2N), 53.8 ([C3]CH2N or [C2]
CH2N), 52.0 ([C3]CH2N or [C2]CH2N), 50.1 ([C3]CH2N), 47.7 ([C2]
CH2N), 44.6 (PhCH2N), 26.3 (CH2CH2CH2). 19F NMR (CDCl3,
d
(ppm) 149.7 (m-PhCH2N), 142.0 (i-PhCH2N), 131.3 (o-PhCH2N),

280
L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
Table 1
Crystallographic data of compounds 1e3, 5, 7, 8, 11e13, 15 and 16.
Compound
1.4H2O
2
3
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions:
a (Å)
C12 H32 N4 O4
296.42
150
0.71073
Triclinic
P ꢀ1
C12 H26 Cl2 N4
297.27
150
0.71073
Monoclinic
C2/c
C26 H38 Br2 N4
566.40
150
0.71073
Triclinic
P ꢀ1
6.2557(9)
12.891(2)
8.2052(3)
b (Å)
6.668(1)
14.743(3)
11.1548(5)
c (Å)
10.212 (1)
95.164 (9)
105.49 (1)
98.213 (9)
9.682 (2)
90
98.60 (1)
90
17.1566 (7)
92.369 (2)
98.603 (2)
105.315 (3)
a
b
g
(ꢂ)
(ꢂ)
(ꢂ)
Volume (Å3)
402.6 (1)
1819.4 (5)
1492.1 (1)
Z
1
4
2
Calculated density (g mꢀ3
)
1.223
0.091
164
1.085
0.349
640
1.261
2.735
584
Absorption coefficient (mmꢀ1
F (000)
)
Crystal size (mm)
0.02 ꢁ 0.10 ꢁ 0.20
0.02 ꢁ 0.05 ꢁ 0.40
0.20 ꢁ 0.20 ꢁ 0.20
Theta range for data collection (ꢂ)
Limiting indices
3.43e25.68
2.11e27.54
2.94e25.68
ꢀ7ꢃh ꢃ 7, ꢀ8ꢃk ꢃ 8, ꢀ12 ꢃ l ꢃ 12
3796/1503 [0.0206]
ꢀ16 ꢃ h ꢃ 16, ꢀ18 ꢃ k ꢃ 19, ꢀ12 ꢃ l ꢃ 12
ꢀ10 ꢃ h ꢃ 8, ꢀ13 ꢃ k ꢃ 13, ꢀ20 ꢃ l ꢃ 20
Reflections collected/unique [Rint
Completeness to (%)
]
10236/2091 [0.1065]
17893/5602 [0.0311]
q
98.2 (
q
¼ 25.68)
99.8 (
q
¼ 27.54)
99.1 (
q
¼ 25.68)
Refinement method
Full-matrix least squares on F2
1503/0/103
Full-matrix least squares on F2
2091/0/86
Full-matrix least squares on F2
5602/0/307
Data/restraints/parameters
Goodness-of-fit on F2
1.062
0.976
1.080
Final R indices [I > 2
s
(I)]a
R1 ¼ 0.0389, wR2 ¼ 0.0995
R1 ¼ 0.0506, wR2 ¼ 0.1043
Multi-scan
0.257 and ꢀ0.163
R1 ¼ 0.0627, wR2 ¼ 0.1249
R1 ¼ 0.1097, wR2 ¼ 0.1389
Multi-scan
R1 ¼ 0.0842, wR2 ¼ 0.2597
R1 ¼ 0.1128, wR2 ¼ 0.2792
Multi-scan
1.914 and ꢀ0.557
R indices (all data)a
Absorption correction
Largest diff. peak/hole (e Åꢀ3
)
0.409e0.293
Compound
5
7
8
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions:
a (Å)
C34 H54 Br2 N4
678.61
150
0.71073
Triclinic
P ꢀ1
C28 H36 Br2 F6 N4
702.41
150
0.71073
Triclinic
P ꢀ1
C42 H70 Br2 N4
790.82
150
0.71073
Orthorhombic
Pbca
8.9852 (6)
20.611 (1)
20.752 (1)
78.485 (3)
89.970 (4)
79.869 (3)
3704.7 (4)
4
7.879 (1)
8.1794 (8)
12.572 (1)
77.808 (3)
87.573 (4)
74.562 (3)
763.3 (1)
1
8.950 (1)
11.512 (1)
40.085 (6)
90
90
90
4130.1 (9)
4
1.272
1.996
1680
b (Å)
c (Å)
a
b
g
(ꢂ)
(ꢂ)
(ꢂ)
Volume (Å3)
Z
Calculated density (g mꢀ3
)
1.217
2.214
1424
1.528
2.716
356
Absorption coefficient (mmꢀ1
F (000)
)
Crystal size (mm)
0.10 ꢁ 0.10 ꢁ 0.40
0.01 ꢁ 0.05 ꢁ 0.20
0.01 ꢁ 0.20 ꢁ 0.20
Theta range for data collection (ꢂ) 2.56e25.50
2.64e27.12
2.49e25.39
Limiting indices
Reflections collected/unique [Rint
ꢀ10 ꢃ h ꢃ 10, ꢀ24 ꢃ k ꢃ 24, ꢀ25 ꢃ l ꢃ 24 ꢀ9ꢃh ꢃ 10, ꢀ10 ꢃ k ꢃ 10, ꢀ15 ꢃ l ꢃ 16 ꢀ9ꢃh ꢃ 10, ꢀ10 ꢃ k ꢃ 13, ꢀ48 ꢃ l ꢃ 44
]
64402/13494 [0.0726] 9541/3293 [0.0460] 22314/3769 [0.0776]
Completeness to
Refinement method
q
(%)
98.0 (
q
¼ 25.50)
97.4 (
q
¼ 27.12)
99.2 (
q
¼ 25.39)
Full-matrix least squares on F2
13494/36/706
Full-matrix least squares on F2
3293/0/177
Full-matrix least squares on F2
3769/0/223
Data/restraints/parameters
Goodness-of-fit on F2
1.105
1.060
1.082
Final R indices [I > 2
s
(I)]a
R1 ¼ 0.0834, wR2 ¼ 0.2341
R1 ¼ 0.1380, wR2 ¼ 0.2545
Multi-scan
1.824 and ꢀ2.268
R1 ¼ 0.0514, wR2 ¼ 0.1331
R1 ¼ 0.0687, wR2 ¼ 0.1395
Multi-scan
1.748 and ꢀ2.351
R1 ¼ 0.0568, wR2 ¼ 0.1077
R1 ¼ 0.1000, wR2 ¼ 0.1159
Multi-scan
0.704 and ꢀ0.703
R indices (all data)a
Absorption correction
Largest diff. peak/hole (e Åꢀ3
)
Compound
11.2H2O
12
13
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions:
a (Å)
C14 H34 I2 N4 O2
544.25
150
0.71073
Monoclinic
P21/n
C24 H36 N4
380.57
150
0.71073
Monoclinic
C2/c
C24 H26 F10 N4
560.49
150
0.71073
Triclinic
P ꢀ1
7.6735 (2)
15.1331 (5)
8.9944 (3)
24.828 (3)
8.3866 (8)
21.039 (2)
7.3089 (6)
7.7185 (6)
11.997 (1)
b (Å)
c (Å)

L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
281
Table 1 (continued )
Compound
11.2H2O
12
13
a
b
g
(ꢂ)
(ꢂ)
(ꢂ)
90
90
79.295 (5)
81.375 (6)
62.341 (4)
587.42 (9)
1
1.584
0.151
288
106.142 (1)
90
1003.29 (5)
2
1.802
3.147
536
91.801 (4)
90
4378.6 (8)
8
1.155
0.069
1664
Volume (Å3)
Z
Calculated density (g mꢀ3
)
Absorption coefficient (mmꢀ1
F (000)
)
Crystal size (mm)
0.10 ꢁ 0.22 ꢁ 0.24
0.08 ꢁ 0.16 ꢁ 0.18
0.06 ꢁ 0.08 ꢁ 0.28
Theta range for data collection (ꢂ) 2.69e34.99
2.50e25.74
3.01e27.95
Limiting indices
Reflections collected/unique [Rint
ꢀ12 ꢃ h ꢃ 12, ꢀ24 ꢃ k ꢃ 24, ꢀ14 ꢃ l ꢃ 14 ꢀ30 ꢃ h ꢃ 30, ꢀ10 ꢃ k ꢃ 10, ꢀ25 ꢃ l ꢃ 17 ꢀ9ꢃh ꢃ 9, ꢀ10 ꢃ k ꢃ 10, ꢀ15 ꢃ l ꢃ 15
]
22531/4402 [0.0326] 18956/4165 [0.0802] 7023/2797 [0.0320]
Completeness to
Refinement method
q
(%)
99.5 (
q
¼ 34.99)
99.6 (
q
¼ 25.74)
99.0 (
q
¼ 27.95)
Full-matrix least squares on F2
4402/0/109
Full-matrix least squares on F2
4165/0/261
Full-matrix least squares on F2
2797/0/176
Data/restraints/parameters
Goodness-of-fit on F2
1.084
0.944
1.058
Final R indices [I > 2
R indices (all data)a
s
(I)]a
R1 ¼ 0.0191, wR2 ¼ 0.0440
R1 ¼ 0.0244, wR2 ¼ 0.0454
Multi-scan
0.539 and ꢀ0.602
R1 ¼ 0.0491, wR2 ¼ 0.0923
R1 ¼ 0.1051, wR2 ¼ 0.1056
Multi-scan
0.192 and ꢀ0.205
R1 ¼ 0.0462, wR2 ¼ 0.1065
R1 ¼ 0.0804, wR2 ¼ 0.1154
Multi-scan
0.269 and ꢀ0.287
Absorption correction
Largest diff. peak/hole (e Åꢀ3
)
Compound
15
16.NaBr
Empirical formula
Formula weight
Temperature (K)
Wavelength (Å)
Crystal system
Space group
Unit cell dimensions:
a (Å)
C26 H34 N6
430.59
150
0.71073
Triclinic
P ꢀ1
C26 H34 Br F6 N4 Na
619.46
150
0.71073
Triclinic
P ꢀ1
8.2348 (6)
12.2201 (8)
13.769 (1)
113.966 (3)
95.313 (2)
103.161 (2)
1205.9 (2)
2
7.805 (1)
9.289 (2)
20.268 (4)
93.073 (8)
95.166 (7)
98.258 (7)
1445.0 (4)
2
b (Å)
c (Å)
a
b
g
(ꢂ)
(ꢂ)
(ꢂ)
Volume (Å3)
Z
Calculated density (g mꢀ3
)
1.186
0.073
464
1.424
1.498
636
Absorption coefficient (mmꢀ1
F (000)
)
Crystal size (mm)
0.10 ꢁ 0.16 ꢁ 0.20
0.02 ꢁ 0.15 ꢁ 0.25
Theta range for data collection (ꢂ)
Limiting indices
1.65e25.43
2.02e25.78
ꢀ9ꢃh ꢃ 9, ꢀ14 ꢃ k ꢃ 14, ꢀ16 ꢃ l ꢃ 16
ꢀ9ꢃh ꢃ 9, ꢀ11 ꢃ k ꢃ 11, ꢀ24 ꢃ l ꢃ 24
10881/5393 [0.1155]
Reflections collected/unique [Rint
Completeness to (%)
]
9635/4346 [0.0386]
q
97.5 (
q
¼ 25.43)
96.9 (
q
¼ 25.78)
Refinement method
Full-matrix least squares on F2
4346/0/297
Full-matrix least squares on F2
5393/72/344
Data/restraints/parameters
Goodness-of-fit on F2
0.982
1.128
Final R indices [I > 2
R indices (all data)a
s
(I)]a
R1 ¼ 0.0522, wR2 ¼ 0.1389
R1 ¼ 0.1019, wR2 ¼ 0.1760
Multi-scan
0.208 and ꢀ0.204
R1 ¼ 0.1679, wR2 ¼ 0.3830
R1 ¼ 0.2076, wR2 ¼ 0.4074
Multi-scan
1.322 and ꢀ1.261
Absorption correction
Largest diff. peak/hole (e Åꢀ3
)
P
P
P
P
a
R1
¼
jjF0j ꢀ jFcjj= jF0j; wR2 ¼ f ½wðF20 ꢀ Fc2Þ2ꢄ= ½wðF02Þ2ꢄg1=2
.
119.6 (p-PhCH2N), 56.3 (PhCH2N), 51.7 ([C3]CH2N), 48.3 ([C2]CH2N),
46.4 ([C3]CH2N), 44.9 ([C2]CH2N), 24.6 (CH2CH2CH2). Anal. calcd for
applied using SADABS [11]. The structures were solved by direct
methods using SIR92 [12], SIR97 [13] or SIR2004 [14]. Structure
refinement was done using SHELXL-97 [15]. These programs are
part of the WinGX software package version 1.80.05 [16]. The
hydrogen atoms bonded to nitrogen were located in the difference
map and refined freely. The hydrogen atoms bonded to carbon were
included in fixed positions and allowed to refine riding on the
parent atom. Torsion angles, mean square planes and other
geometrical parameters were calculated using SHELX [15]. Illus-
trations of the molecular structures were made with Mercury 3.0
[17] or ORTEP-3 [18] for Windows.
C
24H32N8O8: C, 51.42; H, 5.75; N, 19.99. Found: C, 50.80; H, 5.99; N,
18.48. FT-IR (KBr, cmꢀ1): 3107 (nN-H), 1540 and 1343 (nNO2).
2.3. X-ray crystallography
Crystallographic and experimental details of data collection and
crystal structure determinations are available in Table 1. Suitable
crystals of compounds 1.4H2O, 2, 3, 5, 7, 8, 11, 12, 13, 15 and 16 were
coated and selected in Fomblin® oil. Data were collected using
Compounds 2, 3 and 5 crystallize with a disordered molecule of
solvent. As all attempts to model the disorder did not lead to
acceptable solutions, the Squeeze/PLATON [19] sequence was
applied. The poor diffracting power and quality of the crystals of
compounds 3, 5 and 16 led to high Rint values. Restraints were
graphite monochromated Mo-K
a
radiation (
l
¼ 0.71073 Å) on a
Bruker AXS-KAPPA APEX II diffractometer equipped with an Oxford
Cryosystem open-flow nitrogen cryostat. Cell parameters were
retrieved using Bruker SMART software and refined using Bruker
SAINT on all observed reflections [10]. Absorption corrections were

282
L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
Fig. 1. a) ORTEP diagram of 1,4,8,11-tetraazatricyclo[9.3.1.14,8]hexadecane, 1, showing thermal ellipsoids at 40% probability level. Co-crystallized water molecules are omitted for
clarity; b) Best view of 1 showing hydrogen bonds as blue dashed lines. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version
of this article.)
Table 2
Hydrogen bond distances (Å) and angles (ꢂ) in compounds 1.4H2O, 2, 7, 12, 13, 15 and 16.
^
D-H/A
d(D-H)
d(H/A)
d(D/A)
(DHA)
Symmetry operation
1.4H2O
O(1)-H(2O)/N(1)
O(2)-H(3O)/O(1)
O(2)-H(4O)/O(1)
N(1)-H(1N)/Cl(1)
C(4)-H(4B)/F(2)
O(1)-H(1O)/I(1)
O(1)-H(2O)/I(1)
C(3)-H(3B)/O(1)
C(6)-H(6A)/O(1)
C(6)-H(6B)/I(1)
C(7)-H(7B)/I(1)
N(2)-H(2N)/N(3)
N(4)-H(4N)/N(1)
C(1)-H(1A)/F(5)
C(4)-H(4A)/F(1)
C(1)-H(1B)/F(3)
C(2)-H(2A)/F(5)
C(5)-H(5B)/F(2)
C(22)-H(22)/N(2)
N(4)-H(4N)/N(2)
C(22)-H(22)/F(3)
C(2)-H(2N)/Br(1)
0.86 (2)
0.66 (3)
0.85 (3)
0.91 (3)
0.99
0.89 (2)
0.84 (2)
0.99
0.99
0.99
0.98
0.89 (2)
0.92 (2)
0.99
0.99
0.99
1.93(2)
2.17(3)
2.04(3)
2.16(3)
2.66
2.69(2)
2.82(3)
2.59
2.70
3.13
3.06
2.46 (2)
2.46(2)
2.47
2.35
2.63
2.776 (2)
2.818 (2)
2.876 (2)
3.064 (3)
3.379
3.561 (1)
3.657 (1)
3.233 (2)
3.503
169 (2)
166 (3)
169 (2)
174 (3)
129
167(1)
176(2)
123
138
141
161
133 (1)
135 (2)
115
141
157
e
e
ꢀx,ꢀy,ꢀz
2
7
11
e
1ꢀx,ꢀy,1ꢀz
3/2ꢀx, ½þy, ½ꢀz
2ꢀx,1ꢀy,1ꢀz
1ꢀx,1ꢀy,1ꢀz
2ꢀx,1ꢀy,1ꢀz
3.953
4.003
2ꢀx,1ꢀy,1ꢀz
1ꢀx,1ꢀy,1ꢀz
12
13
3.130 (2)
3.177 (2)
3.025 (3)
3.184 (3)
3.560 (3)
3.636 (3)
3.489 (3)
3.244 (3)
2.99 (1)
3.464
e
e
e
1ꢀx,1ꢀy,1ꢀz
2ꢀx,1ꢀy,2ꢀz
0.99
0.99
0.95
0.8 (1)
0.953
1.0 (1)
2.67
2.63
2.38
2.2 (1)
2.572
2.8 (1)
168
146
151
157 (12)
156
ꢀ1þx,y,z
2ꢀx,ꢀy,2ꢀz
15
16
e
e
e
e
3.673 (8)
150 (8)

L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
283
Fig. 2. a) ORTEP diagram of 1,8-diazonia-4,11-triazatricyclo[9.3.1.14,8]hexadecane dichloride, 2, showing thermal ellipsoids at 40% probability level. Hydrogen bonds are represented
as dashed lines. b) View, along the b-axis, of the supramolecular structure. Chloride anions are represented using the space filling model.
applied to compounds 5 and 16 in order to model the disorder
[C2] chains attached to nitrogen atom N(1) occupying an equatorial
and an axial position of each ring. The methylene cross-bridges
between the nitrogens of the latter rings point to opposite faces
of the macrocycle. The molecular parameters obtained for the
macrocycle frame of 1.4H2O are analogous to those reported for 1
(CSD refcode BOBHOP [20]) and 1.6H2O (CSD refcode PUHPOX [6])
and do not deserve further discussion.
The reactions of 1 with electrophiles lead to the selective for-
mation of trans-disubstituted compounds. Molecular Electrostatic
Potential calculations have shown that the deepest negative po-
tentials in the cyclam frame are located on one pair of trans ni-
trogen atoms (N(1) in Fig. 1a) that simultaneously display non-
bonding electron pairs pointing out of the macrocycle backbone
observed in the tBu and CF3 groups, respectively.
3. Results and discussion
1,4,8,11-tetraazatricyclo[9.3.1.14,8]hexadecane, 1, shown in
Fig. 1a, was prepared according to a published procedure [6] and
obtained as a tetrahydrate by slow evaporation of a concentrated
solution in a THF/H2O mixture. The molecular structure of 1 reveals
the presence of one ten-membered and two six-membered rings
with internal angles around the nitrogen atoms of approximately
109.5ꢂ in agreement with their sp3 hybridization. Each six-
membered ring adopts a distorted chair conformation with the
Table 3
Selected bond lengths (Å) and angles (ꢂ) for 2, 3, 5, 7 and 8.
2
3a
3b
5a
5b
5c
7
8
11
NþeCaminal
NþeC
1.505 (4)
1.502 (4)
1.495 (4)
1.445 (3)
1.462 (3)
1.474 (4)
1.540 (7)
1.492 (7)
1.536 (7)
1.416 (7)
1.462 (6)
1.475 (7)
1.522 (6)
1.515 (6)
1.504 (6)
1.441 (6)
1.456 (6)
1.471 (6)
1.499 (9)
1.501 (8)
1.514 (9)
1.440 (9)
1.453 (9)
1.456 (9)
1.519 (8)
1.521 (9)
1.504 (9)
1.448 (9)
1.474 (8)
1.430 (9)
1.526 (8)
1.513 (9)
1.522 (9)
1.445 (9)
1.478 (9)
1.450 (10)
1.523 (5)
1.528 (5)
1.522 (5)
1.440 (5)
1.472 (5)
1.472 (5)
1.511 (5)
1.513 (5)
1.527 (5)
1.438 (5)
1.468 (5)
1.466 (5)
1.515 (1)
1.520 (2)
1.518 (2)
1.439 (1)
1.461 (2)
1.473 (2)
NeCaminal
NeC

284
L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
Fig. 3. a) ORTEP diagram of 7 showing thermal ellipsoids at 40% probability level. Bromide counter-ions are omitted for clarity. b) View, along the a-axis, of the supramolecular
structure of 7. Intermolecular CeH/F bonds between molecules are shown as blue dashed lines. (For interpretation of the references to colour in this figure legend, the reader is
referred to the web version of this article.)
[6]. This circumstance is responsible for the establishment of
a hydrogen bond between the N(1) atom of the cyclam ring and the
H(2O) atom of one co-crystallized water molecule with a distance
of 1.93(2) Å (Fig. 1b). Detailed information about the hydrogen
bonds is given in Table 2. The four water molecules in 1.4H2O create
tetrameric clusters arranged in a coplanar square-like fashion with
internal angles of ca 91ꢂ and 108ꢂ. In the (H2O)4 cluster the O/O
distances are 2.818(2) and 2.876(2) Å. The supramolecular structure
consists of unidimensional infinite chains of 1 and (H2O)4 clusters
growing in the b direction linked to each other by Ncyclam/Hwater
hydrogen bonds (see Fig. SM1). This assembly differs from the one
displayed by the hexahydrated compound where the water mole-
cules define hexameric clusters that are intercalated between two
1,4,8,11-tetraazatricyclo[9.3.1.14,8]hexadecane units [6]. The
hydrogen bonds established between the nitrogen atom N(2) and
the water molecules are in 1.4H2O slightly longer (1.93(2) Å vs.
1.840 Å) than in the structure of the hexahydrated of 1 described in
the literature [6]. In the anhydrous form of 1, the supramolecular
arrangement is based on the establishment of hydrogen in-
teractions between the two most electronegative trans-nitrogen
atoms of the cyclam framework and the hydrogens belonging to the
macrocyclic [C2] chains of parent molecules [20].
structure is shown in Fig. 2a. Both protons in 2 are selectively
located on the two trans-nitrogen atoms that in 1 display the most
negative charges. The N(1)-H(1N) bond length of 0.91(3) Å is in
agreement with values reported, the hydrogens being located from
the electron density map [21,22]. Both nitrogen atoms show sp3
hybridization and (R,R) configuration. The distances N(1)-C(2),
N(1)-C(3) and N(1)-C(6) are similar and slightly longer than N(2)-
C(i) bonds reflecting, in a first instance, the positive charge on
N(1) (see Table 3). On the other hand, the distance between N(2)
and the aminal carbon C(6) is the shortest of all NeC bonds possibly
as a consequence of an anomeric effect involving the non-bonding
electron pair (lp) in N(1) [21]. This explains N(2) and N(1) aminal
carbon C(6) shortening/lengthening of the distances, respectively,
due to the overlap of the sp3 orbitals across lp-N(1)-C(6)-N(2). This
is maximised if the dihedral angle defined is close to antiperiplanar
(180ꢂ) or eclipsed (0ꢂ), as observed in the structure of the cation
[1H2]2þ in 2 that displays a torsion angle of 168ꢂ. Relevant bond
lengths and angles for 2 are presented in Table 3. Intermolecular
hydrogen bonds are established between the N(1)-H(1N) group of
the macrocycle and the Cl(1) anions with an interaction distance of
2.16(3) Å (see Table 2). These interactions are responsible for the
supramolecular arrangement of 2 that show 2D grid networks of
cyclam cations (2þ) and chloride anions (Clꢀ) as depicted in Fig. 2b.
Trans-N,N'-dibenzylcyclam, 3e10, and trans-N,N'-dimethylcy-
clam, 11, were obtained by reactions of 1 with two equivalents of
appropriate benzyl halides (bromide or chloride) or methyl iodide,
respectively, as shown in Scheme 1. These products are the result of
Compound 1 undergoes diprotonation in acidic media to give
1,8-diazonia-4,11-diazatricyclo[9.3.1.14,8]hexadecane salts as the
dichloride, [1H2]Cl2, 2, which was obtained as a white crystalline
material suitable for single crystal X-ray diffraction from a diluted
aqueous solution [21]. An ORTEP depiction of the molecular

L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
285
Fig. 4. a) ORTEP diagram of compound 11 showing thermal ellipsoids at 40% probability level. Co-crystallized water molecules and iodide anions are omitted for clarity. b) View,
along the a-axis, of the supramolecular structure of 11. Water molecules and iodide anions zigzag chain is depicted. Intermolecular OeH/I interactions are shown as blue dashed
lines. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
electrophilic attack of the benzyl halides or methyl iodide to the
most negative nitrogen atoms of 1. Compounds 3e11 are hygro-
scopic solids that can hydrolyze in air depending on the nature of
the substituent groups of the aromatic rings. Compounds having
electron withdrawing groups such as F, 4, CN, 6, CF3, 7 or NO2, 10,
slowly hydrolyse in the presence of moisture originating the cor-
responding trans-dibenzyl cyclams 13, 15, 16 and 19. These re-
actions are immediate for 4, 6 and 10 in acetone/water solutions;
compound 7 is relatively more resistant to hydrolysis and, although
pure NMR spectra could not be recorded (the sample showed
already some hydrolysis product, 16), crystals suitable for X-ray
structure determination grew from acetone/water solution. It was
also observed that compounds having more than one alkyl group in
the aromatic rings, as 8 (tBu) and 9 (Me), are fairly soluble in water
or mixtures of water with polar organic solvents as acetone or
dimethyl sulfoxide. The characterization of compounds 4 and 6e10
by NMR spectroscopy was therefore hampered by their solubility/
stability properties.
The 1H and 13C NMR spectra of compounds 3, 5 and 11 reveal
that all compounds display Ci symmetry in solution. The proton
NMR spectra reveal ten multiplets corresponding to the methylene
protons of the macrocycle backbone, integrating to two protons
each. Additionally, two AB systems corresponding to the bridging
methylene protons (2JH-H ¼ 9e10 Hz) and to the benzylic protons of
the pendant arms (2JH-H ¼ 12e13 Hz) are observed in 3 and 5. In 11
the pendant methyl groups appear in the region 3.23e3.18 ppm,
overlapping with proton resonances of the macrocyclic [C2] chain.
The carbon NMR spectra show seven resonances assigned to the

286
L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
Fig. 5. ORTEP diagrams of compounds 12 (a), 13 (b), 15 (c) and 16 (d) showing thermal ellipsoids at 40% probability level. In 16, the co-crystallized NaBr molecule was omitted for
clarity. The dashed lines represent hydrogen bonds.
methylene carbons and one set of resonances belonging to the
phenyl or methyl groups.
structures of 5. Interestingly, the bonds between the aminal car-
bons and the neutral nitrogens in 3a, 5a, 7, 8 and 11 are significantly
shorter than the two other CeN bonds to that nitrogen atom as
observed in 2 (see Table 2). However, in 3b, 5b and 5c this effect is
almost negligible, raising the question about the importance of
anomeric effect in this class of compounds. ORTEP representations
of the solid-state molecular structures of 7 and 11 are shown in
Figs. 3a and 4a, respectively (for 3, 5 and 8, see Fig. SM2).
Crystals of 3, 5, 7, 8 and 11 suitable for single crystal X-ray
diffraction were obtained from concentrated water/acetone mix-
tures. The asymmetric unit of 3 displays two molecules (3a and 3b)
and the asymmetric unit of 5 contains three different molecules
(5a-5c). The molecular structures of these compounds show the
pendant arms in mutually trans positions pointing to opposite sides
of the macrocycle, which cause the nitrogen atoms in 3, 7, 8 and 11
to adopt (R,R) or (S,S) configurations. Diverse nitrogen configura-
tions ((R,R), (S,S) and (R,S)) were observed for the molecular
At the supramolecular level the disordered bromine counter-
ions in 3 preclude any packing consideration. In compounds 5
and 8 there are no relevant intermolecular interactions but in 7 the
Fig. 6. Best view of the supramolecular structure of 15 revealing the intermolecular hydrogen bonds as blue dashed lines. (For interpretation of the references to colour in this figure
legend, the reader is referred to the web version of this article.)

L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
287
Fig. 7. View, along the b-axis, of 16 revealing the interaction between macrocycles and co-crystallized NaBr. Intermolecular bonds are shown as dashed lines: Na/Br interactions
(green), NeH/Br (blue), CeH/Br (cyan) and CeH/F (red). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this
article.)
X-ray crystal analysis reveals the presence of CeH/F halogen
bonds, C(4)-H(4B) and F(2) with a distance of 2.664 Å that promotes
the formation of unidimensional chains as shown in Fig. 3b. The
average distance of 1.316 (8) Å for the CeF bonds in 7 are within the
ranges usually observed [23].
In compound 11 the co-crystallized water molecules display
hydrogen bonds with the iodide anions that alternate in a zigzag
motif with distances of 2.69(2) and 2.82(3) Å. These interactions
create water/iodine parallel chains that intercalate cations 11þ as
shown in Fig. 4b and Fig. SM3. The interactions of the hydrogen
atoms belonging to the [C3] chains, methylene cross-bridges and
methyl groups of the cyclam framework with the oxygens and io-
dides determine the tridimensional arrangement (see details in
Table 2).
Basic hydrolysis of compounds 3e11 gave the correspondent
H2(R2Cyclam) products, 12e20, in variable yields (41e100%) (see
Scheme 1) [8,9]. These compounds are hygroscopic and, under air,
give rise to colorless oils which can be converted to white solids
after various freeze-thaw-pump cycles under nitrogen.
The comparison of the NMR spectra of salts 3e11 with those of
12e20 reveals that the molecular symmetry changed from Ci to C2v
upon hydrolysis. In compounds 12e20 the macrocycle geminal
protons are equivalent, giving rise to the emergence of only five
signals integrating to four protons each. The benzylic protons of the
cyclam pendant arms in 12e19 show up as singlets in accordance
with allowed nitrogen inversion.
at opposite sides of the macrocyclic ring. Despite the structural
arrangement of the cyclam ring, one can not consider intramolecular
hydrogen bonds between N(2)-H(2N) and N(1) as the corresponding
angles are narrower than 110ꢂ [25]. In 13, intramolecular hydrogen
bonds are established between hydrogen atoms of the macrocycle
ring and the fluorine atoms of the C6F5 moieties (dC(1)-H(1A)/
¼ 2.47 Å and dC(4)-H(4A)/F(1) ¼ 2.35 Å). At a supramolecular level,
F(5)
C(1)-H(1B)/F(3), C(2)-H(2A)/F(5) and C(5)-H(5B)/F(2) intermo-
lecular hydrogen bonds are established with distances of 2.63, 2.67
and 2.63 Å, respectively (see Table 2 and Fig. SM4).
In compound 15 the X-ray crystal analysis reveals C(22)-H(22)/
N(2) that the hydrogen bonding (dC(22)-H(22)/N(2) ¼ 2.38 Å) create
a unidimensional chain shown in Fig. 6. The average planes defined
by two consecutive cyclam rings of molecules 15a and 15b define
dihedral angles of 25.97ꢂ leading to a helicoidal motif.
In compound 16 the two benzyl pendant arms point to one side
of the macrocyclic ring as observed in 12. However, the structural
arrangement of the macrocycle framework in 16 results from the
establishment of one intramolecular hydrogen bond between N(4)-
H(4N) and N(2) that forms two 9-membered rings (see details in
Table 2). The nitrogen atom involved in the hydrogen bond displays
tetrahedral geometry but does not constitute a stereogenic center.
The structural differences between 16 and the molecules described
above might be due to the presence of co-crystallized NaBr in a 1:1
ratio. The supramolecular structure of 16 is constructed by units of
two organic molecules and two Naþ and Brꢀ ions that form a square
with NaeBr distances of 3.34(1) and 3.47(1) Å and internal angles of
108.9(3)ꢂ and 71.1(3)ꢂ (Fig. 7). This pair is linked to two cyclam
moieties by a hydrogen bridge between C(2)-H(2N) and Br(1) with
a distance of 2.8(1) Å. Each of these supramolecular structures are
linked to another by a hydrogen bridge between C(22)-H(22) and
F(3) with a bond length of 2.572 Å (see Table 2 and Fig. 7 for details).
Crystals of 12, 13, 15 and 16 suitable for single crystal X-ray
diffraction were obtained from chloroform solutions. ORTEP rep-
resentations of 12, 13, 15 and 16 solid-state molecular structures are
shown in Fig. 5.
In 12 the two benzyl pendant arms are located at the same side
of the macrocyclic ring. The structural arrangement of the macro-
cycle framework is determined by the establishment of intra-
molecular hydrogen bonds between N(2)-H(2N) and N(4)-H(4N),
and N(3) and N(1), respectively (see Table 2). These interactions
form two 6-membered heterocycles and impel both NBn atoms to
adopt a tetrahedral geometry with (R,R) configuration. Intra-
molecular NeH/N hydrogen bonds with comparable bond lengths
and angles are responsible for the stabilization of crystal structures
in other reported trans-disubstituted cyclams [24].
4. Concluding remarks
In 1,4,8,11-tetraazatricyclo[9.3.1.14,8]hexadecane, 1, the deepest
negative potential of the cyclam ring corresponds only to one pair
of trans nitrogen atoms due to the stereochemical conformation
imposed by the methylene cross-bridges. These two nitrogen atoms
are not only the less sterically hindered but they also have the
electron lone pair pointing out of the macrocycle backbone. In
In compounds 13 and 15 the two benzyl pendant arms are located

288
L.G. Alves et al. / Journal of Molecular Structure 1098 (2015) 277e288
(d) P. Mahato, A. Ghosh, S. Saha, S. Mishra, S.K. Mishra, A. Das, Inorg. Chem. 49
(2010) 11485e11492;
consequence, hydrogen bonds are established between those ni-
trogen atoms of the cyclam ring and the hydrogen atoms of co-
crystallized water molecules. The formation of such interactions
may ultimately end up in the protonation of the nitrogen atoms of
the cyclam ring in acidic media with formation of dicationic spe-
cies. Similarly, the formation of trans-N,N'-dibenzyl and trans-N,N'-
dimethyl cationic derivatives can be achieved by reaction of 1 with
two equivalents of the appropriate benzyl or methyl halides. These
reactions follow a similar route as the protonation reactions, where
the aryl or alkyl halides suffer a nucleophilic attack by the most
negative nitrogen atoms of 1. In these compounds, the bond be-
tween the aminal carbon and the neutral nitrogen is significantly
shorter than the two other CeN bonds to that nitrogen atom as
observed in the protonated species. This observation reveals that
cations of the type 1,8-R2-4,11-diazoniatricyclo[9.3.1.14,8]hex-
adecane-1,8-diium display a N-Caminal bond shortening effect if
R ¼ H, Me or Bn’. In some cases this effect is minimized by charge
delocalization. The comparison of the NMR spectra of salts with
those of neutral compounds reveals that the molecular symmetry
changed from Ci to C2v upon hydrolysis. The NMR spectra of all
compounds of the same family display the same pattern, revealing
that the solid-state molecular arrangements are not kept in solu-
tion. The supramolecular architectures created in the solid state
crystalline forms are determined by the establishment of inter-
molecular hydrogen bonds that are broken upon dissolution in
polar solvents.
In the cyclam families studied herein it can be said that the
supramolecular arrangement depends on the nature of the sub-
stituents of the aromatic ring of the macrocyclic pending groups
(tBu, CN, CF3, C6F5) but it is mainly dictated by their relative posi-
tioning in the ring. In general, para-substitued benzyl groups are
not significantly involved in intramolecular or intermolecular in-
teractions except when the substituents are fluorinated groups.
Thus, compounds 7 and 16, displaying CF3 groups, reveal supra-
molecular CeH/F interactions originating unidimensional chains
in the former and 2D sheets in the latter case. The overall packing's
obtained are the result of an energetic interplay between strongly
directed hydrogen bonds and a large number of CeH/F weaker
interactions.
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~
^
The authors are grateful to Fundaçao para a Ciencia e a Tecno-
logia, Portugal, for funding (UID/QUI/00100/2013, RECI/QEQ-QIN/
0189/2012, SFRH/BD/44295/2008, SFRH/BPD/86815/2012) and to
the Portuguese NMR Network (IST-UTL Centre).
Appendix A. Supplementary data
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Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.205.03715.0. Figures SM1e4 are pre-
sented as Supporting Information. CCDC 1054086-1054096 contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge via http://www.ccdc.cam.ac.uk/
conts/retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: þ44 1223
336033).
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