Competition between the donor and acceptor hydrogen bonds of the threads in the formation of [2]rotaxanes by clipping reaction

Article abstract of DOI:10.1039/c7nj02443f

The synthesis of benzylic amide [2]rotaxanes using 1,2-bis(aminocarbonyl-(1′-tert-butyl-1H-pyrazole-[3′]5′-yl))-ethanes as templates is reported. These templates are equipped with tert-butyl pyrazole-based stoppers and have donor (N-H) and acceptor (CO) hydrogen bond groups. The synthesis of [2]rotaxanes has been shown to be highly dependent on the tert-butylpyrazole stoppers. While the thread with 1′,3′-disubstituted pyrazoles as stopper units was shown to be an excellent template for the synthesis of [2]rotaxanes, the thread with 1′,5′-disubstituted pyrazoles as stopper units did not yield the expected [2]rotaxane. The structure of the synthesized [2]rotaxanes was characterized using NMR experiments and X-ray diffraction, with the latter showing that the macrocycle adopts a distorted chair conformation. An in-depth study of the isolated thread's X-ray structures and concentration-dependent NMR experiments seem to explain the dependence of the rotaxane formation on the substitution pattern of the thread's pyrazole stoppers.

Full text of DOI:10.1039/c7nj02443f

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N. Zanatta, New J. Chem., 2017, DOI: 10.1039/C7NJ02443F.
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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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Competition Between the Donor and Acceptor Hydrogen Bonds of the Threads in
the Formation of [2]Rotaxane by Clipping Reaction
a
a
a
a
Marcos A. P. Martins* , Geórgia C. Zimmer , Leticia V. Rodrigues , Tainára Orlando ,
a
b
b
a
a
Lilian Buriol , Mateo Alajarin , Jose Berna , Clarissa P. Frizzo , Helio G. Bonacorso
a
and Nilo Zanatta .
a
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química,
Universidade Federal de Santa Maria, 97105ꢀ900 Santa Maria, RS, Brazil.
b
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Eꢀ
30100 Murcia, Spain
*eꢀmail: mmartins@base.ufsm.br
Abstract: The synthesis of benzylic amide [2]rotaxanes using 1,2ꢀbis (aminocarbonylꢀ
1'ꢀtertꢀbutylꢀ1Hꢀpyrazolꢀ[3']5'ꢀyl))ꢀethanes as templates is reported. These templates
(
are equipped with tertꢀbutyl pyrazoleꢀbased stoppers and have donor (NꢀH) and
acceptor (C=O) hydrogen bond groups. The synthesis of [2]rotaxanes has been shown to
be highly dependent on the tertꢀbutylpyrazole stoppers. While the thread with 1',3'ꢀ
disubstituted pyrazoles as stopper units was shown to be an excellent template for the
synthesis of [2]rotaxanes, the thread with 1',5'ꢀdisubstituted pyrazoles as stopper units
did not yield the expected [2]rotaxane. The structure of the synthesized [2]rotaxanes
was characterized by NMR experiments and Xꢀray diffraction, with the latter showing
that the macrocycle adopts a distorted chair conformation. The depth study of the
isolated thread’s Xꢀray structures and concentrationꢀdependent NMR experiments
seems to explain the dependence of the rotaxane formation on the substitution pattern of
the thread’s pyrazole stoppers.
Introduction
Mechanically interlocked structures such as rotaxanes and catenanes are considered to
1
be privileged scaffolds for the construction of artificial molecular machines. Clearly,
rotaxanes — which are molecules composed of macrocycles trapped on a thread with
2
,3
two bulky groups — are the most numerous group. The assembly of the components
thread and macrocycle — is mainly driven by nonꢀcovalent interactions that are
—

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4
5
6
based on: solvophobic effects, π⋅⋅⋅π-stacking interactions, metal ion coordination
7
hydrogen bonding, and in recent years, halogenꢀbondꢀdonor motifs in anion receptor
8
design .
In particular, in Leighꢀtype rotaxanes, which are formed by a fiveꢀcomponent clipping
9
,10
reaction, the nature and directionality of the hydrogen bonding govern the formation
1
1
of these mechanically interlocked molecules. Generally, the templates used in this
12
synthetic protocol need to have good hydrogenꢀbonding acceptors, in addition to good
geometrical complementarity with their donor counterparts. Several factors are known
to affect both template efficacy and the nature of the hydrogenꢀbonding interactions; for
example: the hydrogenꢀbond basicity of the functional groups (amides are better than
1
3
ester), the preorganization of binding sites (the rigid fumaramide is better than
1
4
succinamide), distance between the binding sites (succinamide is better than
1
5
16,17
adipamide), and the bulkiness of the stopper.
In this work, the rotaxanes were formed by a tetralactam macrocycle and an effective
,4ꢀdiamide linker as thread, in which 1',3'ꢀ or 1',5'ꢀdisubstituted tertꢀbutyl pyrazoles
were used as stoppers. In general, diamide templates with twoꢀatom spacers are good
1
1
8
binding sites for the tetralactam macrocycles in clipping reactions; however, in this
18–20
work, we developed less common threads,
which have fourꢀatom spacers between
the interaction sites, or more specifically, a 1,4ꢀdiaminecarbonyl linker with acceptor
and donor hydrogenꢀbonding atoms. We subsequently evaluated: the efficiency of this
template in the formation of [2]rotaxanes by clipping reactions, and the influence of the
dimerization thread process on clipping reactions.
21
We have already demonstrated in previous works that heterocyclic compounds like 3ꢀ
aminoꢀ4ꢀhaloꢀ5ꢀmethylisoxazoles, which contain both donor and acceptor hydrogen
bond groups in their structures, can combine to form dimers in solution — an event that
1
can be monitored by following the H NMR chemical shift changes with the progressive
increase in the compound concentration. The dimerization occurs because parts of the
molecule are involved in intermolecular interactions, thus indicating which molecular
22
dimer is formed in solution. With this work, it is evident that the first dimers in the
selfꢀassembly can clearly be detected already in solution by NMR experiments,
especially if they are formed by hydrogen bonding.
2
3–27
It is worth noting that, despite examples of benzylic amide rotaxanes
being widely
reported, the competition between the hydrogen bonding selfꢀassembly of the thread

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and the association of macrocycle precursors with the thread during the formation of the
interlocked molecules is a phenomenon that has yet to be explored.
Based on these considerations, the aim of this investigation was to combine our
2
1,28
experience in molecular selfꢀ and heteroꢀassembly
,2ꢀbis (aminocarbonylꢀ(1'ꢀtertꢀbutylꢀ1Hꢀpyrazolꢀ[3']ꢀ5'ꢀyl)) ethane threads containing
substituted 1',3'ꢀ and 1',5'ꢀpyrazoles as stoppers, in rotaxaneꢀforming clipping reactions.
to investigate the suitability of
1
21
For this task, the supramolecular cluster approach and computational calculations
were used to estimate the energies of intermolecular interactions in the selfꢀassembly of
two types of threads. Additionally, NMR spectroscopy techniques gave valuable
information about the intermolecular interactions in the selfꢀassembly and heteroꢀ
assembly processes in solution.
Results and Discussion
Among the diverse templates used to direct the formation of benzylic amide
1
7,4
29,30
[
(
2]rotaxanes, succinamide,
fumaramide (highꢀtemplating capacity),
adipamide
1
5
31,32
lowꢀtemplating capacity), and related diamideꢀbinding motifs
have been reported.
These threads are extensively used, mainly because they are good hydrogen bond
acceptors, and also due to the good matching tendency of their carbonyl groups with the
hydrogen bond acceptors of the macrocycle. Efficient templates, such as fumaramide
and succinamide threads, have two carbon atoms as the spacer between the carbonyl
groups. On the other hand, the adipamide function has fourꢀcarbon atom spacers, which
reduce its ability to establish a strong hydrogenꢀbonding network with the NH donor of
the macrocycle’s precursors. In this work, we first aimed to synthesize an
unprecedented 1,4ꢀdiaminecarbonyl thread for the preparation of benzylic amide
[
2]rotaxanes. Our 1,4ꢀdiaminecarbonyl threads have four atoms as spacers between the
carbonyl groups (two carbon atoms and two nitrogen atoms), which makes this model
an unknown template for the construction of hydrogenꢀbonded rotaxanes. It is worth
highlighting that this template has both acceptor (CO) and donor (NH) hydrogenꢀ
bonding groups in the same molecule, thus giving these species the ability to selfꢀ
assemble and form dimeric associations.
The synthetic approach for the preparation of our 1,4ꢀdiaminecarbonyl linkers started
with the synthesis of stoppers. The integration of pyrazole groups as bulky stoppers in a
thread model requires a number of strategy choices. Thus, the enones 1a-f were

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3
3
synthesized in accordance with previously reported procedures. The isomeric 1’,5’ꢀ
pyrazoles (3a-f) and 1’,3’ꢀpyrazoles (4a-f) were synthesized according to the procedure
34
proposed by Martins et al. performed with slight modifications. The wide range of
compounds were proposed to verify the minor influence that each substituent can have
on the [2]rotaxane formation. The aforementioned compounds are obtained with good
yields (78–88% for 3a-f and 69–81% for 4a-f) see Scheme 1.
O
OEt
O
OMe
ii
EtO
H N
R1
+
2
R1
N
N
H
N
.HCl
O
1a-f
2
4a-f
i
R1
N
O
N
EtO
3
a-f
i: EtOH, KOH, 78 °C, 15 h
ii: EtOH, pyridine, 78 °C, 16 h
1
[a]
R
Yield (%)
3
4
a
b
c
d
e
f
Me
Pr
Ph
81
78
87
83
88
85
70
69
81
76
70
72
4ꢀFꢀC
4ꢀClꢀC
4ꢀBrꢀC
6 5
H
6
H
5
6
H
5
[
a]
Yield of the isolated product.
Scheme 1. Preparation of 1’,5’ꢀ and 1’,3’ꢀ pyrazoles.
1
13
The pyrazoles 3a-f and 4a-f were characterized by analyzing the H and C NMR
spectra and HRMSꢀTOF were performed to new compounds, see Experimental Section.
1
3
1
HMQC and Cꢀ H HMBC spectra were performed for some compounds to complete
characterizations (see ESI† for spectra data). For the identification of the isomers, the
1
5
1
Nꢀ H HMBC technique was performed for compound 3a. The spectrum of compound

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3
2
3
a showed the J coupling of N2 (N sp ) with CH
3
, thus proving the formation of the
1,5ꢀisomer (see ESI†).
Subsequently, the hydrolysis reaction of the carboxylate units, which led to the
formation of the acids 5a-f and 6a-f were obtained at good yields (92–98% and 75–92
%, respectively), see Scheme 2. The structures of compounds 5a–f and 6a-f were
1
13
determined using H and C NMR spectroscopy and HRMSꢀTOF were carried out for
new compounds, see Experimental Section. After correctly identifying each of the
obtained isomers, we then turned our attention to the synthesis of the threads (8a-f and
9a-f) — the protocols used are outlined in Scheme 2. Compounds 8a-f and 9a-f were
prepared by the reactions between pyrazoles 5a-f and 6a-f, and ethaneꢀ1,2ꢀdiamine 7, at
a 2:1 molar ratio. Reactions were performed with triphenylphosphite (2.1 equiv.), using
3
5
pyridine as the solvent, at 115 °C for 6 h. The products 8a-f and 9a-f were obtained at
good yields (70–75% and 69–89%, respectively). Compounds 8a-f and 9a-f were
1
13
characterized by H and C NMR spectra and mass spectrometry (HRMSꢀTOF). The
1
H NMR data showed a chemical shift for H , within a range of 6.21–6.75 ppm and
e
6
.53–6.68 ppm for compounds 8a-f and 9a-f, respectively; while for H
shift was within a range of 3.62–3.71 ppm. NH signals were within the ranges of 6.75–
.45 ppm and 7.31–7.50 ppm for the 1’,5’ꢀisomer and 1’,3’ꢀisomer, respectively. The
a
the chemical
7
1
3
C NMR chemical shift of the C
e
in the 1’,5’-isomer and 1’,3’ꢀisomer were within a
signal was within
range 105.6–108.3 ppm and 108.5–110.0 ppm, respectively. The CH
2
a range of 39.6–40.6 ppm and 39.1–39.4 ppm for the 1’,5’ꢀisomer and 1’,3’ꢀisomer,
respectively (for the lettering see Scheme 2).
The construction of the [2]rotaxanes was done via the fiveꢀcomponent clipping
methodology. The reactions between the threads of 8a-f (1 equiv.), isophtaloyl
dichloride (8 equiv.), and pꢀxylylenediamine (8 equiv.) were performed in the presence
of Et N (16 equiv.), using CHCl as the solvent, at a temperature of 15–35 °C for 20
3
3
1
8,36
h.
The same conditions were also used for the threads of 9a-f (Scheme 3). The wide
1
range of different pyrazole substituents (R ) were used to verify the subtle influence that each
one could have on the [2]rotaxanes formation.

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i: EtOH, NaOH, 78 °C, 4 h ii: EtOH, NaOH, 78 °C, 3 h
iii: Pyridine, triphenylphosphite, 115 °C, 6h
1
[a]
R
Yield (%)
5
6
8
9
a
b
c
d
e
f
Me
Pr
92
89
94
95
97
98
75
91
90
82
90
92
90
77
73
75
71
70
84
95
69
89
80
72
Ph
6 4
4ꢀFꢀC H
6 4
4ꢀClꢀC H
6 4
4ꢀBrꢀC H
[
a]
Yield of the isolated product.
Scheme 2. Preparation of 1,2ꢀbisꢀ(aminocarbonylꢀ(1'ꢀtertꢀbutylꢀ1Hꢀpyrazolꢀ[3']5'ꢀyl))ꢀ
ethane templates.

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2
R = 1,5ꢀ and 1,3ꢀpyrazole
i: thread (1 equiv.), isophthaloyl dichloride (8 equiv.), pꢀxylylenediamine (8 equiv.),
Et N (16 equiv.), CHCl , 15–35 °C, 20h
3
3
Scheme 3. Synthesis of [2]rotaxanes.
The threads of 9a-f proved to act as templates for the clipping reactions, leading to the
formation of the [2]rotaxanes 10b-f. However, the threads of 8a-f were unproductive in
obtaining the corresponding rotaxane. The tertꢀbutyl groups of the pyrazole stoppers in
8a-f would interfere during the rotaxane’s heteroꢀassembly process, preventing the
formation of the hydrogen bond between thread and macrocycle precursor. It is well
know that for the formation of [2]rotaxanes multiple hydrogen bonds interactions are
37
necessary.
The rotaxanes 10b-f — in which the R group = Pr, Ph, 4ꢀFꢀC
were isolated at yields of 7–19 % (Scheme 4). Among these examples, it is worth
noting that the yield of rotaxane 10f (19%) is similar to the yields obtained with other
1
6
4 6 6 4
H , 4ꢀClꢀC H4, 4ꢀBrꢀC H
—
9
,17
wellꢀknown templates.
We reasoned that supplementary nonꢀcovalent interactions
should be established between the macrocyclic precursor and the pꢀbromophenyl
substituted pyrazole during the course of the rotaxane formation reaction, which
cooperatively stabilizes the intermediate hydrogenꢀbonded aggregate and leads to the
final rotaxane. In addition, the different substituents showed that the steric effects of
halogen and propyl group does not influence the formation of [2]rotaxane. Interestingly,
during these assays, the amideꢀbased [2]rotaxane 10a was not obtained. The pyrazole
1
1
groups substituted with an R group (R = Me) are probably too small to kinetically trap
the macrocycle in the axis which dethreads, thus precluding the isolation of the
interlocked compound.

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i: isophtaloyl dichloride, pꢀxylylenediamine, Et N, CHCl , 15–35 °C, 20h
3
3
1
a
Comp.
R
[2]rotaxane
10a
Yield (%)
b
9a
Me
Pr
ꢀ
9b
10b
7
9
c
Ph
10c
10
13
14
19
9d
4ꢀFꢀC
6
H
4
10d
9e
4ꢀClꢀC
6
H
4
10e
9
f
4ꢀBrꢀC
6
H
4
10f
[
a]
b]
Yield of the isolated product.
The product was not obtained.
[
Scheme 4. Synthesis of compounds 10b-f
1
The comparison between the H NMR spectra of the [2]rotaxanes 10b-f and the thread
for 9b-f showed several relative signal movements that should be highlighted (Figure
1
). For example, compound 10e showed that the most significant shifting is that
produced by the amide signal (H ), which is shielded by 0.2 ppm (3.69 ppm thread and
.49 ppm [2]rotaxane) in relation to the thread, due to the proximity of the aromatic
rings of the macrocycle around this fragment.
a
3

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1
3
Fig. 1. Partial H NMR spectra of: (a) the thread 9e (600MHz, CDCl , 298K); and (b)
the [2]rotaxane 10e (600 MHz, CDCl , 298K). *Solvent.
3
Additionally, it is also possible to observe significant upfield shifts: δ = 0.74, 0.17, 0.28,
and 0.23 for the signals of the H , H , H , and H hydrogens, respectively, of the
e
j
l
m
pyrazole groups of the rotaxane with respect to the unwrapped thread. The upshifting of
these signals may be interpreted as being due to the proximity of the macrocycle’s
isophthalamide units in relation to the pyrazole groups. These changes in chemical shift
are the result of the diamagnetic shielding effect caused by aromatic rings. The H
protons of the macrocyclic methylene group appear as a singlet at a chemical shift of
.38–4.40 ppm. In the benzylic amide rotaxanes that have a slow ring rotation, the
E
4
benzylic hydrogens of the macrocycle are diastereotopic and appear as two separated
signals; however, in the case of 10e, these nuclei resonate as a singlet due to the fast
9
pirouetting ring motion (for the lettering see Scheme 4).
3
Compound 10e was solubilized in CHCl /MeOH (9:1) and exposed to slow evaporation
at room temperature in order to grow suitable monocrystals of the interlocked species
for Xꢀray diffraction analysis. The crystal structure reveals a multicomponent crystal
formed by one independent molecule of [2]rotaxane and two molecules of solvent
(
water).
The molecular structure obtained from the Xꢀray diffraction data of the [2]rotaxane 10e
Figure 2) shows that: the phenyl group's pꢀxylylenediamine is spatially close to the H
(
a

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of the thread, and the phenyl group's isophthaloyl dichloride is spatially close to He.
1
These spatial proximities explain the shieldings observed in the H NMR spectra.
The macrocycle adopts a distorted chair conformation — this distortion is probably
required to maximize the intermolecular interactions between the thread and the
macrocycle (Figure 2). The crystal structure of 10e shows the two N–H(mac)ꢁꢁꢁO(thr)
hydrogen bonds between the NH groups of the macrocycle and the C(O) groups of the
.
..
amide thread, both with a distance of d(D A) 2.828 Å and an angle of 153°.
Fig. 2. ORTEP diagrams of the [2]rotaxane 10e. Displacement ellipsoids are drawn at
the 50% probability level, and H atoms are represented by circles with arbitrary radii.
After the full characterization of the [2]rotaxanes in the crystals and in solution (by
NMR), the next step was the investigation of the thread structure in both solid and
solution states. In order to find some structural factor that explains the exclusive
formation of [2]rotaxane from threads 9a-f, we firstly performed the crystallization of
threads 8c and 8e (1’,5’ꢀ thread) and 9c (1’,3’ꢀthread). Suitable monocrystals of 8c
3
(1’,5’ꢀthread) and 9c (1’,3’ꢀthread) were obtained from solvent mixtures of CHCl and
EtOH (1:3) and CHCl and MeOH (1:1), respectively. Their Xꢀray structures revealed
3
two main differences: (i) the diamide thread 8c has an asymmetric structure and 9c is
crystallized as a symmetric structure; and (ii) they possess different conformations
(Figure 3), because the dihedral angles of the two structures are different. The thread 8c
has dihedral angles of N52'ꢀC51'ꢀC5'ꢀN1' -130.21° and N52'ꢀC51'ꢀC5'ꢀN1' 117.19°;
whereas thread 9c has dihedral angles of N32ꢀC31ꢀC3ꢀN2 6.57° and ꢀ6.57° (for Crystal

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data, see ESI†). The monocrystals of 8e were obtained from solvent mixtures of CHCl
3
and MeOH (9:1). Compound 8e (1’,5’ꢀthread) had a different conformation to that of
compound 8c, which had a distorted conformation (see Figure 3). The main difference
is the dihedral angles of N52ꢀC53ꢀC53’ꢀN52’ for compound 8c (176.56°) and 8e
(58.98°).
8
c
9c
8e
®
Fig. 3. Molecular structures of compounds 8c, 8e, and 9c, represented by ORTEP
diagrams, with thermal ellipsoids drawn at 50% probability.
Thus, with the aim of understanding the differences in the conformations of the threads
c, 8e, and 9c, a supramolecular study of compounds 8c and 9c —using Quantum
Theory of Atoms in Molecules analysis (QTAIM) and NMR spectroscopy techniques
could provide valuable information about the intermolecular interactions in the selfꢀ
8
—
assembly and heteroꢀassembly of molecules.
We started our study by defining the most energetic dimers for compounds 8c and 9c
via the supramolecular cluster approach, using data obtained by Xꢀray analysis, in
2
1
accordance with the methodology of Martins et al. The cluster formed by the first
coordination sphere is the portion that has all the necessary information for
38–40
understanding the intermolecular interactions of the entire crystal system.
The most
stable dimers for compounds 8c and 9c are shown in Figure 4 — the energy values for
compounds 8c (M1ꢁꢁꢁM2) and compound 9c (M1ꢁꢁꢁM2/ M1ꢁꢁꢁM3) were ꢀ31.76 and ꢀ
ꢀ1
2
0.31 kcalꢁmol , respectively. These dimers were submitted QTAIM analysis, and from
this analysis, the presence of intermolecular interactions is given by a bond critical point

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4
1,42
(
BCP) along the bond path connecting two interacting atoms . Previously, we
showed that a good correlation between the sum of the electron density at the BCP and
the sum of the dimer energy allowed the partitioning of the interaction energy into
21
atom⋯atom . This analysis showed that for compound 8c, the most stable dimers are
ꢀ1
connected by a strong hydrogen bond (NHꢁꢁꢁO), with an energy value of ꢀ7.5 kcal⋅mol
see Figure 4a); while for compound 9c, the most stable dimers are connected by only
(
lpꢁꢁꢁπ and CHꢁꢁꢁπ interactions, which do not have hydrogen bonds. In other words, in
this compound the acceptor of hydrogen bond sites are free to interact in the heteroꢀ
assembly, thus making possible the synthesis of [2]rotaxane using the clipping
methodology (see Figure 4b).
(
a)
(
b)
Fig. 4. View of some BCPs connecting interacting atoms in dimer interactions: a) 1’,5’ꢀ
thread (8c); and b) 1’,3’ꢀthread (9c).
The QTAIM analyses was performed for the [2]rotaxane 10e, and they show hydrogen
bonds with the carbonyl groups in the thread (see Figure 5). The hydrogen bonding

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ꢀ1
between the thread and the macrocycle had an energy value of ꢀ5.61 kcal·mol . It must
be emphasized that this hydrogen bonding is less stable than the hydrogen bonds that
exist in the selfꢀassembly of the thread (8c).
Fig. 5. View of the BCPs of the hydrogen bonds for compound 10e.
The most stable dimers determined by supramolecular study can be correlated by
43
studying spectroscopy techniques. In accordance with Spitaleri et al., the dimers
detected in solution by NMR spectroscopy techniques are maintained throughout the
additional stages of aggregation and, therefore, they are found intact in the final
21,43
crystal.
Considering the steric effect of tertꢀbutyl groups of the pyrazole stoppers in 8a-f prevent
2]rotaxane formation, additional studies of selfꢀ and heteroꢀassembly of threads were
[
carried in solution to assess other variables that can affect the rotaxane formation. Thus,
given the results observed in these supramolecular clusters, we analyzed both threads
(1’,3’ꢀ and 1’,5’ꢀ) via concentrationꢀdependent NMR spectroscopy to show the behavior
of the donor and acceptor sites of hydrogen bond. The dimers can be detected by
dilution of the samples and observing the dependence of some signals’ chemical shifts
on the concentration. Consequently, we investigated threads 8c (1’,5’ꢀthread) and 9c
(
1’,3’ꢀthread) in CDCl solution, in order to determine the influence of intermolecular
3

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1
interactions on the solution conformations of the molecules. The H NMR dilution
curves were constructed for 8c and 9c, and the dependence of the chemical shift on the
concentration of the amide groups was evaluated in CDCl
3
for 8c and 9c (Figure 6).
(a)
(b)
1
Fig. 6. H NMR chemical shifts at 25 °C, as a function of the concentration (M) in
CDCl for: (a) compound 8c (1’,5’ꢀthread) and (b) compound 9c (1’,3’ꢀthread). The
3
concentrations were used 0.25, 0.125, 0.0625, 0.0312, 0.0156, 0.0078, 0.0039 and 0.00195 M.
In compound 8c, the amide hydrogen protons show a downfield shift (Figure 6a) as the
concentration increases, which is probably due to the formation of a hydrogen bond
between the dimers as well as the selfꢀassembly process (Kass = 3.25 M). Meanwhile,
compound 9c shows a upfield signal shift with the increasing concentration (Kass = 83.9
M), thus indicating that the main interaction at the 1’,3’ꢀthread is not the same bond in
solution, which is in agreement with the data obtained in solid state (Figure 6b). The
study of the associations of compounds 8c and 9c (Figure 6) showed that the
intermolecular interactions have a role in these systems either leading to or preventing
the formation of [2]rotaxanes. These analyses were done for compounds 8e and 9e, and
the data showed the same result as for compounds 8c and 9c (see ESI†). Experiments
with concentration variation were performed to extrapolate the effects of intermolecular
interactions. It was observed a relation between the increase of concentration and the
1
change of the chemical shifts of the H NMR, which indicates effects of selfꢀassembly.
It was observed at low concentrations only subtle changes, due to limitations of the
technique in this concentration range.
Thus, considering these results, we continued to investigate the heteroꢀassembly of
threads in solution, via NMR spectroscopy (see ESI†). The study was used to examine
the efficiency of the thread as a good acceptor or donor hydrogen bond in heteroꢀ

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assembly conditions. In order to mimic the interactions that occur in the reactional
environment and lead to the formation of [2]rotaxane, we chose Nꢀbenzylbenzamide to
represent the portion of the macrocycle in the analysis of the heteroꢀassembly
interactions with threads 8c, 8e, 9c, and 9e. The concentration of the 1’,3’ꢀ and 1’,5’ꢀ
thread was constant, whereas the concentration of Nꢀbenzylbenzamine was kept variable
(0.5 M at 0.0078M).
The NMR analysis, which involved monitoring the amide protons (NH) of the thread
and the Nꢀbenzylbenzamide, showed that the 1’,5’ꢀthread behaves like a donor
hydrogen bond group. The NH thread’s downfield signal shifts as the concentration of
Nꢀbenzylbenzamide increases, which indicates the donor character of the hydrogen
bonds in threads 8c and 8e in the heteroꢀassembly. For this analysis, it is also possible to
determine that the amide group of the thread is a donor hydrogen bond, and that the
carbonyl group of the Nꢀbenzylbenzamide is a hydrogen bond acceptor group in heteroꢀ
assembly. The proximity of the tertꢀbutyl group (of the pyrazole stoppers) to the
carbonyl group prevents the thread from being only a hydrogen bond acceptor, which
justifies the two conformations of the 1’,5’ꢀthread in solid state. Thus, in the QTAIM
analysis, the 1’,5’ꢀthread had two intramolecular CHꢁꢁꢁO interactions between the
carbonyl and tertꢀbutyl groups, which contributes with the steric effect theory (see
ESI†).
On the other hand, the NH 1’,3’ꢀthread’s chemical shift remained constant when the
concentration of the Nꢀbenzylbenzamide increases, which indicates the hydrogen
bonding’s acceptor character in the thread in the heteroꢀassembly (see ESI†). In selfꢀ
assembly, the 1’,3’ꢀthread not have hydrogen bonds in either liquid or solid state;
however, in heteroꢀassembly this template behaves like a good acceptor bond and yields
[
2]rotaxane 10e-f.
Conclusions
In this work we showed the ability of 1,2ꢀbis (aminocarbonylꢀ(1'ꢀtertꢀbutylꢀ1Hꢀpyrazolꢀ
[
3']5'ꢀyl))ꢀethanes as templates for the synthesis of benzylic amide [2]rotaxanes that
have substituted tertꢀbutyl pyrazoles as stoppers. We also demonstrated that the
competition between the selfꢀassembly and heteroꢀassembly of the thread — which is
ruled by the substitution pattern of the pyrazoles — either furnishes or prevents the
formation of the interlocked compound. Thus, the 1,4ꢀdiamidecarbonyl 9a-f linker act

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as a template for the construction of [2]rotaxanes, and the bulky pyrazoles have
potential to be stoppers.
The conformation adopted by the thread makes possible the synthesis of new
[
2]rotaxanes or the avoidance of the clipping reaction. The intermolecular interactions
were studied in solution and in solid state. The homoꢀassembly of the threads was
1
studied based on the concentrationꢀdependent chemical shifts of H NMR signals in 8c
and 9c solution. The study of the heteroꢀassembly of threads was accompanied by
1
concentrationꢀdependent chemical shifts of the H NMR signals of Nꢀbenzylamide, as a
mimic of the macrocycle.
The supramolecular cluster approach was used to interpret the crystalline structure
obtained by Xꢀray diffraction. This study showed that the 1’,5’ꢀpyrazoleꢀthread formed
a hydrogen bond in selfꢀ and heteroꢀassembly — this thread does not act as a hydrogen
bond acceptor in the heteroꢀassembly because of the proximity of the pyrazole stoppers’
tertꢀbutyl groups to the carbonyl group; however, it is a good hydrogen bond donor in
the heteroꢀassembly. Thus, the steric effect of the tertꢀbutyl groups of the 1’,5’ꢀ
pyrazoleꢀstoppers is an important contribution in the approximation of the macrocycle’s
precursor blocks to yield [2]rotaxanes. On the other hand, the study of the 1’,3’ꢀ
pyrazoleꢀthread showed that: this compound has only hydrogen bonding acceptor
characteristics, and the carbonylic oxygen did not indicate steric hindrance by the tertꢀ
butyl groups. In other words, the 1’,3’ꢀpyrazoleꢀthread was shown to be the only good
hydrogen bond acceptor that yields the [2]rotaxanes 10b-f.
Experimental Section
General Methods: Unless otherwise indicated, all of the common reagents and solvents
were used as obtained from commercial suppliers without further purification. Column
chromatography was done using silica gel (60 Å, 40–60 µm, SDS) as stationary phase,
and TLC was performed on precoated silica gel on aluminum cards (0.25 mm thick,
1
13
with 254 nm fluorescent indicator, Fluka) and observed under UV light. The H and C
1
NMR spectroscopic data were recorded with a Bruker DPX 200 ( H NMR at 200.13
1
3
1
MHz and C NMR at 50.32 MHz), Bruker Avance II ( H NMR at 400.13 MHz and
1
3
1
13
C NMR at 100.62 MHz) and/or Bruker Avance III ( H NMR at 600.13 MHz and
NMR at 150.92 MHz) in CDCl /TMS and MeOD/TMS solutions at 298–313 K, and the
chemical shifts (δ values) are given in ppm. For pyrazoles and threads the melting
C
3

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points were carried out by MQAPFꢀ302 melting point apparatus. The melting point for
TM
Rotaxanes were carried out on MDSC Q2000 (Tꢀzero
DSC technology, TA
Instruments Inc., New Castle, DE, USA). The heating rate used for the samples was
ꢀ1
1
0 °C min . The samples were subjected to three cycles of heating and cooling in
temperature ranges between ꢀ80 and 300 °C, however, no thermal events were observed
between this temperature. Then thermogravimetric analyses were carried out for
rotaxanes on a TGAQ5000 (TA Instruments Inc., USA) and decomposition was
−
1
observed above 305 °C. The heating rate was 10 °C min and the N
2
flow rate was
−1
2
5 mL min from 0° to 900 °C. Mass spectra were registered in EI mode (70 eV) on
a HP 5973 MSD instrument connected to a HP 6890GC and interfaced with a Pentium
PC. The GC was equipped with a splitꢀsplitless injector, autosampler, crossꢀlinked HPꢀ5
capillary column (30 m, 0.32 mm ID), and helium was used as the carrier gas. Liquid
chromatography coupled to mass detector (LCꢀMS/MS) was performed in a system
Agilent Model 6460 with electrospray ionization (ESI) coupled to QQQ detector. The
voltage of the capillary was maintained at 3500V. The source temperature was 300 ° C
with a flow rate of 5 L/min. The jetstream temperature was 250 °C with a flow rate of
11 L/min. All samples were injected with autosampler, 1ꢂL by volume. Data were
acquired in scan mode in the range m/z 50ꢀ500 and the product ion mode (product ion)
MS/MS. Exact mass analyses of the new compounds were performed on a
HPLC/MICROTOF ESIꢀMS mass spectrometer with direct insertion in positive
electrospray mode. IR spectra were obtained with a Bruker Tensorꢀ27 Sample
ꢀ1
Compartment RTꢀDLaꢀTGS spectrometer, using KBr pallets in the 4000 to 400 cm
region.
Single-crystal structure determination
Crystallographic measurements were made on a Bruker D8 Venture area detector
Photon 100 CMOS with graphiteꢀmonochromated MoꢀKα radiation (λ = 0.71073 Å).
44,45
The structure was solved by software package WinGX.
Crystallographic information files (cifs) for the studied compounds have been deposited
at Cambridge Crystallographic Data Centre (CCDC) with the following identification
reference codes CCDCꢀ1045024 (10e), CCDCꢀ1498468 (8c), CCDCꢀ1498649 (8e) and
CCDCꢀ1459084 (9c).

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Table 1. Crystallographic Data and refinement parameters of compounds 8c
,
8e,
9c and 10e
.
Compound
1’,5’ꢀThread 8c
1’,5’ꢀThread 8e
1’,3ꢀ’Thread 9c
[2]rotaxane 10e
Empirical formula
C
30
H
36
N
6
O
2
C
15
H17ClN
3
O
C
30
H
36
N
6
O
2
31 5 4
C H33ClN O
Molecular weight
Temperature (K)
Crystal system
Space group
512.65
293
290.77
293
512.65
298
575.07
100
Monoclinic
P 2 /c
Monoclinic
Monoclinic
P 2 /c
Triclinic
C2c
1
P1ꢀ
1
Cell parameters
a (Å)
13.0096(5)
18.5432(5)
12.0412(5)
90(5)
26.6417 (8)
11.3041 (3)
9.7939 (2)
90
6.9687(3)
12.1818(6)
16.6042(9)
90
9.6985(7)
b (Å)
c (Å)
α (°)
β (°)
γ (°)
11.4602(9)
14.9575(12)
80.519(4)
73.258(4)
76.892(4)
100.744(5)
90(5)
91.318 (2)
90
99.584
90
3
V (Å )
2853.9 (4)
4
2948.76 (13)
8
1389.88(12)
2
1541.7(2)
2
Z
ꢀ
3
Calcd. density (g.cm )
1.193
1.310
0.258
1224
1.225
0.079
548
1.239
0.166
606
ꢀ
1
Abs. Coef. (mm )
F (000)
0.612
1096
Crystal size (mm)
0.46×0.43×
0.77×0.54× 0.44 0.65× 0.24×0.23 0.30×0.20× 0.12
0.25
θ range for data
4.20 to 68.18
1.96 to 27.57
2.49 to 30.10
1.83 to 27.24
collection (deg)
h,k,l range
ꢀ15 ≤ h ≤ 15
ꢀ34 ≤ h ≤ 34
ꢀ14 ≤ k ≤ 14
ꢀ12 ≤ l ≤ 12
ꢀ9≤ h ≤ 9
ꢀ17≤ k ≤ 17
ꢀ23≤ l ≤ 23
ꢀ12≤ h ≤12
ꢀ14 ≤ k ≤ 14
ꢀ19 ≤ l ≤ 19
ꢀ22 ≤ k ≤ 21
ꢀ14 ≤ l ≤ 14
Reflections
22676 / 5035
[R(int) =
40005/3402
95541 / 4058
43020 / 6748
collected/unique
[R(int) = 0.0275] [R(int) =0.0990] [R(int) = 0.0446]
0.0257]
Data/restraints/parameters
5035 / 0 / 343
3402/ 0 / 171
4058 / 0 / 180
6748 / 2 / 372
Absorption correction
Refinement method
Multiꢀscan
Fullꢀmatrix
leastꢀsquares on
F^2
Multiꢀscan
Multiꢀscan
Fullꢀmatrix
leastꢀsquares on
F^2
Gaussian
Fullꢀmatrix leastꢀ
squares on F^2
Fullꢀmatrix leastꢀ
squares on F^2
Final R indices
R all data
R1 = 0.0996,
wR2 = 0.33
R1 = 0.0387,
WR2= 0.1041
R1 = 0.0506,
wR2 = 0.1384
R1 = 0.0506,
wR2 = 0.1417
R1 = 0.1086,
wR2 = 0.345
R1= 0.0485
wR2= 0.1112
R1 = 0.0660,
wR2 = 0.1538
R1 = 0.0676,
wR2 = 0.1495
2
Goodness of fit on F
1.176
1.052
1.057
1.082

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Largest diff. peak and hole
0.576 and ꢀ
0.539
0.186 and ꢀ0.255 0.306 and ꢀ.221
0.291 and ꢀ0.692
3
(
e Å )
33
Materials. Compounds 1a-f were prepared as previously reported.
Synthesis of the 1-(1,1-dimethylethyl)-1H-pyrazol-5-carboxylate ethyl 3a-f: An
enone (1a-f, 1mmol), tertꢀbutylhydrazine hydrochloride 2 (0.186 g, 1.5 mmol) and
KOH (0.084 g, 1.5 mmol) and EtOH (5 mL) were placed in a roundꢀbottomed flask.
The mixture was magnetically stirred at 78°C for 15h. At the end of the reaction time,
the EtOH solvent in the mixture was evaporated under reduced pressure. Chloroform
(10 mL) was then added and the reaction mixture was washed with water (3×10 mL).
The combined organic phases were dried with anhydrous Na SO and the solvent was
2
4
evaporated under reduced pressure. The pyrazoles 3a-f were obtained in pure form
without further purification.
1-(1,1-Dimethylethyl)-3-methyl-1H-pyrazole-5-carboxylate ethyl (3a): was prepared
from enone 1a (0.172 g, 1 mmol), tertꢀbutylhydrazine hydrochloride 2 (0.186 g, 1.5
1
mmol) and KOH (0.084 g, 1.5 mmol). Yield: 0.170 g, 81%. M.p: yellow Oil. H NMR
3
(
200 MHz, CDCl3, 25 °C): δ = 6.66 (s, 1H, H4), 4.30 (q, JH,H = 7.1 Hz, 2H, H7), 2.25
3
13
(
d, 3H, H11), 1.69 (s, 9H, tBu), 1.36 (t, JH,H = 7.1 Hz, 3H, H8). C NMR (100 MHz,
CDCl , 25 °C): δ = 160.7 (C=O), 144.4 (C3), 133.2 (C5), 113.1 (C4), 61.7 (C9), 60.8
3
+
(
C7), 29.6 (tBu), 14.1 (C8), 13.2 (C11). MS (EI, 70 eV): m/z (%) = 210 (14) [M] , 155
(45), 126 (40), 109 (100).
1-(1,1-Dimethylethyl)-3-propyl-1H-pyrazole-5-carboxylate ethyl (3b): was prepared
from enone 2b (0.200 g, 1 mmol), tertꢀbutylhydrazine hydrochloride 2 (0.186 g, 1.5
1
mmol) and KOH (0.084 g, 1.5 mmol). Yield: 0.186 g, 78%. M.p: Yellow oil. H NMR
3
(
(
(
(
200 MHz, CDCl3, 25 °C): δ = 6.67 (s, 1H, H4), 4.30 (q, JH,H = 7.1 Hz, 2H, H7), 2.57
3
m, 3H, H11), 1.70 (s, 9H, tBu), 1.66 (m, 2H, H12), 1.36 (t, JH,H = 7.1, 3H, H8), 0.96
3
13
t, JH,H = 7.36, 3H, H13). C NMR (100 MHz, CDCl3, 25 °C): δ = 160.6 (C=O), 149
C3), 132.9 (C5), 112.1 (C4), 61.7 (C9), 60.8 (C7), 29.9 (C11), 29.5 (tBu), 22.7 (C12),
+
1
4.1 (C8), 13.8 (C13). MS (EI,70 eV): m/z (%) = 238 (16) [M] , 154 (100), 137 (83),
08 (48).
1

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3-Phenyl-1-(1,1-dimethylethyl)-1H-pyrazol-5-carboxylate ethyl (3c): was prepared
from enone 1c (0.234 g, 1 mmol), tertꢀbutylhydrazine hydrochloride 2 (0.186 g, 1.5
mmol) and KOH (0.084 g, 1.5 mmol). White solid. Yield: 0.236 g, 87%. M.p: 76ꢀ78 °C.
1
4
3
H NMR (200 MHz, CDCl
3
, 25 °C): δ = 7.82 (dd, 2H, JH,H = JH,H= 1.3 Hz, 8.2 Hz,
3
H12), 7.28ꢀ7.43 (m, 3H, HAr), 7.20 (s, 1H, H4), 4.35 (q, 2H, JH,H = 7.1, H7), 1.77 (s,
3
13
9
H, tBu), 1.40 (t, 3H, JH,H = 7.1, H8). C NMR (100 MHz, CDCl
3
, 25°C): δ = 160.4
(C=O), 147.1 (C3), 133.9 (C5), 133.0 (C11), 128.5 (C13), 127.6 (C14), 125.4 (C12),
110.7 (C4), 62.7 (C9), 61.1 (C7), 29.5 (tBu), 14.2 (C8). HRMS (ESIꢀTOF) m/z: [M +
+
H] calcd. for C H N O 273.1603; found: 273.1597
16
21
2
2
3-(4-Fluorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazol-5-carboxylate ethyl (3d): was
prepared from enone 1d (0.252 g, 1 mmol, tertꢀbutylhydrazine hydrochloride 2 (0.186
1
g, 1.5 mmol) and KOH (0.084 g, 1.5 mmol). Yield: 0.241 g, 83%. M.p: 81ꢀ84 °C. H
4
3
NMR (200 MHz, CDCl
3
, 25 °C): δ = 7.78 (dd, JH,H = JH,H 5.43 Hz, 8.87 Hz, 2H, HAr),
3
3
7
1
1
3
.08 (t, J = 8.6 Hz, 2H, HAr), 7.14 (s, 1H, H4), 4.35 (q, J = 7.1 Hz, 2H, H7),
H,H
H,H
3
13
.76 (s, 9H, tBu), 1.40 (t, JH,H = 7.1, 3H, H8). C NMR (100 MHz, CDCl
3
, 25 °C): δ =
1
4
62.5 (d, JC,F = 249.3 Hz, C14), 160.3 (C=O), 146.3 (C3), 134.1 (C5), 129.3 (d, JC,F
=
3
2
.14 Hz, C11), 127.1 (d, JC,F = 8.0 Hz, C13), 115.4 (d, J = 21.5 Hz, C12), 110.4
C,F
(C4), 62.8 (C9), 61.1 (C7), 29.5 (tBu), 14.2 (C8). HRMS (ESIꢀTOF) m/z: [M +
+
H] calcd. for C16
H20FN
O
2 2
291.1509; found: 291.1512
3
-(4-Chlorophenyl)-1-(1,1-dimethylethyl)-1
was prepared from enone 1e (0.268 g, 1 mmol, tertꢀbutylhydrazine hydrochloride
(0.186 g, 1.5 mmol) and KOH (0.084 g, 1.5 mmol). Yield: 0.269 g, 88%. M.p: 62ꢀ64
H-pyrazole-5-carboxylate ethyl (3e):
2
1
3
°
C. H NMR (200 MHz, CDCl
3
, 25 °C): δ = 7.73 (d, JH,H = 8.49 Hz, 2H, H12), 7.34 (d,
3
3
J
H,H = 8.5 Hz, 2H, H13), 7.15 (s, 1H, H4), 4.34 (q, JH,H = 7.1 Hz, 2H, H7), 1.76 (s, 9H,
3
13
tBu), 1.39 (t, JH,H = 7.1 Hz, 3H, H8). C NMR (100 MHz, CDCl
3
, 25 °C): δ = 160.2
(C=O), 146.0 (C3), 134.2 (C5), 133.3 (C14), 131.6 (C11), 128.7 (C13), 126.6 (C12),
110.6 (C4), 62.9 (C9), 61.1 (C7), 29.5 (tBu), 14.2 (C8). HRMS (ESIꢀTOF) m/z: [M +
+
H] calcd. for C16
2
H20ClN O
2
307.1213; found: 307.1221.
3-(4-Bromophenyl)-1-(1,1-dimethylethyl)-1
H-pyrazole-5-carboxylate ethyl (3f):
was prepared from enone 1f (0.313 g, 1 mmol), tertꢀbutylhydrazine hydrochloride 2

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(0.186 g, 1.5 mmol) and KOH (0.084 g, 1.5 mmol). Yield: 0.298 g, 85%. M.p: 80ꢀ83
1
3
°
C. H NMR (200 MHz, CDCl
3
, 25°C): δ = 7.68 (d, JH,H = 8.3, Hz, 2H, H13), 7.50 (d,
3
3
J
H,H= 8.4 Hz, 2H, H13), 7.16 (s, 1H, H4), 4.34 (q, JH,H= 7.1, 2H, H7), 1.76 (s, 9H,
3
13
tBu), 1.40 (t, JH,H= 7.1, 3H, H8). C NMR (100 MHz, CDCl
3
, 25 °C): δ = 160.2
(C=O), 146.0 (C3), 134.2 (C5), 132.0 (C11), 131.6 (C13), 126.9 (C12), 121.5 (C14),
110.6 (C4), 62.9 (C9), 61.2 (C7), 29.5 (tBu), 14.2 (C8). HRMS (ESIꢀTOF) m/z: [M +
+
H] calcd. for C16
H20BrN
2
O
2
351.0708; found: 351.0717.
Synthesis of the 1-(1,1-dimethylethyl)-1
enone (1a–f, 1 mmol), tertꢀbutylhydrazine hydrochloride 2 (1.2 mmol, 0.148), pyridine
1.2 mmol, 0.097 mL), and EtOH (5 mL) were placed in a roundꢀbottomed flask. The
H-pyrazol-3-carboxylate ethyl 4a-f: An
(
mixture was magnetically stirred at 78 °C for 16 h. At the end of the reaction time, the
EtOH solvent in the mixture was evaporated under reduced pressure. Chloroform (10
mL) was then added and the reaction mixture was washed with water (3×10 mL). The
combined organic phases were dried with anhydrous Na SO and the solvent was
2
4
evaporated under reduced pressure. The pyrazoles 4a-b were predicated by column
chromatography with hexane/ethyl acetate (8:2 v,v). Compounds 4c-f were
recrystallized by hexane.
1-(1,1-Dimethylethyl)-5-methyl-1
H-pyrazol-3-carboxylate ethyl (4a): was prepared
from enone 1a (0.172 g, 1 mmol), tertꢀbutylhydrazine hydrochloride 2 (0.148 g, 1.2
46
mmol) and pyridine (0.097 mL, 1.2 mmol). This compound is reported in literature,
1
however, the spectroscopic data are incomplete. Yield: 0.147 g, 70%. M.p: Oil. H
3
NMR (200 MHz, CDCl
3
, 25°C): δ = 6.55 (sl, 1H, H4), 4.35 (q, JH,H= 7.1 Hz, 2H, H7),
3
3
13
2
.47 (d, JH,H= 0.6 Hz, 3H, H11), 1.67 (s, 9H, tBu), 1.37 (t, JH,H= 7.1 Hz, 3H, H8). C
NMR (100 MHz, CDCl , 25 °C): δ = 162.8 (C=O), 140.2 (C5), 139.2 (C3), 110.9 (C4),
3
61.0 (C9), 60.3 (C7), 29.6 (tBu), 14.5 (C11), 14.2 (C8). MS (EI,70 eV): m/z (%) = 210
+
(
23) [M] , 155 (35), 126 (40), 109 (100).
5-(1,1-Dimethylethyl)-5-propyl-1H-pyrazole-3-carboxylate ethyl (4b): was prepared
from enone 1a (0.200 g, 1 mmol, tertꢀbutylhydrazine hydrochloride 2 (0.148 g, 1.2
1
mmol) and pyridine (0.097 mL, 1.2 mmol). Yield: 0.164 g, 69%. M.p: Oil. H NMR
3
(200 MHz, CDCl
3
, 25 °C): δ = 6.53 (s, 1H, H4), 4.36 (q, JH,H = 7.1, 2H, H7), 2.78 (m,
3
2
H, H11), 1.74 (m, 2H, H12), 1.67 (s, 9H, tBu), 1.38 (t, JH,H = 7,1, 3H, H8), 1.04 (t,

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3
13
J
3
H,H = 7,34, 3H, H13). C NMR (100 MHz, CDCl , °C): δ = 162.9 (C=O), 144.5 (C5),
140.3 (C3), 109.1 (C4), 61.2 (C9), 60.4 (C7), 30.1 (C11), 30.1 (tBu), 22.4 (C12), 14.3
+
(
C8), 13.9 (C13). HRMS (ESIꢀTOF) m/z: [M + H] calcd. for C13
H
23
N
2
O
2
239.1760;
found: 239.1762
5-Phenyl-1-(1,1-dimethylethyl)-1
H-pyrazole-3-carboxylate ethyl (4c): was prepared
from enone 1c (0.234 g, 1 mmol, tertꢀbutylhydrazine hydrochloride 2 (0.148 g, 1.2
47
mmol) and pyridine (0.097 mL, 1.2 mmol). This compound is reported in literature,
1
however the spectroscopic data are incomplete. Yield: 0.220 g, 81%. M.p: 78ꢀ82 °C. H
3
NMR (200 MHz, CDCl , 25°C): δ = 7.35ꢀ7.43 (m, 5H, HAr), 6.68 (s, 1H, H4), 4.39 (q,
3
3
13
J
H,H= 7.1 Hz, 2H,H7), 1.50 (s, 9H, tBu), 1.39 (t, 3H, JH,H= 7.1, H8). C NMR (100
MHz, CDCl , 25°C): δ = 162.7 (C=O), 144.0 (C5), 140.5 (C3), 133.1 (C11), 130.4
3
(C12), 128.7 (C14), 127.9 (C13), 112.0 (C4), 62.7 (C9), 60.6 (C7), 30.9 (tBu), 14.3
+
(
C8). MS (EI,70 eV): m/z (%) = 272 (20) [M] , 216 (100), 171 (29), 114 (51).
5
-(4-Fluorophenyl)-1-(1,1-dimethylethyl)-1
was prepared from enone 1d (0.252 g, 1 mmol, tertꢀbutylhydrazine hydrochloride 2
0.148 g, 1.2 mmol) and pyridine (0.097 mL, 1.2 mmol). This compound is reported in
H-pyrazole-3-carboxylate ethyl (4d):
(
4
8
literature, however the spectroscopic data are incomplete. Yield: 0.220 g, 76%. M.p:
1
7
2ꢀ78 °C. H NMR (200 MHz, CDCl
3
, 25 °C): δ = 7.37 – 7.24 (m, 2H, H13), 7.10 (t,
3
3
J
H,H= 8.6, 2H, HAr), 6.67 (s, 1H, H4), 4.39 (q, 2H, JH,H= 7.1 Hz, HAr), 1.50 (s, 9H,
3
13
tBu), 1.39 (t, J = 7.1 Hz, 3H, H8). C NMR (100 MHz, CDCl , 25°C): δ = 162.9 (d,
H,H
3
1
3
J
C,F = 249.3 Hz, C14), 162.6 (C=O), 142.9 (C5), 140.5 (C3), 132.2 (d, JC,F= 8.2 Hz,
4
2
C12), 129.0 (d, JC,F = 3.6 Hz, C11), 115.0 (d, JC,F = 21.6 Hz, C13), 112.2 (C4), 62.7
+
(
C9), 60.6 (C7), 30.9 (tBu), 14.2 (C8). MS (EI,70 eV): m/z (%) = 290 (13) [M] 234
(100), 188 (32), 132 (63).
5-(4-Chlorophenyl)-1-(1,1-dimethylethyl)-1
H- pyrazole-3-carboxylate ethyl (4e):
was prepared from enone 1e (0.268 g, 1 mmol), tertꢀbutylhydrazine hydrochloride 2
(0.148 g, 1.2 mmol) and pyridine (0.097 mL, 1.2 mmol). Yield: 0.214 g, 70%. M.p:
1
3
1
07ꢀ110 °C. H NMR (200 MHz, CDCl
3
, 25 °C): δ = 7.40 (d, JH,H = 8.5 Hz, 2H,
3
3
H13), 7.28 (d, JH,H= 8.4 Hz, 2H, H12), 6.67 (s, 1H, H4), 4.39 (q, JH,H= 7.1 Hz, 2H,
3
13
H7), 1.50 (s, 9H, tBu), 1.39 (t, JH,H= 7.1 Hz, 3H, H8). C NMR (100 MHz, CDCl
3
, 25
°C): δ = 162.5 (C=O), 142.6 (C5), 140.6 (C3), 135.0 (C14), 131.7 (C12), 131.5 (C11),

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128.2 (C13), 112.2 (C4), 62.7 (C9), 60.6 (C7), 30.9 (tBu), 14.3 (C8). HRMS (ESIꢀTOF)
+
m/z: [M + H] calcd. for C16
H
20ClN
2
O
2
307.1213; found: 307.1198
5-(4-Bromophenyl)-1-(1,1-dimethylethyl)-1
H-pyrazole-3-carboxylate ethyl (4f):
was prepared from enone 1f (0.313 g, 1 mmol), tertꢀbutylhydrazine hydrochloride 2
(0.148 g, 1.2 mmol) and pyridine (0.097 mL, 1.2 mmol). Yield: 0.253 g, 72%. M.p:
1
3
1
18ꢀ122 °C. H NMR (200 MHz, CDCl
3
, 25 °C): δ = 7.57 (d, JH,H = 8.3, 2H, H13),
3
3
7
.22 (d, JH,H= 8.5 Hz, 2H, H12), 6.66 (s, 1H, H4), 4.39 (q, JH,H= 7.1 Hz, 2H,H7), 1.50
3
13
(
(
(
s, 9H, tBu), 1.39 (t, J = 7.1 Hz, 3H, H8). C NMR (100 MHz, CDCl ): δ = 162.5
H,H 3
C=O), 142.6 (C5), 140.6 (C3), 131.9 (C12), 131.1 (C13), 123.2 (C14), 112.1 (C4), 62.8
+
C9), 60.6 (C7), 30.9 (tBu), 14.3 (C8). HRMS (ESIꢀTOF) m/z: [M + H] calcd. for
C H BrN O 351.0708; found: 351.0710
16
20
2
2
Synthesis of the 1- (1,1-dimethylethyl)-1H-pyrazole-5-carboxylic acid 5a-f:
Pyrazoles (3a–f, 1 mmol), NaOH (1.8 mmol, 0.072g) and EtOH (10 mL) were placed in
a roundꢀbottomed flask. The mixture was magnetically stirred at 78 °C for 4 h. At the
2
end of the reaction time, a solution of HCl/H O (1:10, v.v 25 mL) was added. The EtOH
solvent in the mixture was evaporated under reduced pressure. Chloroform (10 mL) was
then added and the reaction mixture was washed with water (3×10 mL). The combined
2 4
organic phases were dried with anhydrous Na SO and the solvent was evaporated
under reduced pressure. The products 5a-f were obtained in pure form without further
purification.
1-(1,1-dimethylethyl)-3-methyl-1
H-pyrazol-5-carboxylic acid (5a): was prepared
from pyrazole 3a (0.210 g, 1 mmol) and NaOH (0.072g, 1.8 mmol). This compound is
49
reported in literature, however the spectroscopic data are incomplete. White solid,
1
yield 92%. M.p: 147ꢀ148 °C. H NMR (200 MHz, CDCl
3
, 25°C): δ = 10.60 (sl, 1H,
13
OH), 6.85 (s, 1H, H4), 2.28 (s, 3H, CH
3
), 1,73 (s, 9H, tBu). C NMR (100 MHz,
CDCl , 25°C): δ = 164.5 (C=O), 144.8 (C3), 132.3 (C5), 115.1 (C4), 62.3 (C8), 29.6 (
3
+
+
3 9 14 2 2
tBu), 13.1 (CH ). MS (ESI): [(M+H) 183], [(M+Na) 205]. C H N O (182.1055).
1-(1,1-Dimethylethyl)-3-propyl-1
H-pyrazole-5-carboxylic acid (5b): was prepared
from pyrazole 3b (0.238 g, 1 mmol) and NaOH (0.072 g, 1.8 mmol).This compound is
49
reported in literature, however the spectroscopic data are incomplete. White solid,

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1
3
yield 89%. M.p: 68ꢀ69 °C. H NMR (200 MHz, CDCl , 25°C): δ = 6.86. (s, 1H, H4),
3
2
.60 (m, 2H, CH
2
), 1.72 (s, 9H, tBu), 1.67 (m, 2H, CH
). C NMR (100 MHz, CDCl , 25°C): δ = 164.7 (C=O), 132.0 (C5), 149.5 (C3),
), 29.6 (tBu), 22.72 (CH ), 13.9 (CH ). MS (ESI):
(210.1368).
2
), 0.97 (t, JH,H= 7.36 Hz, 3H,
13
CH
3
3
114.2 (C4), 62.4 (C8), 29.9 (CH
2
2
3
+
+
[
(M+H) 211], [(M+Na) 233]. C11
H
18
N
2
O
2
1-(1,1-Dimethylethyl)-3-phenyl-1
H-pyrazol-5-carboxylic acid (5c): was prepared
from pyrazole 3c (0.272 g, 1 mmol) and NaOH (0.072 g, 1.8 mmol). This compound is
49
reported in literature, however the spectroscopic data are incomplete. White solid,
1
yield: 94%. M.p: 180ꢀ183 °C. H NMR (200 MHz, CDCl , 25°C): δ = 8.88 (sl, 1H,
3
3
OH), 7.83 (d, JH,H = 6.85 Hz, H11), 7.40 (s, 1H, H4), 7.31ꢀ7.45 (m, 3H, HAr), 1.80 (s,
13
9
H, tBu). C NMR (100 MHz, CDCl
3
, 25°C): δ = 166.6 (C=O), 144.7 (C3), 139.5 (C5),
+
1
27.9ꢀ132.7 (CAr), 112.5 (C4), 63.0 (C8), 30.9 (tꢀBu). MS (ESI): [(M+H) 245],
+
[
(M+Na) 267]. C14
H
16
N
2
O
2
(244.1212).
3-(4-Fluorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazole-5-carboxylic acid (5d): was
prepared from pyrazole 3d (0.290 g, 1 mmol) and NaOH (0.072 g, 1.8 mmol). White
1
solid, yield 95%. M.p.: 200ꢀ202 °C. H NMR (200 MHz, CDCl
3
, 25°C): δ = 7.78 (dd,
4
3
J , J = 5.39 Hz, 8.87 Hz, 2H, HAr), 7.30 (s, 1H, H4), 7.08 (t, 2H, HAr), 1.79 (s,
H,F
H,H
13
1
9
3
H, tBu). C NMR (100 MHz, CDCl , 25°C): δ = 163.4 (C=O), 162.7 (d, JC,F,=
2
3
2
46.67, C13), 146.6 (C3), 132.7 (C5), 129.1 (d, JC,F, = 3.2 Hz, CAr), 127.2 (d, J= 8.07
4
Hz, CAr), 115.6 (d, J= 21.78 Hz, CAr), 112.3 (C4), 63.3 (C8), 29.6 (tꢀBu). HRMS
+
(
ESIꢀTOF) m/z: [M + H] calcd. For C14
H16FN
2
O
2
263.1196; Found: 263.1188
3-(4-Chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazole-5-carboxylic acid (5e): was
prepared from pyrazole 3e (0.306 g, 1 mmol) and NaOH (0.072g, 1.8 mmol). White
1
solid, yield 97%. M.p.: 203ꢀ204 °C. H NMR (200 MHz, CDCl
3
, 25°C):δ = 7.76 (d,
3
13
J
H,H = 8.6 Hz, 2H, H11), 7.35ꢀ7.40 (m, 3H, Hꢀ4 and H12), 1.80 (s, 9H, tꢀBu). C NMR
3
(100 MHz, CDCl , 25°C): δ = 163.3 (C=O), 146.3 (C3), 133.6 (C5), 132.7 (C13), 131.3
(C10), 128.8 (C12), 126.7 (C11), 112.5 (C4), 63.4 (C8), 29.5 (tBu). HRMS (ESIꢀTOF)
+
m/z: [M + H] calcd. for C14
H
16ClN
2
O
2
279.0900; found: 279.0891
3-(4-Bromofenil)-1-(1,1-dimethylethyl)-1
H-pyrazole-5-carboxylic acid (5f): was
prepared from pyrazole 3f (0.351 g, 1 mmol) and NaOH (0.072 g, 1.8 mmol). White

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1
solid, yield: 98% M.p.: 211ꢀ213 °C. H NMR (200 MHz, CDCl
3
, 25°C):δ = 7.70 (d,
3
3
J
H,H= 8.10 Hz, 2H, H11), 7.53 (d, JH,H= 8.06 Hz, 2H, H12), 7.36 (s, 1H, H4), 1.80 (s,
13
9
3
H, tBu). C NMR (100 MHz, CDCl , 25°C): δ = 163.8 (C=O), 146.4 (C3), 132.8
(C5), 131.8 (CAr), 127.1 (C11), 121.8 (C13), 112.6 (C4), 63.5 (C8), 29.5 (CtBu).
+
HRMS (ESIꢀTOF) m/z: [M + H] calcd. for C14
H
16BrN
2
O
2
323.0395 found: 323.0411.
Synthesis of the 1- (1,1-dimethylethyl)-1H-pyrazole-3-carboxylic acid 6a-f:
Pyrazoles (4a–f, 1 mmol), NaOH (1.8 mmol, 0.072 g) and EtOH (10 mL) were placed
in a roundꢀbottomed flask. The mixture was magnetically stirred at 78 °C for 3h. At the
2
end of the reaction time, a solution of HCl/H O (1:10, v.v 25 mL) was added. The EtOH
solvent in the mixture was evaporated under reduced pressure. Chloroform (10 mL) was
then added and the reaction mixture was washed with water (3×10 mL). The combined
2 4
organic phases were dried with anhydrous Na SO and the solvent was evaporated
under reduced pressure. The products 6a-f were obtained in pure form without further
purification.
1-(1,1-dimethylethyl)-5-methyl-1
H-pyrazol-3-carboxylic acid (6a) was prepared
from pyrazole 4a (0.210 g, 1 mmol) and NaOH (0.072 g, 1.8 mmol).This compound is
46
reported in literature, however the spectroscopic data are incomplete. White solid.
1
Yield: 0.136 g, 75%. M.p.: 147ꢀ148 °C. H NMR (200 MHz, CDCl
3
, 25°C):δ = 9.30 (sl,
1
3
1
H, H7), 6.63 (s, 1H, H4), 2.49 (s, 3H, H10), 1.68 (s, 9H, H9). C NMR (100 MHz,
CDCl , 25°C): δ = 167.2 (C=O), 139.8 (C5), 139.1 (C3), 111.52 (C4), 61.3 (C8), 29.62
3
+
+
(
tBu), 14.5 (CH ). MS (ESI): [(M+H) 183], [(M+Na) 205]. C H N O (182.1055).
3 9 14 2 2
1-(1,1-Dimethylethyl)-5-propyl-1H-pyrazole-3-carboxylic acid (6b) was prepared
from pyrazole 4b (0.238 g, 1 mmol) and NaOH (0.072g, 1.8 mmol). This compound is
50
reported in literature, however the spectroscopic data are incomplete. White solid.
1
Yield: 0.1911 g, 91%. M.p.: 154ꢀ157 °C. H NMR (200 MHz, CDCl
3
, 25°C):δ = 9.13
(sl, 1H, OH), 6.68 (s, 1H, H4), 2.79 (m, 2H, H10), 1.74 (m, 2H, H11), 1.67 (s, 9H, tBu),
3
13
1
.04 (t, JH,H= 7.35 Hz, 3H, H12). C NMR (100 MHz, CDCl
3
, 25°C): δ = 165.2
), 30.1 (tBu), 22.4
CH ), 13.8 (CH ). MS (ESI): [(M+H) 211], [(M+Na) 233]. C H N O (210.1368).
(
C=O), 145.5 (C5), 139.5 (C3), 109.2 (C4), 61.5 (C8), 30.2 (CH
2
+
+
(
2
3
11 18
2
2

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1-(1,1-Dimethylethyl)-5-phenyl-1
H-pyrazol-3-carboxylic acid (6c) was prepared
from pyrazole 4c (0.272 g, 1 mmol) and NaOH (0.072 g, 1.8 mmol). This compound is
51
reported in literature, however the spectroscopic data are incomplete. White solid.
1
Yield: 0.2196 g, 90%. M.p.: 166ꢀ168 °C. H NMR (200 MHz, CDCl
3
, 25°C):δ = 7.88
1
3
(
sl, 1H, H10), 7.35ꢀ7.43 (m, 5H, HAr), 6.75 (s, 1H, H4), 1.5 (s, 9H, tBu). C NMR
(
100 MHz, CDCl , 25°C): δ = 166.6 (C=O), 144.7 (C5), 139.5 (C3), 127.9ꢀ132.7 (CAr),
3
+
+
1
12.5 (C4), 63.0 (C8), 30.9 (CtBu). MS (ESI): [(M+H) 245], [(M+Na) 267].
14 16 2 2
C H N O
(244.1212).
5-(4-Fluorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazole-3-carboxylic acid (6d) was
prepared from pyrazole 4d (0.290 g, 1 mmol) and NaOH (0.072 g, 1.8 mmol).White
1
solid, yield: 0.215 g, 82%. M.p.: 208ꢀ210 °C. H NMR (200 MHz, CDCl , 25°C):δ =
3
7.80 (sl, 1H, OH), 7.34 (m, 2H, H12), 7.12 (t, 2H, H11), 6.76 (s, 1H, H4), 1.51 (s, 9H,
13
1
tBu). C NMR (100 MHz, CDCl
3
, 25°C): δ = 166.7 (C=O), 163.0 (d, JC,F= 249.4 Hz,
3
4
C13), 143.5 (C5), 139.6 (C3), 132.3 (d, J = 8.2 Hz, C11), 128.7 (d, J = 3.62 Hz,
C,F
C,F
2
C10), 115.1 (d, JC,F = 21.78 Hz, C12), 112.8 (C4), 63.0 (C8), 30.9 (CtBu). HRMS (ESIꢀ
+
TOF) m/z: [M + H] calcd. for C14
H16FN
2
O
2
263.1196, found: 263.1188.
5-(4-Chlorophenyl)-1-(1,1-dimethylethyl)-1H-pyrazole-3-carboxylic acid (6e) was
prepared from pyrazole 4e (0.306 g, 1 mmol) and NaOH (0.072 g, 1.8 mmol). White
1
solid, yield: 0.250 g, 90%. M.p.: 194ꢀ197 °C. H NMR (200 MHz, CDCl
3
, 25°C):δ =
3
3
8
.62 (sl, 1H, OH), 7.41 (d, J = 8.55 Hz, 2H, H12), 7.30 (d, 2H, JH,H= 8.43 Hz, H11),
H,H
13
6
3
.75 (s, 1H, H4), 1.51 (s, 9H, tBu). C NMR (100 MHz, CDCl , 25°C): δ = 166.6
(C=O), 143.3 (C5), 139.6 (C3), 135.2 (C13), 131.7 (C11), 131.2 (C10), 128.3 (C12),
+
1
12.7 (C4), 63.1 (C8), 30.9 (CtBu). HRMS (ESIꢀTOF) m/z: [M + H] calcd. for
14 2 2
C H16ClN O 279.0900 found: 279.0891.
5-(4-Bromofenil)-1-(1,1-dimethylethyl)-1H-pyrazole-3-carboxylic acid (6f) was
prepared from pyrazole 4f (0.351 g, 1 mmol) and NaOH (0.072 g, 1.8 mmol). White
1
solid, yield: 0.297 g, 92%. M.p.: 192ꢀ210 °C. H NMR (200 MHz, CDCl
3
, 25°C):δ =
3
3
7
1
1
.57 (d, JH,H= 8.5 Hz, 2H, H12), 7.23 (d, JH,H = 8.56 Hz, 2H, H11), 6.75 (s, 1H, H4),
13
.51 (s, 9H, tBu). C NMR (100 MHz, CDCl
3
, 25°C): δ = 166.0 (C=O), 143.4 (C5),
39.8 (C3), 132.0 (C11), 131.7 (C10), 131.3 (C12), 123.4 (C13), 112.6 (C4), 63.2 (C8),

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+
3
0.0 (CtBu). HRMS (ESIꢀTOF) m/z: [M + H] calcd. for C14
H
2
16BrN O
2
323.0395,
found: 323.0406.
Synthesis of the 1,2-bis (aminocarbonyl- (1'-(1',1'-dimethylethyl)-1
yl))-ethane 8a-f and Synthesis of the 1,2-bis (aminocarbonyl- (1'-(1',1'-
dimethylethyl)-1 -pyrazol-3'-yl))-ethane 9a-f: The mixture of pyrazoles 5a-f or 6a-f
2 mmol), 1,2ꢀdiaminoethane 7 (0.06 g, 1 mmol), triphenylphosphite (0.578 mL, 2.2
H-pyrazol-5'-
H
(
mmol), and pyridine (5 mL) were placed in a roundꢀbottomed flask. The mixture was
magnetically stirred at 115 °C for 6 h. At the end of the reaction time, the mixture was
evaporated under reduced pressure. An oil product was obtained for compounds 8a-b
and 9a-b. These compounds were purified by column chromatography with
chloroform/methanol (97/3 v.v). A white precipitate was obtained from the solution for
the products 8c-f and 9c-f. This solid was then filtered and washed with ethanol.
1,2-Bis(aminocarbonyl-(1'-(1',1'-dimethylethyl)-3'-methyl-1H-pyrazol-5'-yl))-
ethane (8a) was prepared from pyrazole 5a (0.364 g, 2 mmol), 1,2ꢀdiaminoethane 7
(0.06 g, 1 mmol), triphenylphosphite (0.578 mL, 2.2 mmol) and pyridine (5 mL) NaOH
1
(
1.8 mmol, 0.072g).White solid. Yield: 0.349 g, 90%. M.p.: 214ꢀ218 °C. H NMR (200
3
MHz, CDCl , 25°C):δ = 6.86 (sl, 2H, NH), 6.21 (s, 2H, He), 3.58 (sl, 4H, CH
2
), 2.21 (s,
1
3
6
1
H, CH ), 1.63 (s, 18H, tBu). C NMR (100 MHz, CDCl , 25°C): δ = 163.7 (C=O),
3
3
2 3
44.8 (Cf), 29.8 (CtBu), 136.8 (Cd), 108.3 (Ce), 61.4 (Ci), 40.2 (CH ), 13.18 (CH ).
+
HRMS (ESIꢀTOF) m/z: [M + H] calcd. for C20
H
33
N
6
O
2
389.2665, found: 389.2650.
1,2-Bis(aminocarbonyl-(1'-(1',1'-dimethylethyl)-3'-propyl-1
H-pyrazol-5'-yl))-
ethane (8b) was prepared from pyrazole 5b (0.420 g, 2 mmol), 1,2ꢀdiaminoethane
7
(0.06 g, 1 mmol), triphenylphosphite (0.578 mL, 2.2 mmol) and pyridine (5 mL)
1
NaOH (1.8 mmol, 0.072g). White solid, Yield: 0.342 g, 77 %. M.p.: 178ꢀ179 °C. H
NMR (200 MHz, CDCl
3
, 25°C):δ = 7.36 (sl, 2H, NH), 6.63 (s, 2H, He), 3.63 (sl, 4H,
3
Ha), 2.76 (m, 4H, Ck), 1.72 (m, 4H, Hl), 1.64 (s, 18H, tBu), 1.03 (t, JH,H = 7.34, 3H,
13
3 3
CH ). C NMR (100 MHz, CDCl , 25°C): δ = 163.2 (C=O), 145.0 (Cf), 142.7 (Cd),
3
106.8 (Ce), 60.9 (Ci), 39.2 (Ca), 30.2 (Ck), 30.1 (CtBu), 22.3 (Cl), 13.9 (CH ). HRMS
+
(
ESIꢀTOF) m/z: [M + H] calcd. for C H N O 445.3291; found 445.3308.
2
4
41
6
2

New Journal of Chemistry
Page 28 of 39
View Article Online
DOI: 10.1039/C7NJ02443F
1,2-Bis(aminocarbonyl-(3'-phenyl)-(1'-(1',1'-dimethylethyl))-1H-pyrazol-5'-yl))-
ethane (8c) was prepared from pyrazole 5c (0.488 g, 2 mmol), 1,2ꢀdiaminoethane 7
(0.06 g, 1 mmol), triphenylphosphite (0.578 mL, 2.2 mmol) and pyridine (5 mL) NaOH
1
(
1.8 mmol, 0.072g).White solid. Yield: 0.373 g, 73 %. M.p.: 207ꢀ210 °C. H NMR (200
3
MHz, CDCl
3
, 25°C):δ = 7.75 (d, JH,H= 6.8, 4H, HAr), 7.23ꢀ7.40 (m, 6H, HAr), 6.95
13
(
sl, 2H, NH), 6.75 (s, 2H, He), 3.60 (m, 4H, Ha), 1.70 (s, 18H, HtBu). C NMR (100
3
MHz, CDCl , 25°C): δ = 163.5 (C=O), 147.5 (Cf), 137.4 (Cd), 132.9 (Ck), 128.6 (Cm),
127.7 (Cn), 125.4 (Cl), 105.8 (Ce), 62.2 (Ci), 40.2 (CH
2
), 29.7 (CtBu). ). HRMS (ESIꢀ
+
+
TOF) m/z: [M + H] calcd. for C H N O 513.2978; [M + Na] calcd. for
3
0
37
6
2
30 36 6 2
C H N O Na 535.2797; found 513.2978; 535.2783.
1,2-Bis(aminocarbonyl-(3'-(4'-fluorophenyl)-1'-(1',1'-dimethylethyl)-1
H-pyrazol-
5'-yl))- ethane (8d) was prepared from pyrazole 5d (0.524 g, 2 mmol), 1,2ꢀ
diaminoethane 7 (0.06 g, 1 mmol), triphenylphosphite (0.578 mL, 2.2 mmol) and
pyridine (5 mL) NaOH (1.8 mmol, 0.072g).White solid. Yield: 0.411 g, 75%. M.p.:
1
2
7
3
22ꢀ224 °C. H NMR (400 MHz, CDCl
3
: MeOD (9:1), 25°C):δ = 7.45 (sl, 2H, NH),
4
3
.30 (dd, JH,F, JH,H = 4.99 Hz, 8.41Hz, 4H, HAr), 7.09 (t, 4H, HAr), 6.67 (s, 2H, He),
1
3
.69 (m, 4H, Ha), 1.46 (s, 18H, Hj). C NMR (100 MHz, CDCl
3
: MeOD (9:1), 25°C): δ
1
4
=
163.7 (C=O), 162.5 (d, JC,F= 246.4 Hz, Cn), 146.9 (Cf), 137.8 (Cd), 129.3 (d, JC,F
=
3
2
3
.2 Hz, Ck), 127.0 ( d, JC,F = 8.02 Hz, Cl), 115.3 (d, JC,F= 21.7 Hz, Cm), 105.6 (Ce),
+
6
2.1 (Ci), 39.6 (Ca), 29.6 (CtBu). HRMS (ESIꢀTOF) m/z: [M + H] calcd. for
+
C
30
H
35
F
2
N
6
O
2
549.2790; [M + Na] calcd. for C30
H
34
F
2
N
6
O
2
Na found 549.2795;
571.2610.
1,2-Bis(aminocarbonyl-(3'-(4'-chlorophenyl)-1'-(1',1'-dimethylethyl)-1
H-pyrazol-
5'-yl))-ethane (8e) was prepared from pyrazole 5e (0.556 g, 2 mmol), 1,2ꢀ
diaminoethane 7 (0.06 g, 1 mmol), triphenylphosphite (0.578 mL, 2.2 mmol) and
pyridine (5 mL) NaOH (1.8 mmol, 0.072 g).White solid. Yield: 0.412 g, 71%. M.p.:
1
3
2
17ꢀ221 °C. H NMR (200 MHz, CDCl , 25°C):δ = 7.67 (d, J = 8.6 Hz, 4H, Hꢀl),
3 H,H
3
7
.31 (d, JH,H= 8.6 Hz, 4H, Hm), 6.75 (sl, 2H, Hꢀb), 6.73 (s, 2H, He), 3.66 (sl, 4H,
1
3
2 3
CH ), 1.71 (s, 18H, tBu). C NMR (100 MHz, CDCl , 25°C): δ = 163.4 (C=O), 146.7
(Cf), 137.7 (Cd), 133.5 (Cn), 131.7 (Ck), 128.8 (Cm), 126.7 (Cl), 105.8 (Ce), 62.5 (Ci),
+
40.6 (CH
2 2 6 2
), 29.9 (CtBu). HRMS (ESIꢀTOF) m/z: [M + H] calcd. for C30H35Cl N O
+
5
81.2199; [M + Na] calcd. for C30
2 6 2
H34Cl N O Na 603.2018.Found 581.2186; 603.2007.

Page 29 of 39
New Journal of Chemistry
View Article Online
DOI: 10.1039/C7NJ02443F
1,2-Bis(aminocarbonyl-(3'-(4'-bromophenyl)-1'-(1',1'-dimethylethyl)-1H-pyrazol-
5'-yl))-ethane (8f) was prepared from pyrazole 5f (0.646 g, 2 mmol), 1,2ꢀ
diaminoethane 7 (0.06 g, 1 mmol), triphenylphosphite (0.578 mL, 2.2 mmol) and
pyridine (5 mL) NaOH (1.8 mmol, 0.072g).White solid. Yield: 0.469 g, 70%. M.p.:
1
3
2
20ꢀ223 °C. H NMR (200 MHz, CDCl , 25°C):δ = 7.61 (d, J = 8.4 Hz, 4H, Hl),
3 H,H
3
7
.47 (d, JH,H = 8.2 Hz, 4H, Hm), 6.91 (sl, 2H, HN), 6.75 (s, 2H, He), 3.66 (sl, 4H,
1
3
2 3
CH ), 1.70 (s, 18H, tBu). C NMR (100 MHz, CDCl , 25°C): δ = 163.4 (C=O), 146.7
(Cf), 137.7 (Cd), 132.1 (Ck), 131.7 (Cm), 127.0 (Cl), 121.6 (Cn), 105.8 (Ce), 62.5 (Ci),
+
4
6
6
2 2 6 2
0.6 (CH ), 29.8 (CtBu). HRMS (ESIꢀTOF) m/z: [M + H] calcd. for C30H35Br N O
+
71.1168; [M + Na] calcd. for C30
93.0949.
2 6 2
H34Br N O Na 693.0987. Found: 671.1166;
1,2-Bis(aminocarbonyl-(1'-(1',1'-dimethylethyl)-5'-methyl-1H-pyrazol-3'-yl))-
ethane (9a) was prepared from pyrazole 6a (0.364 g, 2 mmol), 1,2ꢀdiaminoethane 7
(0.06 g, 1 mmol), triphenylphosphite (0.578 mL, 2.2 mmol) and pyridine (5 mL) NaOH
1
(
1.8 mmol, 0.072g).White solid. Yield: 0.326 g, 84%. M.p.: 182ꢀ184 °C. H NMR (200
MHz, CDCl
s, 6H, CH ), 1.63 (s, 18H, tBu). C NMR (100 MHz, CDCl
42.8 (Cf), 139.5 (Cd), 108.6 (Ce), 60.6 (Ci), 39.1 (CH
3
, 25°C):δ = 7.31 (sl, 2H, NH), 6.53 (s, 2H, He), 3.62 (m, 4H, CH
2
), 2.45
1
3
(
3
3
, 25°C): δ = 163.1 (C=O),
1
2
3
), 29.8 (CtBu), 14.5 (CH ).
+
+
HRMS (ESIꢀTOF) m/z: [M + H] calcd. for C20
H
33
N
6
O
2
389.2665; [M + Na] calcd. for
20 32 6 2
C H N O
Na411.2484 found: 389.2650; 411.2480.
1,2-Bis(aminocarbonyl-(1'-(1',1'-dimethylethyl)-5'-propyl-1
H-pyrazol-3'-yl))-
ethane (9b) was prepared from pyrazole 6b (0.420 g, 2 mmol), 1,2ꢀdiaminoethane 7
(0.06 g, 1 mmol), triphenylphosphite (0.578 mL, 2.2 mmol) and pyridine (5 mL) NaOH
1
(
1.8 mmol, 0.072g).White solid. Yield: 0.4218 g, 95%. M.p.: 114ꢀ115 °C. H NMR (200
MHz, CDCl
3
, 25°C):δ = 7.36 (sl, 2H, NH), 6.63 (s, 2H, He), 3.63 (sl, 4H, CH
2
), 2.76
3
13
(
m, 4H, Hk), 1.74 (m, 4H, Hl), 1.64 (s, 18H, Hj), 1.03 (t, J = 7.34 Hz, 6H, Hm).
C
H,H
NMR (100 MHz, CDCl
3
, 25°C): δ = 163.2 (C=O), 145.0 (Cf), 142.7 (Cd), 106.8 (Ce),
). HRMS (ESIꢀTOF)
m/z: [M + H] calcd. for C H N O 445.3291; [M + Na] calcd. for C H N O Na
60.9 (Ci), 39.2 (Ca), 30.2 (Ck), 30.14 (CtBu), 22.3 (Cl), 13.9 (CH
3
+
+
2
4
41
6
2
24 40
6
2
467.3110, found: 445.3286; 467.3117.