Naphthalenophane formaldehyde acetals as candidate structures for the generation of dynamic libraries via transacetalation processes

Article abstract of DOI:10.1016/j.tet.2013.01.080

Lower cyclic oligomers C₂-C₅ of a family of naphthalenophane formaldehyde acetals C_n have been isolated and characterized, the dimer being obtained in two atropisomeric forms, syn-C ₂ and anti-C₂, as confirmed by X-ray analysis. The investigated cyclophanes showed interesting recognition properties towards electron-poor guests (K≈10⁵ M^-1 for association of the guanidinium ion with C₃ in chloroform). A library of macrocycles was generated by acid catalyzed transacetalation of C_n in chloroform, but the dynamic nature of the system was spoiled by the occurrence of irreversible reaction pathways promoted by the relatively easy formation of extended benzyl-like carbocations I.

Full text of DOI:10.1016/j.tet.2013.01.080

Tetrahedron 69 (2013) 2767e2774
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Naphthalenophane formaldehyde acetals as candidate structures for
the generation of dynamic libraries via transacetalation processes
,
a
,
b
Albert Ruggi a, Roberta Cacciapaglia a , Stefano Di Stefano , Enrico Bodo ,
*
*
Franco Ugozzoli c
a
ꢀ
Dipartimento di Chimica and IMC e CNR Sezione Meccanismi di Reazione, Universita La Sapienza, 00185 Roma, Italy
Dipartimento di Chimica, Universita La Sapienza, 00185 Roma, Italy
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Universita di Parma, V. le G. P. Usberti 17/a, 43124 Parma, Italy
b
ꢀ
c
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 October 2012
Received in revised form 10 January 2013
Accepted 28 January 2013
Available online 8 February 2013
Lower cyclic oligomers C2eC5 of a family of naphthalenophane formaldehyde acetals Cn have been iso-
lated and characterized, the dimer being obtained in two atropisomeric forms, syn-C2 and anti-C2, as
confirmed by X-ray analysis. The investigated cyclophanes showed interesting recognition properties
towards electron-poor guests (Kz105 Mꢀ1 for association of the guanidinium ion with C3 in chloroform).
A library of macrocycles was generated by acid catalyzed transacetalation of Cn in chloroform, but the
dynamic nature of the system was spoiled by the occurrence of irreversible reaction pathways promoted
by the relatively easy formation of extended benzyl-like carbocations I.
Keywords:
Naphthalenophane
Atropisomer
Ó 2013 Elsevier Ltd. All rights reserved.
Transacetalation
Guanidinium
1. Introduction
a silver ion acting as a template, we achieved3e5 the extensive
amplification of one of the members of the investigated DL of
Dynamic Covalent Chemistry (DCC)1e5 is the chemistry of fami-
lies of compounds interchanging via the reversible breakage and
formation of covalent bonds. The interest in DCC and in its ‘proof
reading and error checking’ built-in resources has steadily increased
in the last decade, the key to the success of this research field mainly
resting on the prospect of tuning the composition of the equilibrium
mixture in favour of the best ligand for a target guest. The latter is
added to the reaction mixture as a template, and upon equilibration
of a well-behaved reaction system, amplification of the most effi-
cient host is achieved, among all the feasible structures attainable
with the building blocks and the reversible processes at hand. This
approach nicely fits, in a sense, to the currently pursued target of
‘atom economy’ in the frame of sustainable chemistry.
compounds, the cyclic dimer, that on account of its high strain
energy, was a very minor component of the equilibrium mixture in
the absence of the template. Most importantly, beyond these re-
sults, the investigation of these well-behaved transacetalation re-
action systems allowed easy evaluation of the effective molarity
(EM)6 of the interconverting cyclophanes from concentration
profiles.3e5,7e9 When different monomeric building blocks are in-
volved in the cyclooligomerization process, this approach is no-
ticeably the only possible method of access to the experimental
evaluation of EM.7,8 These well-behaved transacetalation systems
have indeed provided the experimental basis of a theory developed
In our previous investigations we showed3 that the acid cata-
lyzed transacetalation of cyclophane formaldehyde acetals in
chloroform solution is a convenient entry into DCC. Long-lived and
well-behaved dynamic libraries (DLs) were obtained when mono-
meric units based on the p-phenylene,3 m-phenylene4 and diphe-
nylmethane5 spacers were involved, (Scheme 1). In the presence of
* Corresponding authors. Fax: þ39 06 490421; e-mail addresses: rob-
erta.cacciapaglia@uniroma1.it (R. Cacciapaglia), stefano.distefano@uniroma1.it
(S. Di Stefano).
Scheme 1. Dynamic libraries of cyclophane formaldehyde acetals (chloroform, 25 ꢁC,
TfOH catalyst).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.080

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A. Ruggi et al. / Tetrahedron 69 (2013) 2767e2774
for the quantitative analysis of reversible cyclooligomerization
processes involving the reaction of different monomeric units.7,8
We have now developed a family of naphthalenophanes Cn with
the aim of testing novel spacer units, useful in attaining a higher
degree of diversity in cross-equilibration experiments, and at im-
proving the binding ability of macrocyclic formaldehyde acetals
interconversion of these two stereoisomers by rotation of the
naphthalenic moiety around the CAreCH2 bonds. In the ‘parallel’
atropisomer syn-C2 (Fig. 1a), both the benzyl (Ha and Hb) and the
OCH2O protons (Hc and Hd) are diastereotopic pairs. An AX sys-
tem with a 13 Hz geminal coupling constant for the benzyl
ArCH2O protons, and an AB system with a 7 Hz geminal coupling
constant for the OCH2O protons, are accordingly found in the 1H
NMR spectrum. A different pattern is found on the other hand in
the spectrum of anti-C2 (Fig. 1b). Both isomers syn-C2 and anti-C2
have a C2 symmetry axis perpendicular to the aromatic moieties
and passing through the middle of the C(9)eC(10) bond of the
two naphthalene rings. In anti-C2 there is an additional C2 sym-
heretofore investigated. In cyclic formals Cn, the wider
p-walls of
the naphthalene spacer moieties should hopefully improve the
binding ability towards cationic or electron-poor guests, thus
widening the prospects of template-driven amplification of selec-
tive ligands in the acid catalyzed transacetalation of these
compounds.
metry axis passing0 through the two OCH2O carbon atoms. The
0
OCH2O protons (Hc and Hd ) thus turn out to be equivalent and
a singlet is accordingly found in the 1H NMR spectrum. An AB
0
0
system is attributed to the benzyl protons (Ha and Hb ), that are
diastereotopic also in this case. Structure assignment of the two
atropisomers syn-C2 and anti-C2 was confirmed by single crystal
X-ray diffraction (see below).
2. Results and discussion
Pure samples of the first members (C2eC5) of the series of
naphthalenophane oligomers Cn were obtained by reaction of
1,5-bis(hydroxymethyl)-3,7-dimethylnaphthalene (1) with bro-
mochloromethane in the presence of NaH (Scheme 2). The re-
action was carried out in boiling THF, and Ziegler’s high dilution
conditions were adopted in order to favour intramolecular over
intermolecular processes. As shown by 1H NMR spectroscopy of
the crude product (see Fig. 1S in ESI), a complex mixture was
obtained. The presence of cyclic oligomers, from the dimer up to
at least the hexamer, was revealed by ESI-TOF-MS, and confirmed
by comparison with the 1H NMR spectrum of pure samples of the
macrocycles syn-C2, anti-C2 and C3eC5, isolated by combined
column chromatography and TLC separations. The presence of
the two methyl substituents in the naphthalene unit simplifies
the pattern of the aromatic protons in the 1H NMR spectrum and
introduces a diagnostic singlet in the high field region. Yields of
cyclic oligomers C2eC5, as calculated from integration of the
corresponding signals in the 1H NMR spectrum of the reaction
mixture (see Fig. 1S in ESI), were as follows: syn-C2, 12%; anti-C2,
5%; C3, 22%; C4, 17%; C5, 11%. As expected, no trace of the cyclic
monomer was found in the reaction mixture, since the five atom
COCOC chain is too short to span the 1,5-positions of the naph-
thalene moiety.
Two atropisomeric10e12 forms of the dimer, syn-C2 and anti-
C2, differing for the mutual arrangement, ‘parallel’ or ‘antiparal-
lel’, respectively, of the two naphthalene moieties, were isolated
and characterized by HRMS ESI-TOF and NMR spectroscopy. As
easily predictable on the basis of the narrow dimension of the
cavity of this cyclophane dimer, steric constrains prevent
1
Fig. 1. H NMR spectrum (OCH2O and ArCH2O protons; CDCl3, 25 ꢁC) of syn-C2 (a) and
anti-C2 (b).
Scheme 2. Naphthalenophane oligomers Cn by reaction of 1 with bromochloromethane in the presence of NaH.

A. Ruggi et al. / Tetrahedron 69 (2013) 2767e2774
2769
The wider dimension of the naphthalenophane cavity of the
higher cyclic oligomers C3eC5 allows rotation of the aromatic
moieties around the CAreCH2 bonds. Interconversion of conformers
is also fast on the 1H NMR time-scale and singlet signals for the
OCH2O and ArCH2O protons are accordingly found in the spectrum.
Fig. 3. Perspective view of the anti-C2 isomer. Only the most significant orientations of
the disordered atoms O1r and O2r have been represented.
2.1. X-ray crystal structure of atropisomeric syn-C2 and anti-
C2
Clear-cut evidence of an effective recognition of Agþ by both the
atropisomeric dimers syn-C2 and anti-C2 has been obtained. In the
presence of excess solid silver bis(trifluorosulfonyl)imide (AgNTf2)
in CDCl3, significant chemical shift differences were observed in the
1H NMR spectrum of syn-C2, consistent with Agþ complexation and
fast exchange between free and associated species on the 1H NMR
time scale (see Fig. 2S in ESI). Largest effects were observed for the
ArH protons, with observed Dd (ppm) values of þ0.23 and þ0.30.
Analogous 1H NMR spectroscopic evidence of Agþ complexation by
anti-C2 was obtained. In the presence of excess solid AgNTf2, the
observed Dd (ppm) values in this case were þ0.45 for one of the two
ArH signals, ꢀ0.30 for the OCH2O protons, and þ0.20 for the CH3
protons, (Fig. 3S in ESI). Smaller effects were observed on the other
1H NMR signals of anti-C2 upon complexation. The observed in-
teraction of Agþ with syn-C2 and anti-C2 is in line with the affinity
Single crystals suitable for X-ray analysis of the two atropiso-
meric forms of the dimer, syn-C2 and anti-C2, were obtained by the
slow evaporation of solutions of the pure compounds in benzene
and in CH2Cl2/CH3CN (1:1, v/v), respectively. Both isomers crystal-
lize in the triclinic system, space group Pꢀ1.
The isomer syn-C2, see Fig. 2, is centrosymmetric and lies on
a crystallographic centre of symmetry and thus there is only one
molecule in the unit cell. The two aromatic rings with C2 and C3 in
common are almost coplanar, being tilted each other of 3.73ꢁ.
shown by the Agþ cation for ligands provided with
p-donor sys-
tems, such as cyclophanes or calixarenes,14 and in particular for the
analogous cyclodimer provided with p-xylylene spacers (Scheme 1,
p-phenylene spacer, n¼2).3,9 Spectral changes were also observed
upon addition of Agþ ions to chloroform solutions of the trimer C3
(observed Dd <0.05 ppm) or of the tetramer C4 (observed Dd
<0.15 ppm), but the effects were definitely smaller, particularly
with the former.
Encouraging evidence was obtained for a strong interaction
between the trimer C3 and the guanidinium ion. The lipophilic
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate ([BArF4]ꢀ)15 coun-
terion was chosen in order to allow solubilization of the guest in
chloroform.
Fig. 2. Perspective view of the centrosymmetric syn-C2 isomer. Only the half
symmetry-independent atoms have been labelled.
The structure of anti-C2, see Fig. 3, is disordered (O1r and O2r are
statistically distributed over two different orientations with occu-
pancy factors 0.7 and 0.3, respectively) and two isomers in the unit
cell are related each other by a centre of symmetry. The two aro-
matic rings with C5a and C6a in common are tilted each other of
3.48ꢁ, whereas the dihedral angle between the two rings with C5b
and C6b in common is 3.18ꢁ.
2.2. Binding tests and acid catalyzed transacetalation
experiments
The binding ability of naphthalenophane formals syn-C2, anti-C2,
C3 and C4 towards cationic guests has been tested (1H NMR spec-
troscopy) in chloroform, i.e., in the solvent chosen for the equili-
bration experiments via acid catalyzed transacetalation.13
The affinity of C3 for the guanidinium ion was tested by 1H NMR
titration. The value Kz105 Mꢀ1 (CDCl3, 25 ꢁC) estimated for 1:1
binding of the guanidinium ion to the cyclic trimer C3 (Fig. 5S in ESI)

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A. Ruggi et al. / Tetrahedron 69 (2013) 2767e2774
is approximately one order of magnitude higher than the value
estimated (Kz104 Mꢀ1, CDCl3, 25 ꢁC; Fig. 6S in ESI) for the binding
of the guanidinium ion to the trimer of the p-phenylene series
(Scheme 1, p-phenylene spacer, n¼3). Introduction of naphthalene
in place of the p-phenylene spacers, thus apparently improves the
1H NMR spectroscopic and HR-ESMS analyses of the reaction
mixtures carried out 2 h after addition of the acid catalyst to the
chloroform solution of Cn, showed that the family of the lower
cyclooligomeric naphthalenophanes was generated, and that the
composition was similar, independent of the nature of the cyclic
oligomer Cn used as feedstock (Fig. 4). But the picture of a well-
behaved family of cyclic oligomers interconverting via acid cata-
lyzed transacetalation (Scheme 3), was actually spoiled by the oc-
currence of secondary processes. From the very beginning of the
equilibration process, a signal at 9.73 ppm, corresponding to the
protons of formaldehyde, appeared in the 1H NMR spectrum of the
reaction mixture. From the area of this signal we could estimate
that after 20 h, the decomposition process responsible for free
formaldehyde production had already affected almost 30% of the
reacting material.
effectiveness of cationep interactions and/or induces a convenient
preorganization of oxygen donors that enhances hydrogen bonding
with the guanidinium ion.
No effect was observed on the 1H NMR spectrum of the dimers
syn-C2 and anti-C2 in CDCl3 upon addition of the guanidinium salt.
In the case of the tetramer C4, modest chemical shift differences
were observed, but definitely much smaller than those observed
with C3.
Experiments on the ring opening oligomerization of naph-
thalenophane formaldehyde acetals Cn through acid catalyzed
transacetalation (Scheme 3) were carried out in CDCl3, at 25 ꢁC,
starting from solutions of a single cyclic oligomer Cn (syn-C2, C3, or
C4) at 20 mM total monomer concentration (cmon), in the presence
of 0.5 mM triflic acid (TfOH).
We have previously shown16 that ringering equilibria of
cyclophane formaldehyde acetals occur via ring-fusion/ring-fission
processes involving acid-catalyzed inter- and intramolecular
transacetalation of the SN2 type. Furthermore, as shown by
Scheme 3. Ringering equilibria of naphthalenophane formaldehyde acetals Cn through acid catalyzed transacetalation.
Fig. 4. Acid catalyzed transacetalation experiments carried out at 20 mM cmon on (a) 10 mM syn-C2, (b) 6.67 mM C3, (c) 5 mM C4 solutions, (CDCl3, 25 C, 0.5 mM TfOH catalyst added
from a 20 mM mother solution in CD3NO2). 1H NMR spectra of the reaction mixtures taken after 2 h from TfOH addition, (CHCl3 marked with an asterisk).

A. Ruggi et al. / Tetrahedron 69 (2013) 2767e2774
2771
previous studies,17 a crucial prerequisite for a dynamic library of
cyclophane formaldehyde acetals to be long-lived, is the absence of
structural features that stabilize a benzyl carbocation and, conse-
quently, make way for SN1-type cleavage of the bond between
a benzyl carbon and a protonated oxygen (Scheme 4, (a)). Alter-
native reaction pathways for the subsequent transformation of
fragmentation products (Scheme 4, (b) and (c)) lead to the libera-
tion of formaldehyde and the concurrent irreversible formation of
AreCH2OCH2eAr ether bridges.
behaved, long-lived DLs of reversibly interchanging oligomeric
cyclophane formals. The durability of the DL is also in this case
reasonably spoiled by the incursion of SN1 fragmentation processes
(Scheme 4, (a)), favoured by the fairly easy formation of extended
benzyl-like carbocations I, that are more stable than benzyl car-
bocation PhCH2þ. Irreversible pathways concurrent with SN1-type
cleavage of the bond between the benzyl carbon and the pro-
tonated oxygen, thus severely wreck the dynamic nature of the
system with naphthalene spacer moieties. In other words, there is
Scheme 4. Alternative reaction paths for the liberation of formaldehyde from protonated cyclophanes Cn.
Consistent with the above view, long-lived DLs of macrocycles
incorporating p-phenylene, m-phenylene, and diphenylmethane
units (Scheme 1), showed no sign of formaldehyde liberation over
several days.3e5 In contrast, liberation of formaldehyde, accom-
panied by irreversible formation of side-products, was reported
for the analogous transacetalation of formaldehyde acetals in-
corporating a calix[4]arene spacer in the cone conformation (2).17
In the latter system, the durability of the DL was spoiled by in-
cursion of the SN1 fragmentation process (Scheme 4, (a)) leading
to benzyl carbocations strongly stabilized by the p-propoxy
substituent.
a sort of leakage in the reaction system, with a relevant portion of
the material being subtracted from the family of reversibly inter-
changing cyclic oligomers.
In order to support this experimental evidence, and to help us
outline a potential boundary between spacer structures leading to
long-lived or short-lived DLs, we carried out an ab initio in-
vestigation on the relative stability of carbocations AeE. The latter
were chosen as model structures of benzyl-like carbocations
generated by the heterolytic cleavage at the benzyl carbon of
protonated cyclophane formaldehyde acetals containing the p-
phenylene, m-phenylene, diphenylmethane, naphthalene, or cal-
ixarene spacer, respectively. Table 1 shows the energy variations in
a vacuum and in chloroform for the heterolytic cleavage described
in Scheme 5. The contribution of the hydride anion is constant
along both series and, consequently, the listed values are a measure
of the relative stability and ease of formation of the given
carbocations.
Table 1
Calculated energy variations (kcal/mol) for the generation of carbocations AeE
(Scheme 5)
D
E (vacuum)
DE (CHCl3)
A
B
C
D
E
244.57
247.68
241.06
233.34
224.06
134.26
137.09
133.66
129.14
124.48
Extensive liberation of formaldehyde in the acid catalyzed
transacetalation of naphthalenophanes Cn, reveals that this class of
compounds is definitely not suitable for the generation of well-

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A. Ruggi et al. / Tetrahedron 69 (2013) 2767e2774
the aromatic spacers by the introduction of naphthalene in place of
phenylene, effectively improved the binding ability towards
electron-poor guests, but quite serious drawbacks followed in the
design of DLs based on the acid catalyzed transacetalation of these
cyclophane formaldehyde acetals, the dynamic nature of this sys-
tem being irreparably wrecked by the occurrence of irreversible
reaction pathways promoted by the easy formation of the
extended-benzyl carbocation I.
Scheme 5. Generation of benzyl-like carbocations by heterolytic cleavage at the
benzyl carbon.
A delicate compromise between increased p-donor character of
the aromatic walls, and thus increased binding ability of the cyclic
oligomers, and a relatively modest promotion of carbocation for-
mation, should be pursued. Results of a computational ab initio
investigation on the relative stabilities of carbocationic species
coming from the possible heterolytic cleavage of the ArCH2eO
bond in a number of different series of cyclophane formaldehyde
acetals will be hopefully useful in the search for convenient spacer
moieties that can be safely employed in the development of well-
behaved and long-lived DLs.
The search of more structured spacer moieties, suitable for op-
timal shape-selectivity in hosteguest interactions, or the search for
spacer moieties provided with guest-selective anchoring groups,
will be also pursued as alternative approaches towards long-lived
DLs based on acid-catalyzed transacetalation of cyclophane for-
mals with optimal binding abilities.
4. Experimental section
4.1. Instruments and general methods
NMR spectra were recorded on 200 MHz and 300 MHz in-
struments. Chemical shifts are reported as
d values in parts per
million from tetramethylsilane added as internal standard. High
resolution mass spectra (HR ES-MS TOF) were taken on an Elec-
trospray Ionization Time of Flight spectrometer. IR spectra were
acquired on a ATR-FTIR Nicolet 6700 spectrometer. Acid catalyzed
equilibration experiments were carried out in the NMR tube, in the
thermostatted probe of the spectrometer.
As predicted, D and E turn out to be the most stable carboca-
tions. Extended conjugation on the naphthalene aromatic moiety in
D and even more, the presence of the þR p-methoxy substituent in
E, efficiently stabilize the positive charge. Thus, in the series in-
volving the calixarene spacer (2)17 or the naphthalene spacer (Cn),
the benzyl carbocation generated by the cleavage of ArCH2eO bond
is stable enough to open the way to heterolytic cleavage at the
benzyl position in chloroform. This does not happen in the series
with p-phenylene,3 m-phenylene4 or diphenylmethane5 spacers,
which generated well-behaved and long-lived DLs, and for which
4.1.1. Acid catalyzed transacetalation. All the experiments were
carried out at 20.0 mM equivalent monomer concentration. 3.0 mg
of the naphthalenophane formal Cn were weighted in an NMR tube
that was closed with a screw-thread cap provided with a PTFE/
silicone septum. After 3 vacuum/argon cycles the calculated vol-
ume of dry CDCl3 was added to the NMR tube. The solution was
thermostatted in the probe of the NMR spectrometer and then 5 mL
of a 20 mM solution of trifluoromethanesulfonic acid in nitro-
methane-d3 were added. 1H NMR spectra were taken at proper time
intervals.
definitely higher DE values have been consistently obtained (Table
1). In these cases, the absence of a strong structural stabilization of
the carbocation, and the low ionization power of chloroform does
not allow a heterolytic cleavage at the benzyl carbon.
4.1.2. Computational details. In the ab initio investigation on the
relative stability of carbocations AeE, the energetic balance of the
heterolytic cleavage given in Scheme 5 was calculated at the B3LYP/
6-311þG(d,p) level of theory18,19 (except for structure E for which
the 6-311þG(d) basis set was used). The total electronic energies
were corrected by adding the zero point energy due to vibrations,
obtained by a normal mode analysis following a full geometrical
optimization of the molecular structures both in a vacuum and in
chloroform, using the PCM20 model in the latter case. Calculations
were performed with the Gaussian09 suite.21
Reaction systems involving aromatic spacers for which
DE
values (Scheme 5, Table 1) close or lower than the naphthalene
spacer D can be calculated, are then unsuitable for future in-
vestigations aimed at the design of long-lived DLs based on acid
catalyzed transacetalation processes.
3. Conclusions
Interesting recognition properties, such as the efficient binding
of the guanidinium ion with the trimer C3, have been observed
among the first members of the cyclic formaldehyde acetals Cn
isolated and characterized in the present investigation (atro-
pisomers syn-C2 and anti-C2, and higher oligomers C3eC5). In this
4.2. Materials
THF was freshly distilled from sodium with benzophenone
added as indicator. CDCl3 used in the transacetalation experiments
was dried over activated molecular sieves (4 A). Bromochloro-
ꢁ
series of compounds, the enhancement of the
p
-donor character of
methane was freshly distilled before use. 1,5-Bis(hydroxymethyl)-

A. Ruggi et al. / Tetrahedron 69 (2013) 2767e2774
2773
3,7-dimethylnaphthalene was dried 2 days in the presence of P2O5
at 110 ꢁC in an Abderhalden drying apparatus under vacuum
(1ꢂ10ꢀ3 mbar) before use in the cyclization reaction Scheme 2.
Commercial samples of TfOH, AgNTf2 and CD3NO2 were used
without further purification.
calculated for C30H32O4þNaþ: 479.2198; found: 479.2184. Mp:
263e265 ꢁC.
4.4.2. Naphthalenophane anti-C2. 1H NMR (200 MHz, CDCl3)
d: 7.13
(s, 4H, ArH); 7.05 (s, 4H, ArH); 5.24 (s, 4H, OCH2O); 5.08 (d, J¼13 Hz,
The dimethyl ester of 3,7-dimethyl-1,5-naphthalenedicarboxylic
4H, ArCHAHxO); 4.43 (d, J¼13 Hz, 4H, ArCHAHxO); 2.34 (s, 12H, CH3).
acid was prepared according to a literature procedure.22
13C NMR (50 MHz, CDCl3)
d: 133.6, 132.7, 129.4, 127.9, 122.7, 100.3,
71.8, 22.0. HR-ESMS calculated for C30H32O4þNaþ: 479.2198;
4.3. 1,5-Bis(hydroxymethyl)-3,7-dimethylnaphthalene (1)
found: 479.2186. Mp: 218e220 ꢁC.
A solution of the dimethyl ester of 3,7-dimethyl-1,5-naphthalen-
edicarboxylic acid (6.39 g, 0.0235 mol) in anhydrous THF (100 mL)
was added dropwise to a suspension of LiAlH4 (2.5 g, 0.066 mol) in
anhydrous THF (100 mL) cooled in an ice bath. The reaction mixture
was stirred overnight at room temperature and then an excess of
Na2SO4$10H2O was added to quench residual LiAlH4. The resulting
mixture was stirred 4 h and then filtered. The solid material was
washed with boiling THF and then removed. Removal of the solvent
under reduced pressure from the filtrate gave 1 (4.12 g, 0.0190 mol;
81% yield) as a white solid. Mp 213e214 ꢁC. nmax (ATR): 3290, 3200,
2910, 1615, 1415, 1335, 1235, 1050, 1020, 995 cmꢀ1.1H NMR (300 MHz,
4.4.3. Naphthalenophane C3. 1H NMR (300 MHz, CDCl3)
6H, ArH); 6.96 (s, 6H, ArH); 4.85 (s, 6H, OCH2O); 4.83 (s, 12H,
ArCH2O); 2.19 (s, 18H, CH3). 13C NMR (50 MHz, CDCl3)
: 133.8,
d: 7.48 (s,
d
133.2, 129.8, 128.0, 122.6, 94.9, 68.7, 21.6. HR-ESMS calculated for
C45H48O6þNaþ: 707.3349; found: 707.3367. Mp: 177e180 ꢁC.
4.4.4. Naphthalenophane C4. 1H NMR (200 MHz, CDCl3)
8H, ArH); 7.15 (s, 8H, ArH); 4.99 (s, 16H, ArCH2O); 4.95 (s, 8H,
OCH2O); 2.24 (s, 24H, CH3). 13C NMR (50 MHz, CDCl3)
: 134.5,133.3,
d: 7.66 (s,
d
130.7, 129.0, þ123.3, 94.5, 68.7, 22.0. HR-ESMS calculated for
C60H64O8þNa : 935.4499; found: 935.4457. Mp: 270e272 ꢁC.
DMSO-d6)
d
: 7.67 (s, 2H, ArH); 7.34 (s, 2H, ArH); 5.32 (t, J¼5.5 Hz, 2H,
CH2OH); 4.89 (d, J¼5.5 Hz, 4H, CH2OH); 2.44 (s, 6H, CH3). 13C NMR
4.4.5. Naphthalenophane C5. 1H NMR (200 MHz, CDCl3)
10H, ArH); 7.24 (s, 10H, ArH); 5.03 (s, 20H, ArCH2O); 4.94 (s, 10H,
OCH2O); 2.35 (s, 30H, CH3). 13C NMR (50 MHz, CDCl3)
: 134.1, 132.9,
d: 7.75 (s,
(75 MHz, DMSO-d6) d: 137.4, 133.5, 129.5,126.4,121.8, 61.5, 21.9. Anal.
Calcd for C14H16O2: C, 77.75; H, 7.46. Found: C, 77.93; H, 7.54.
d
130.4, 128.8, 123.1, 93.9, 68.2, 21.7. HR-ESMS calculated for
4.4. Naphthalenophane formals C2eC5
C75H80O10þNaþ: 1163.5649; found: 1163.5562. Mp: 205e208 ꢁC.
A 60% dispersion of NaH in mineral oil (2.3 g, 0.058 mol) was
washed twice with hexane and once with anhydrous THF and then
anhydrous THF (250 mL) and 1,5-bis(hydroxymethyl)-3,7-
dimethylnaphthalene (1.00 g, 4.62 mmol) were added. The mix-
ture was stirred under argon 10 min and then during 10 h a solution
of CH2BrCl (1.9 mL, 3.8 g, 29 mmol) in THF (250 mL) was slowly
added dropwise by a syringe-pump. When addition was complete,
the reaction mixture was heated at 80 ꢁC and kept under stirring at
this temperature for 3 d. A 1.0 M water solution of NaOH was added
with caution in order to quench NaH excess. When hydrogen
evolution stopped, water (150 mL) was added and the resulting
mixture was extracted with dichloromethane (400 mL). The
aqueous phase was extracted with dichloromethane (2ꢂ200 mL)
and combined organic phases were dried over anhydrous sodium
sulfate and concentrated under vacuum, thus obtaining 0.83 g of
a pale yellow material. Column chromatography (silica gel 60
(0.063e0.200 mm, Merck); heptane/CH2Cl2/AcOEt 7:3:0.5 as elu-
ent) afforded syn-C2 (115 mg, 0.252 mmol; white solid; 11% yield),
and three further fractions containing mixtures of cyclooligomeric
naphthalenophanes, as follows: (a) 91 mg (white solid; anti-
C2þC3); (b) 90 mg (white solid; anti-C2þC3þC4); (c) 90 mg (white
solid; C4þC5).
4.5. Guanidinium tetrakis[3,5-bis(trifluoromethyl)phenyl]
borate
A solution of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]bo-
rate (Na[BArF4])23 (500 mg, 0.564 mmol) in ether (20 mL) was extracted
with an aqueous solution of guanidinium chloride (55 mg, 0.58 mmol)
inwater (20 mL). The organic phase was dried over magnesium sulfate
and the solvent evaporated (high vacuum, 3 d), to give guanidinium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (0.47 g, 0.51 mmol;
90% yield) as a white solid. Mp: 213 ꢁC (dec). nmax (ATR): 3680, 3520,
3400, 1665, 1610, 1360, 1280, 1145, 1125 cmꢀ1
CDCl3)
: 7.70 (m, 8H), 7.56 (s, 4H), 5.60 (br s, 6H); 1H NMR (300 MHz,
DMSO-d6)
: 7.63 (m, 8 H), 6.91 (s, 4H).13C NMR (75 MHz, DMSO-d6)
.
1H NMR (300 MHz,
d
d
d:
161.03 (hept, 1J(13C,10B)¼16.5 Hz), 161.02 (q, 1J(13C,11B)¼49.9 Hz),157.9,
134.1, 128.5 (qq, 2J(13C,19F)¼31.3 Hz, 2J(13C,11B)¼2.8 Hz), 124.0 (q,
1J(13C,19F)¼270.7 Hz), 117.6 (hept, 3J(13C,19F)¼3.6 Hz). HR-ESMS cal-
culated for the [BAr4F] anion [C32H12BF24]ꢀ: 863.0649; found:
863.0716. Anal. Calcd for C33H18BF24N3: C, 42.93; H, 1.97; N, 4.55.
Found: C, 43.25; H, 2.30; N, 4.27.
4.6. X-ray structure determination
Column chromatography (MN Kieselgel 60 M (0.04e0.063 mm/
230e400 mesh ASTM), MachereyeNagel; heptane/CH2Cl2/AcOEt
7:3:0.2) of fraction a afforded anti-C2 (40 mg, 0.088 mmol; white
solid; 4% yield), and C3 (50 mg, 0.073 mmol; white solid; 5% yield).
Column chromatography (MN Kieselgel 60 M (0.04e0.063 mm/
230e400 mesh ASTM), MachereyeNagel; heptane/CH2Cl2/AcOEt
7:3:0.35) of fraction b afforded C4 (75 mg, 0.082 mmol; white solid;
7% yield). Preparative TLC chromatography (20ꢂ20 cm silica gel 60
F254, 0.25 mm, Merck; heptane/CH2Cl2/AcOEt 7:3:0.75) of fraction c
afforded C5 (10 mg, 0.0088 mmol; white solid; 1% yield).
Single crystals of syn-C2 were grown from a benzene solution at
room temperature. The crystals (C30H32O4, M¼456.58) are triclinic,
ꢁ
space group Pꢀ1 at 298 K, a¼8.946(1), b¼9.157(1), c¼8.846(2) A,
3
ꢁ
a
¼95.67(1),
b
¼90.49(1),
g
¼118.98(1)ꢁ, V¼603.87(1) A , Z¼1,
Dcalcd¼1.255 g/cm3,
m
(Cu Ka)¼0.651 mmꢀ1. The intensities of 2452
reflections (2284 independent reflections, Rint¼0.007) were mea-
sured on a Siemens AED diffractometer using monochromated Cu
ꢁ
Ka radiation,
l¼1.54178 A,
u
-scan technique, 2qmax¼70ꢁ, T¼298 K.
The crystal structure was solved by direct methods using the
SIR2004 computer program24 and refined by full-matrix least-
squares refinement using the SHELXL-97 computer program.25 All
non-hydrogen atoms were refined with anisotropic atomic dis-
placements. All the hydrogen atoms, excepting those of a CH2
4.4.1. Naphthalenophane syn-C2. 1H NMR (200 MHz, CDCl3)
d: 7.23
(s, 4H, ArH); 6.69 (s, 4H, ArH); 5.16, 5.15, 5.09 (3 overlapping d,
J¼13 Hz, J¼7 Hz, J¼7 Hz, 8H, ArCHAHxO, OCHAHBO, OCHAHBO); 4.35
(d, J¼13 Hz, 4H, ArCHAHxO); 2.41 (s, 12H, CH3). 13C NMR (50 MHz,
group, were located in the final Fourier DF map, and refined in the
last cycles of the refinement with isotropic thermal displacement
1.2 times that of the carbon atom. The refinement converged to
CDCl3) d: 133.7, 132.9, 128.5, 125.0, 121.5, 96.1, 69.2, 22.0. HR-ESMS

2774
A. Ruggi et al. / Tetrahedron 69 (2013) 2767e2774
genieva-Ilieva, E.; Reyheller, C.; Belenguer, A. M.; Kubik, S.; Otto, S. Chem. Commun.
2011, 47, 9798; (o) Ziach, K.; Ceborska, M.; Jurczak, J. Tetrahedron Lett. 2011, 52,
4452; (p) Schleef, F.; Luning, U. Eur. J. Org. Chem. 2011, 2062; (q) Cacciapaglia, R.; Di
R1¼0.0472, wR2¼0.1468, GOF¼1.022. Geometrical calculations
have been obtained by PARST97.26
Single crystals of anti-C2 were grown from a CH2Cl2/CH3CN (1:1,
v/v) solution at room temperature. The crystals (C30H32O4,
€
Stefano, S.; Lanzalunga, O.; Maugeri, L.; Mazzonna, M. Eur. J. Org. Chem. 2012,1426;
(r) Joshi, G.; Anslyn, E. V. Org. Lett. 2012, 14, 4714; (s) Chung, M.-K.; Waters, M. L.;
ꢂ
Lee, S. J.; Gagne, M. R. J. Am. Chem. Soc. 2012, 134, 11430; (t) Gromova, A. V.; Cis-
M¼456.58) are triclinic, space group Pꢀ1 at 298 K, a¼11.072(1),
zewski, J. M.; Miller, B. L. Chem. Commun. 2012, 48, 2131; (u) Gross, D. E.; Discekici,
E.; Moore, J. S. Chem. Commun. 2012, 48, 4426;(v) Klein, J. M.; Saggiomo, V.; Reck, L.;
ꢁ
b¼12.742(1), c¼9.757(1) A,
a
¼108.16(1),
b
¼107.48(1),
g
¼98.94(1)ꢁ,
V¼1199.5(2) A , Z¼2, Dcalcd¼1.264 g/cm3,
m
(Cu Ka)¼0.656 mmꢀ1
.
Luning, U.; Sanders, J. K. M. Org. Biomol. Chem. 2012, 10, 60; (w) Tonnemann, J.;
3
ꢁ
€
€
Scopelliti, R.; Zhurov, K. O.; Menin, L.; Dehnen, S.; Severin, K. Chem.dEur. J. 2012,18,
9939; (x) Demetriades, M.; Leung, I. K. H.; Chowdhury, R.; Chan, M. C.; McDonough,
M. A.; Yeoh, K. K.; Tian, Y.-M.; Claridge, T. D. W.; Ratcliffe, P. J.; Woon, E. C. Y.;
Schofield, C. J. Angew. Chem., Int. Ed. 2012, 51, 6672.
3. Cacciapaglia, R.; Di Stefano, S.; Mandolini, L. J. Am. Chem. Soc. 2005, 127, 13666.
4. Cacciapaglia, R.; Di Stefano, S.; Mandolini, L.; Mencarelli, P.; Ugozzoli, F. Eur. J.
Org. Chem. 2008, 186.
5. Berrocal, J. A.; Cacciapaglia, R.; Di Stefano, S. Org. Biomol. Chem. 2011, 9, 8190.
6. (a) Mandolini, L. Adv. Phys. Org. Chem. 1986, 22, 1; (b) Galli, C.; Mandolini, L. Eur.
J. Org. Chem. 2000, 3117.
7. Cacciapaglia, R.; Di Stefano, S.; Ercolani, G.; Mandolini, L. Macromolecules 2009,
42, 4077.
8. Di Stefano, S. J. Phys. Org. Chem. 2010, 23, 797.
9. Berrocal, J. A.; Cacciapaglia, R.; Di Stefano, S.; Mandolini, L. New J. Chem. 2012,
36, 40.
The intensities of 4545 reflections (4529 independent reflections,
Rint¼0.035) were measured on a Siemens AED diffractometer using
ꢁ
monochromated Cu Ka radiation,
2
l¼1.54178 A,
u-scan technique,
qmax¼70ꢁ, T¼298 K. The crystal structure was solved by direct
methods using the SIR2004 computer program24 and refined by
full-matrix least-squares refinement using the SHELXL-97 com-
puter program.25 All non-hydrogen atoms were refined with an-
isotropic atomic displacements. The hydrogen atoms were included
in the last cycles of the refinement with the geometrical constraint
ꢁ
CeH 1.0 A using a ‘riding’ model. The refinement converged to
R1¼0.0673, wR2¼0.215, GOF¼0.874. Geometrical calculations have
been obtained by PARST97.26
10. Oki, M. Top. Stereochem. 1983, 14, 1.
11. For selected articles on atropisomerism in cyclophanes, see: (a) Caballero, A.;
White, N. G.; Beer, P. D. Angew. Chem., Int. Ed. 2011, 50, 1845; (b) Burns, N. Z.;
Krylova, I. N.; Hannoush, R. N.; Baran, P. S. J. Am. Chem. Soc. 2009, 131, 9172; (c)
Jia, Y.; Ma, N.; Liu, Z.; Bois-Choussy, M.; Gonzalez-Zamora, E.; Malabarba, A.;
Brunati, C.; Zhu, J. Chem.dEur. J. 2006, 12, 5334; (d) Ricci, G.; Ruzziconi, R.;
Giorgio, E. J. Org. Chem. 2005, 70, 1011; (e) Cristau, P.; Martin, M.-T.; Tran Huu
Duu, M.-E.; Vors, J.-P.; Zhu, J. Org. Lett. 2004, 6, 3183; (f) Ohkita, H.; Ito, S.;
Yamamoto, M.; Tohda, Y.; Tani, K. J. Phys. Chem. A 2002, 106, 2140; (g) Yamato, T.;
Furukawa, T.; Saito, S.; Tanaka, K.; Tsuzuki, H. New J. Chem. 2002, 26, 1035; (h)
CCDC-786217 (for syn-C2), and -786218 (for anti-C2), contain the
crystallographic data (excluding structure factors). These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
€
Hochmuth, D. H.; Konig, W. A. Tetrahedron: Asymmetry 1999, 10, 1089; (i)
Leitner, M. B.; Kreher, T.; Sonnenschein, H.; Costisella, B.; Springer, J. J. Chem.
Soc., Perkin Trans. 2 1997, 377.
ꢀ
Progetti di Ricerca 2010, Universita La Sapienza, and MIUR PRIN
2008 are acknowledged.
12. An important example of atropisomerism in cyclophane systems is found in
calix[4]arenes when all the phenolic functions are alkylated with propyl chains
or longer ones Gutsche, C. D. Calixarenes Revisited; The Royal Society of
Chemistry: Cambridge, 1998.
Supplementary data
1H and 13C NMR spectra, determination of association constants,
and other materials. Supplementary data related to this article can
be found at http://dx.doi.org/10.1016/j.tet.2013.01.080.
13. Formation of ground state charge transfer complexes in ethanol between
molecular oxygen and the naphthalenophanes syn-C2 and anti-C2 have been
reported Rodríguez, L.; Lima, J. C.; Pina, F.; Cacciapaglia, R.; Di Stefano, S.; Ruggi,
A. J. Phys. Chem. A 2011, 115, 123.
ꢂ
14. Lhotak, P.; Shinkai, S. J. Phys. Org. Chem. 1997, 10, 273.
15. (a) Brookhart, M.; Grant, B.; Volpe, A. F., Jr. Organometallics 1992, 11, 3920; (b)
Dirksen, A.; Kleverlaan, C. J.; Reek, J. N. H.; De Cola, L. J. Phys. Chem. A 2005, 109,
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