DDEESSIIGGNN,, SSYYNNTTHHEESSIISS AANNDD SSTTRRUUCCTTUURRAALL AANNAALLYYSSIISS OOFF
SSOOMMEE NNEEWW SSPPIIRRAANNSS,, MMAACCRROOCCYYCCLLEESS AANNDD
MMOOLLEECCUULLAARR DDEEVVIICCEESS.. SSUUPPRRAAMMOOLLEECCUULLAARR
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Ph.D. Thesis Abstract
GÂZ ŞERBAN ANDREI
President of the Jury: Prof. Dr. Florin Dan Irimie Babes Bolyai University
Scientific Advisor: Prof. Dr. Ion Grosu Babes Bolyai University
Reviewers: Prof. Dr. Yvan Ramondenc Université de Rouen
Prof. Dr. Ionel Mangalagiu A.I. Cuza University
Prof. Dr. Cristian Silvestru
C. M. of Romanian Academy Babes Bolyai University
ClujNapoca
2010
Organic Chemistry Department&CCOCCAN BabesBolyai University ClujNapoca, 400028 ROMANIA
Table of Contents 1. Logic gates in supramolecular chemistry ............................................................................................. 3 1.1 Introduction .............................................................................................................................................. 3 1.2 History ......................................................................................................................................................... 3 1.3 Fundamental concepts of logic gate ............................................................................................... 4 1.4 Summary of elementary logic operations ................................................................................... 6 1.5 Logic gate concept in chemistry....................................................................................................... 8 1.6 YES and NOT logic gates .................................................................................................................... 10 1.7 OR and NOR logic gates ..................................................................................................................... 14 1.8 XNOR (eXclusive NOR) and XOR (eXclusive OR) logic gate ............................................... 21 1.9 AND and NAND logic gate ................................................................................................................. 28 1.10 INH (inhibit) logic gate ...................................................................................................................... 34 1.11 Conclusion ............................................................................................................................................... 37 1.12 Bibliography ........................................................................................................................................... 38
2. Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro‐1,3‐dithiane derivatives .............................................................................................................................................. 45 2.1 Introduction ............................................................................................................................................ 45 2.2 Precursors synthesis and structural analysis .......................................................................... 46 2.3 Structural aspects in solid state ..................................................................................................... 50 2.4 Structural aspects in solution ......................................................................................................... 53 2.5 Supramolecular assembly ................................................................................................................ 60 2.6 Conclusions ............................................................................................................................................. 62 2.7 Experimental part ................................................................................................................................ 63
2.7.1 General procedure for the synthesis of 10–14 ............................................................. 65 2.7.2 Synthesis of tetrathiapentaerythritol (3) ..................................................................... 65 2.7.3 3,9‐Bis(meta‐nitrophenyl)‐2,4,8,10‐tetrathiaspiro‐[5.5]undecane (10) ................... 66 2.7.4 3,9‐Bis(meta‐hydroxyphenyl)‐2,4,8,10‐tetrathiaspiro‐[5.5]undecane (11) .............. 67 2.7.5 3,9‐Diisopropyl‐2,4,8,10‐tetrathiaspiro[5.5]undecane (12) ....................................... 68 2.7.6 3,3,9,9‐Tetramethyl‐2,4,8,10‐tetrathiaspiro[5.5]undecane (13) ................................ 69 2.7.7 3,15‐Diphenyl‐7,11,18,21‐tetrathiatrispiro‐[5.2.2.5.2.2]heneicosane (14) ............... 70
2.8 Annexes .................................................................................................................................................... 71 2.9 Bibliography ........................................................................................................................................... 73
3. New cyclophanes with possible applications in Self Assembled Monolayers ................... 79 3.1 Introduction ............................................................................................................................................ 79
Cyclophane chemistry ................................................................................................................. 79 Self assembled monolayers (SAM) ............................................................................................. 79 3.2 Retrosynthetic pathway of target compounds ........................................................................ 81 3.3 Synthesis of podands .......................................................................................................................... 82 3.4 Synthesis of macrocylic intermediates ....................................................................................... 86 3.5 UV‐VIS and fluorescence spectroscopy ...................................................................................... 89 3.6 Cyclic Voltametry ................................................................................................................................. 91 3.7 Complexation properties .................................................................................................................. 91 3.8 Conclusions ............................................................................................................................................. 93 3.9 Experimental part ................................................................................................................................ 94
3.9.1 General methods ............................................................................................................. 94 3.9.2 Synthesis of 2,3‐dimethyl‐1,4‐di(1’,4’‐dioxabutane‐1’‐yl)‐benzene (5a) ................... 96 3.9.3 Synthesis of 2,3‐dimethyl‐1,4‐di(1’,4’,7’‐trioxaheptane‐1’‐yl)‐benzene (5b) ............ 97 3.9.4 2,3‐dimethyl‐4‐(1’,4’,7’‐trioxaheptane‐1’‐yl)‐phenol .................................................. 98 3.9.5 Synthesis of 2,3‐dimethyl‐1,4‐di(1’,4’,7’,10’‐tetraoxadecane‐1’‐yl)‐benzene (5c) ........................................................................................................................................... 99 3.9.6 Synthesis of 1,4‐dibromethyl naphthalene ................................................................. 100 3.9.7 General method for synthesis of cyclophane intermediates ..................................... 101 3.9.8 8,9‐dimethyl‐3,6,11,14‐tetraoxatetracyclo [14,6,21,16,27,10,017,22] 1(26),7,9,16(25),17,19,21,23‐octene ...................................................................................... 101 3.9.9 11, 12‐dimethyl‐3,6,9,14,17,20‐hexaoxatetracyclo [20,6,21,22,210,13,023,28] 1(32),10,12,22(31),23,25,27,29‐octene .................................................................................. 102 3.9.10 14,15‐dimethyl‐3,6,9,12,17,20,23,26‐octaoxatetracyclo [26,6,21,28,213,16,029,34] 1(38),13,15,28(37),29,31,33,35‐octene .................................................................................. 103 3.10 Bibliography .................................................................................................................. 104
4. Synthesis of new molecular tweezers .............................................................................................. 109 4.1 Introduction ......................................................................................................................................... 109 4.2 Retrosynthetic pathway ................................................................................................................. 112 4.3 Synthesis of fragment A .................................................................................................................. 114
4.4 Synthesis of rods ................................................................................................................................ 120 4.5 Synthesis of pedal C .......................................................................................................................... 123 4.6 Conclusions .......................................................................................................................................... 126 4.7 Experimental part ............................................................................................................................. 127
4.7.1 General methods ............................................................................................................. 127 4.7.2 General method for synthesis of substituted oxobutanoic acids ..................................... 128 4.7.3 General method for synthesis of substituted oxobutanoic esters .................................... 130 4.7.4 Synthesis of disubstitued cyclopentadiene ...................................................................... 132 4.7.5 Synthesis of tetrasubstituted ferrocene ........................................................................... 133 4.7.6 Synthesis of 3,5-dibromo-2-methylthiophene ................................................................ 134 4.7.7 Synthesis of 3-bromo-2-methyl-thiophene ..................................................................... 135 4.7.8 Synthesis of perfluorocyclopentene derivative ............................................................... 136 4.7.9 Synthesis of 1-bromo-4-(prop-2-ynyloxy)-benzene ....................................................... 137 4.7.10 Synthesis of 1-(p-acethyl)-3-(p-bromophenoxy)-1-propine ........................................... 138 4.7.11 Synthesis of p-tolylboronic acid ..................................................................................... 139 4.7.12 Synthesis of 4-(bromomethyl)phenylboronic acid .......................................................... 140
4.8 Bibliography ............................................................................................................... 141 5. General remarks .................................................................................................................. 143
SSYYNNTTHHEESSIISS OOFF NNEEWW MMOOLLEECCUULLAARR TTWWEEEEZZEERRSS ((110099))
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LLOOGGIICC GGAATTEESS IINN SSUUPPRRAAMMOOLLEECCUULLAARR CCHHEEMMIISSTTRRYY ((33))
PPaarrtt 11
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3Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro1,3dithiane derivatives
DDEESSIIGGNN,, SSYYNNTTHHEESSIISS AANNDD SSTTRRUUCCTTUURRAALL AANNAALLYYSSIISS
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4 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
2.1 Introduction
Spiranes are compounds that contain rings (at least two) which share one common atom.
The name “spirane” comes from the Latin spira meaning twist or whorl and implies that the
rings of the spiranes are not coplanar.1 A large number of papers have reported on the synthesis,
structure and biological activity of spirane compounds with six-membered rings. Many of
spirane skeletons with sixmembered rings are present in natural compounds with specific
activity: like antibiotics2, pheromones3, marine macrolides4 and antitumor agents5.
Six-membered ring spiranes and polyspiranes are intriguing targets in organic chemistry.
Their stereochemistry is correlated with the helical chirality of the spiro[5.5]undecane
skeleton.6,7,8,9 The conformational analysis of six-membered ring spiranes was mainly carried out
using NMR methods and revealed flexible or anancomeric structures in correlation with the
substitution of the spirane skeleton.6-9,10,11 The majority of the investigations of six-membered
ring spiranes were focused on derivatives bearing 1,3-dioxane rings. The advantage of the
investigations on spiro 1,3-dioxanes consisted of the fact that the stereochemistry of 1,3-dioxane
1 Eliel, E. L.; Wilen, S.H. Stereochemistry of Organic Compounds, John Wiley & Sons: New York, 1994, pp. 1138 2 Boivin, T. L. B. Tetrahedron, 1987, 43, 3309-3362 3 O’Shea, M. G.; Kitching, W. Tetrahedron, 1989, 45, 1177-1186 4 Smith, A. B.; Frohn, M. Org. Lett., 2001, 3, 3979-3982 5 Crimmins, M.; Katz, J.; Washburn, D. G.; Allwein, S. P.; McAtee, L. F. J. Am. Chem. Soc., 2002, 124, 5661-5663 6Grosu, I.; Mager, S.; Plé, G.; Horn, M. J. Chem. Soc., Chem. Commun. 1995, 167-168 7 Grosu, I.; Mager, S.; Plé, G. J. Chem. Soc., Perkin Trans. 2 1995, 1351- 1357 8 Terec, A.; Grosu, I.; Condamine, E.; Breau, L.; Plé, G.; Ramondenc, Y.; Rochon, F. D.; Peulon-Agasse, V.; Opriş, D. Tetrahedron 2004, 60, 3173-3189 9 Cismaş, C.; Terec, A.; Mager, S.; Grosu, I. Curr. Org. Chem. 2005, 9, 1287-1314 10 Grosu, I.; Plé, G.; Mager, S.; Martinez, R.; Mesaroş, C.; Camacho, B. del C. Tetrahedron 1997, 53, 6215-6232 11 Terec, A.; Grosu, I.; Muntean, L.; Toupet, L.; Plé, G.; Socaci, C.; Mager, S. Tetrahedron 2001, 57, 8751-8758
2. Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro-1,3-dithiane derivatives
5Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro1,3dithiane derivatives
system itself is well known12,13,14,15 and spiro-1,3-dioxanes are appropriated for NMR
investigations.16
The 1,3-dithiane derivatives are less studied17 than the corresponding 1,3-dioxanes.
Eliel18 and Pihlaja19 determined the A-values for some alkyl, aryl and polar substituents located
at different positions of the 1,3-dithiane ring. These investigations revealed for alkyl and aryl
groups similar A-values with those found in the cyclohexane series, while for several polar
groups located at position 2 the preference for the axial orientation was observed.
2.2 Precursors synthesis and structural analysis
Starting from pentaerythritol or from 2,2-bis(bromomethyl)-1,3-propanediol commercial
available, pentaerythritol tetrabromide was obtained by a nucleophilic substitution, without any
solvents. The tetrabromide derivative was purified by a Soxhlet extraction using ethanol as a
solvent (Scheme 1).
Scheme 1
Therefore a indirect method to obtain the tetrathiapentaerythritol was followed. Using a
method described by Mitkin and Kutateladze20 when the bromine was substituted by potassium
thioacetate gave the protected tetraacetylated tetrathiapentaerythritol in moderate yield due to
difficulties in the workup procedure. Using a freshly obtained potassium salt follow to an
increase of the yield. Tetrathiapentaerythritol was obtained by reduction in presence of LiAlH4
12 Kleinpeter, E. Adv. Het. Chem. 1998, 69, 217-269 13 Kleinpeter, E. Adv. Het. Chem. 2004, 86, 41-127 14 Eliel, E.; Wilen, S. H. Stereochemistry of organic compounds, John Wiley & Sons: New York, 1994, pp 686-754 15 Anteunis, M. J. O.; Tavernier, D.; Borremans, F. Heterocycles 1976, 4, 293-371 16 Grosu, I.; Mager, S.; Plé, G.; Darabanţu, M. Résonance Magnétique Nucléaire Apliquée à l’Analyse Structurale de Composés Organiques, Publications de l’Université de Rouen, 1999, pp 145-190 17 Kleinpeter, E. Conformational Analysis of Six-Membered Sulfur-Containing Heterocycles in Conformational Behavior of Six-Membered Rings – Analysis, Dynamics, and Stereoelectronic Effects, editor Juaristi, E. VCH Publisher: New York, 1995, pp 201-243 18 Eliel, E. L.; Hutchins, R. O. J. Am. Chem. Soc. 1969, 91, 2703-2715 19 Pihlaja, K. J. Chem. Soc. Perkin Trans. 2 1974, 890-895 20 Mitkin, O. D.; Wan, Y.; Kurchan, A. N.; Kutateladze, A. G. Synthesis 2001, 1133-1142.
6 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
followed by a acidic work-up. (scheme 3) Any attempts to obtain the desire compound following
a basic condition work-up failed.
Scheme 2
We considered it of interest to find an appropriate procedure for the direct synthesis of
spiro compounds with 2,4,8,10-tetrathiaspiro[5.5]undecane skeleton and to investigate the
stereochemistry and the properties of some 3,9-substituted derivatives of this tetrathiaspirane.
New 3,9-substituted-2,4,8,10-tetrathiaspiro[5.5]undecane derivatives 10-13 and
7,11,18,21-tetrathiatrispiro[5.2.2.5. 2.2]heneicosane 14 were obtained by the direct reaction of
tetrathiapentaerythritol 3 with several carbonyl compounds (Scheme 5).21
Scheme 3
21 Gâz, Ş. A.; Condamine, E.; Bogdan, N.; Terec, A.; Bogdan, E.; Ramondenc, Y.; Grosu, I. Tetrahedron 2008, 64, 30-31, 7295-7300
7Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro1,3dithiane derivatives
A recently published procedure22 for the synthesis of the 1,3-dithiane ring based on I2
catalysis was successfully adapted to prepare spiranes with 2,4,8,10-tetrathiaspiro[5.5]undecane
skeleton (yields 49-74 %). The mechanism of this reaction is not yet well known. All the other
essays of usual thioacetalization23 reactions of the starting carbonyl compounds failed.
2.3 Structural aspects in solid state
The solid state molecular structure for 10 was determined by single crystal X-ray
diffractometry. The ORTEP diagram (Figure 1) reveals the chair conformation for the 1,3-
dithiane units. The aromatic rings are equatorial and exhibit a rotameric behaviour close to that
of the bisectional conformer. The angle between the aromatic ring and the best plane of the 1,3-
dithiane ring is of 26° 28’, while the angle between the aromatic rings is of 52° 42’.
Figure 1 ORTEP diagram for compound 10.
The lattice exhibits a zigzag arrangement of the molecules (Figure 2). Each molecule
exhibits four CH–π interactions. Two of them involve the axial proton of the inside methylene
groups (positions 1,11) of the 1,3-dithiane units and the aromatic groups of two neighboring
molecules. The other two interactions are located on the aromatic rings and involve the axial
protons of the methylene inside groups of the 1,3-dithiane units of the same neighboring spirane
22 Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H. J. Org. Chem. 2001, 66, 7527-7529 23 Bonifačič, M.; Asmus, K.-D. J. Org. Chem. 1986, 51, 1216-1222
8 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
molecules (the distances from the axial H atoms to the centroid of the aromatic rings are d = 2.92
Å).
Figure 2 View of the lattice for 10 along the c crystallographic axis
The solid state molecular structure24 for 12 was also determined by single crystal X-ray
diffractometry. The ORTEP diagram (Figure 3) reveals a centrosymmetric molecule with a
monoclinic (C2/c) symmetry and the chair conformation for the 1,3-dithiane unit with the
isopropyl substituents oriented to the equatorial position.
24 Gâz, Ş. A.; Dobre, I.; Varga, R.; Ramondenc, Y.; Grosu, I. Acta Crystallogr., Sect. E. in preparation
9Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro1,3dithiane derivatives
Figure 3 ORTEP diagram for compound 12
2.4 Structural aspects in solution
The stereochemistry of compounds 10-14 in solution was deduced from NMR
investigations. Despite the lower difference between the energies of chair and TB (twist-boat)
conformers (ΔG°TB-Chair = 2.9 kcal/mol)14 in 1,3-dithiane series than in the series of other six
membered rings (e.g. cyclohexane, ΔG°TB-Chair = 4.9 kcal/mol; 1,3-dioxane, ΔG°TB-Chair = 5.7
kcal/mol)14 the chair conformers are the main ones and in the further discussions only their
contributions to the stereochemistry of the compounds are considered. The characteristic
stereoisomers for 10-14 are similar with those found for the corresponding spiranes with 1,3-
dioxane units.
Compound 10-12 exhibit anancomeric structures and the flipping of the 1,3-dithiane rings
is shifted towards the conformers in which the larger substituents occupy the equatorial positions
[R2 = meta-C6H4NO2 (10); meta-C6H4OH (11); -CH(CH3)2 (12). Compounds 10-12 are chiral
(due to the specific axial and helical chirality of spiro compounds with six-membered rings) and
they are obtained as racemates (Scheme 6). The CH2 groups of the spirane units are different in
NMR. Positions 1 and 11 are oriented towards the other 1,3-dithiane ring and they are named
methylene inside, while the other two CH2 groups (positions 5 and 7) are oriented in opposite
direction and they are named methylene outside groups.
10 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Scheme 4
On the other hand due to the anancomeric behavior of the compounds the NMR spectra
exhibit different signals for the axial and equatorial protons of the spirane units. The equatorial
protons of the methylene inside groups are considerably more deshielded than those of the
methylene outside positions (Figure 5, Table 2). The assignment of the signals was carried out
on the basis of NOESY or/and ROESY experiments. Table 1 NMR data (δ ppm) for compounds 6-8
Compound
Solvent Temperature(K)
δ (ppm) CH2 inside CH2 outside
equatorial axial equatorial axial 10 CDCl3 295 4.12 2.91 2.72 3.15 11 CDCl3 295 4.17 2.93 2.66 3.34 12 CDCl3 295 3.83 2.57 2.52 2.83 13 CD2Cl2 308 2.68 13 CD2Cl2 195 3.67 2.59 2.24 3.11 14 CD2Cl2 295 3.04 2.91 14 CD2Cl2 190 3.84 2.54 2.28 2.78
The 1H NMR pattern for the spirane units exhibits two AB (AX) systems (Figure 5) with
more deshielded equatorial protons for the methylene inside groups. (they are the closest to the
sulfur atoms of the neighboring heterocycle). The signals of the equatorial protons exhibit a
further splitting due to the long range coupling (4J≈2 Hz) possible as result of the W (M)
arrangement of the bonds Heq– C1(11)–C6–C5(7)–Heq.
11Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro1,3dithiane derivatives
Figure 4 1HNMR spectrum (CDCl3, rt, fragment) of compound 10
Compound 13 is flexible and both 1,3-dithiane rings are flipping. The flipping of one of
the heterocycles transforms one enantiomer of the compound into the other (M P; Scheme 7).
S
S
SS
S
S
SS
M P Scheme 5
The flexible behavior of the compound is proved by the NMR spectra. At rt, the 1H NMR
spectrum of 13 (Figure 7) exhibits only two singlets; a more deshielded one (δ = 2.96 ppm) for
the protons of the heterocycles and another one (δ = 1.67 ppm) for the protons of the methyl
groups. The variable temperature NMR experiments (Figure 7) show the obtaining of the
(de)coalescences of the signals at lower temperatures (T= 255 K) and the spectrum run at 195 K
reveals the frozen structure.
12 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Figure 5 Variable temperature 1H NMR experiments (CD2Cl2, fragments) for compound 13
The pattern of the NMR spectrum at 195 K for the protons of the spirane unit is similar
with the spectra of the anancomeric compounds (Table 2, Figures 5 and 7) while for the methyl
groups at positions 3 and 9 the spectrum shows two singlets corresponding to the axial (δax =
1.69 ppm) and equatorial (δeq = 1.48 ppm) orientations, respectively.
Rotation barriers were estimated using coalescence temperatures and the chemical shifts
measured in frozen structures for equatorial and axial protons of 1,3-dithianes rings (Table 3). 1H-NMR variable temperature experiments were carried out recording spectra every 15 degrees.
Standard deviations were established using ΔG# values calculated at observed coalescence
temperature (Tc), Tc-10 and Tc+10. Table 2 Flipping barriers calculated from the coalescence temperatures and the chemical shifts of the signals for the protons 3,9 CH3(ax), 3,9 CH3(eq),1(11)-Hax, 5(7)-Hax, 1(11)-Heq and 5(7)-Heq measured in the low temperature 1H NMR spectra (CD2Cl2, 500 MHz) for compound 13
Compd
T (K) 3(9) 1(11) 5(7) CH3(ax),CH3(eq) Heq, Hax Hax, Heq
Δδ (Hz) 3(9) 1(11) 5(7) CH3(ax),CH3(eq) Heq, Hax Hax,Heq
ΔG# (kcal/mol) 3(9) 1(1 5(7) CH3(ax),CH3(eq) Heq, Hax Hax, Heq
Mean ΔG# (kcal/mol) values
9 250 255 255 108.5 538.2 434 11.83 11.27 11.38 11.49±0.30
CH3 eq (3,9)
CH3 eq (3,9)
13Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro1,3dithiane derivatives
2.5 Supramolecular assembly
The use of inorganic materials as support for mediator compounds represents a useful and
promising approach to obtain modified electrodes. Among these materials, zeolites and clays
offer the most complete range of interesting properties required at an electrochemical interface
(shape, size and charge selectivity, physical and chemical stability, high ion exchange capacity in
a micro-structured environment, hydrophilic character etc.). Particularly, electroanalysis is of
great interest for zeolite and clay modified electrodes applications.25
Spirane 11 (named TTU) have been chosen to be laid out on bentonite. Physical-chemical
characterization of carbon paste electrodes, incorporating a synthetic zeolite (Z) (13X type, from
Aldrich) and a mineral clay (B) (bentonite, from Valea Chioarului, Maramures county, Romania)
modified with TTU (TTU-Z-CPEs and TTU-B-CPEs), using Scanning Electron Microscopy
(SEM) and Energy Dispersive X Ray Spectroscopy (EDS) was performed (figure 9).
Figure 6 SEM images corresponding to B (A) and TTU-B (B)
Other electrochemical analysis were performed such as a study of the influence of some
experimental parameters (pH, and potential scan rate) on the voltammetric response of TTU-Z-
CPES and TTU-B-CPEs, determination of the electrochemical parameters for the heterogeneous
electron transfer process corresponding to modified electrodes, evaluation of electrocatalytic
efficiency for NADH mediated oxidation at TTU-Z-CPES and TTU-B-CPEs, using cyclic
voltammetry (CV) (figure 10) and rotating disk electrode (RDE) experiments.
25 Serban, S.; Murr, N. E. Biosens. Bioelectron. 2004, 20, 161-166
14 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Figure 7 a) Cyclic voltammograms for B-CPES, TTU-Z-CPEs and TTU-B-CPEs; b) Experimental dependence of (Ep -
Eo’) on the logarithm of the scan rate for TTU-Z-CPEs.
Modified electrodes with electrocatalytic activity towards NADH oxidation were
obtained by adsorption of a new spiro-1,3-dithiane derivative (TTU) on a synthetic zeolite (13X,
from Aldrich) and on a mineral clay (bentonite), followed by their incorporation in carbon paste.
The characteristics of the voltammetric response of TTU-Z-CPEs and TTU-B-CPES (ΔEp
of 31 and 27 mV, respectively and Ipa/Ipc of ~ 1) pointed out to a quasi-reversible, surface
confined redox process.
TTU-Z-CPEs and TTU-B-CPES showed moderate electrocatalytic efficiency towards
NADH oxidation, at an overpotential with more than 200 mV lower than that observed on
unmodified electrodes and good electrocatalytic rate constants (k.obs, [NADH]=0 = 71.1 M-1 s-1, pH 7
for TTU-B-CPEs).
TTU-B-CPEs presents a more favorable electrocatalytic behavior towards NADH
oxidation than TTU-Z-CPEs, proved by the higher electrocatalytic efficiency (240 % > 82 %;
both measured at 200 mV vs. SCE) and higher electrocatalytic rate constant.
The mechanism of NADH electro-oxidation obeys the Michaelis-Menten formalism.
15Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro1,3dithiane derivatives
2.6 Conclusions
The efficient synthesis of some new spiro and trispiro-1,3-dithianes is reported. The first
single crystal X-ray molecular structure for compounds with 2,4,8,10-tetrathia-
spiro[5.5]undecane shows the chair conformers for the 1,3-dithiane rings and the zigzag
disposition of the molecules in the lattice. The NMR studies reveal flexible, semiflexible and
anancomeric structures in correlation with the substituents located at the extremities of the
spirane skeleton. The barriers (ΔG# = 10.95-11.83 kcal/mol) for the flipping of the heterocycles
in the flexible and semiflexible compounds were calculated by variable temperature NMR
experiments.
16 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
NNEEWW CCYYCCLLOOPPHHAANNEESS WWIITTHH PPOOSSSSIIBBLLEE
AAPPPPLLIICCAATTIIOONN IINN SSEELLFF AASSSSEEMMBBLLEEDD
MMOONNOOLLAAYYEERRSS
PPaarrtt 33
New cyclophanes with possible applications in Self Assembled Monolayers 17
3.1 Introduction
Cyclophane chemistry
Even if Pellegrin26 synthesized the first member of cyclophanes ([2.2]metacyclophane 1)
in 1899, the spectacular chemical domination era of cyclophanes chemistry begins after more
than half a century, once with the synthesis of compound 2 (scheme 1) by Cram and Steinberg.27
Scheme 6
Ever since the cyclophane chemistry has been developed continuously especially due to
the various important applications which they present in divers domains such as host molecules
for different cations or small neutral molecules, chiral ligand or industrial applications. The
ability to place certain groups (i.e. two aromatic systems) within close proximity of each other
often results in interesting geometries28 and chemical properties29,30. They are fundamentally
interesting compounds.31 which exhibit interesting properties which make them particularly
useful for industrially purposes. Being typically rigid structures they found use in material
science and surface chemistry.32 From industrial point of view cyclophane can be used as
monomers for obtaining new polymers with interesting properties. The surfaces of theses 26 Pellegrin, M. M. Recl. Trav. Chim. Pays-Bas 1899, 18, 457-465 27 Cram, D. J. Steinberg, H. J. Am. Chem. Soc. 1951, 73, 5691-5704 28 Bodwell, G. J.; Bridson, J. N.; Cyrañski, M. K.; Kennedy, J. W. J.; Krygowski, T. M.; Mannion, M. R.; Miller, D. O. J. Org. Chem. 2003, 68, 2089-2098 29 Cram, D. J. Rec. Chem. Prog. 1959, 20, 1959 30 Staab, H. A.; Krieger, C.; Wahl, P.; Kay, K., -Y Chem. Ber. 1987, 120, 551-558 31 Cram, D. J.; Cram, J. M. Acc. Chem. Res. 1971, 4, 204-213 32 Greiner, A. Trends Polym. Sci. 1997, 5, 12-16
3. New cyclophanes with possible applications in Self Assembled Monolayers
18 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
polymers are very stable therefore they were used in medicine.33 Similar to fullerenes, most
cyclophanes have an internal cavity intrinsic to their structure and can act as a host having a
potential useful application for both catalysis34 and medical purposes.35
Self assembled monolayers (SAM)
Considerable attention has been drawn during the last few decades to modify noble metal
surfaces by forming ordered organic films of few nanometers to several hundred nanometers
thickness.36 One of the simplest means of forming these ultrathin films is by the simple
immersion of the noble metal surface in a dilute solution (mM) of the organic molecule at
ambient conditions and this unimolecular organic films are popularly known as self-assembled
monolayers (SAM). A self assembled monolayer is an organized layer of amphiphilic
molecules in which one end of the molecule, the “head group” shows a special affinity for a
surface. SAMs also consist of a tail with a functional group at the terminal end as seen in figure
1.
Figure 8 Schematic representation of a SAM structure
33 Gleiter, R.; Hopf, H. Modern Cyclophanes Chemistry , Wiley-VCH, Verlag GmbH & Co. KGaA, Weinheim, Germany, 2004 34 Diederich, F.; Schürmann, G.; Chao, I. J. Org. Chem. 1988, 53, 2744-2757 35 Peterson, B. R.; Diederich, F. Angew. Chem. Int. Ed. Eng. 1994, 33, 1625-1628 36 Chaki, N.; Aslam, M.; Sharma, J.; Vijayamohanan, K. Proc. Indian Acad. Sci. 2001, 113, 5-6, 659-670
New cyclophanes with possible applications in Self Assembled Monolayers 19
3.2 Retrosynthetic pathway of target compounds
The goal was to combine the properties of both cyclophane and self assembled
monolayers. Therefore we proposed the synthesis of compound 7 (figure 3) and to analyse the
properties for the cyclophane such in complexation behavior and the electrochemical properties
of SAMs.
Figure 9 Retrosynthetic pathway for the target compounds 3
Following the suggested retrosynthetic pathway the synthesis should start from
commercially available compounds 3 and 4, obtaining in the first step new podands 5(a,b,c),
followed by a macrocyclisation in order to close the cycle, bromination and substitution with
thiol groups in order to achieve the desired cyclophane 7(a,b,c).
3.3 Synthesis of podands
Synthesis of podands 5(a,b,c) starts from commercial available quinone 4 and substituted
polyethylene glycol 3(a,b,c). Podand 5a was synthesized following a modified method described
in literature.37 Starting from quinone 4 and 2-chloro-ethanol, using an ethanolic hydroxide
solution after seven days we obtained the desired compound (scheme 2) in 62 % yields.
37 Shinkai, S.; Inuzuka, K.; Miyazaki, O.; Manabe, O. J. Am. Chem. Soc. 1985, 107, 3950-3955
20 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
OH
OH
Cl OH
Cl OH
NaOH
N2
ethanol
O
O
OH
OH4 3a 5a
yield 62%
Scheme 7
The structural analysis of compound 5a was performed. 1H–NMR spectrum exhibit a
broad signal at 1.9 ppm for the OH protons and another singlet corresponding to the methyl
groups at 2.18 ppm. At 4.02 ppm a multiplet for the methylenic protons Hb and Hd was observed.
In the aromatic region only one signal is observed for Ha protons as a singlet at 6.67 ppm (figure
4).
Figure 10 1H–NMR of podand 5a showing both aliphatic and aromatic part
All the attempts to obtain compound 5b failed. Instead we notice that the reaction
underwent with good yield to the monoderivative 8b (scheme 3 and figure5).
ppm (f1)2.03.04.05.06.07.0
0
1000
2000
3000
4000
5000
60007.26
0
6.66
6
4.03
64.
023
4.01
94.
007
3.97
03.
960
3.95
53.
943
3.93
9
2.18
5
1.92
2
2.00
4.254.45
2.92
6.50
-CH3
Ha
O
O
H3C
H3C
OH
OH
Ha
Ha
HO
Hb
Hd
Hd
Hb
New cyclophanes with possible applications in Self Assembled Monolayers 21
Scheme 8
Changing the strategy (in all our previous attempts compound 3b was added dropwise),
and following a literature method described by Balzani and coworkers,38 using DMF as solvent
and increasing the reaction time we obtained podand 5b in good yields (42%).
Podand 5c was obtained in the same manner described above for 5b using another solvent
instead. The 1H-NMR follows the same pattern for all signals as were shown for compound 5a
and 5b (scheme 4 and figure 7).
Scheme 9
38 Anelli, P. L.; Ashton, P. R.; Ballardini, R.; Balzani, V.; Delgado, M.; Gandolfi, M. T.; Goodnow, T. T.; Kaifer, A. E.; Philp, D.; Pietraszkiewicz, M.; Prodi, L.; Reddington, M. V.; Slawin, A. M. Z., Spencer, N.; Stoddart, J. F.; Vicent, C.; Williams, D. J. J. Am. Chem. Soc. 1992, 114, 193-218
22 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Figure 11 1H NMR spectrum for compound 5c
3.4 Synthesis of macrocylic intermediates
In order to obtain the intermediate macrocyles it is necesary to synthesize first 1,4-
dibrommethyl naphthalene. Starting from commercially available compounds, naphthalene,
formaldehyde and a mixture of acids and using a method described in literature39 we obtained
compound 6 in fair yield (scheme 5).
Br
Br
CH2O
HBrH3PO4
CH3COOH
6yield 25%
Scheme 10
39 Lock, G.; Schneider, R. Chem. Ber. 1958, 91, 1770-1774
ppm (f1)2.03.04.05.06.07.0
0
1000
2000
3000
4000
7.26
0
6.64
0
4.06
94.
054
4.03
73.
860
3.84
23.
827
3.74
53.
739
3.73
33.
726
3.71
93.
702
3.69
53.
688
3.68
33.
622
3.60
73.
593
2.15
5
2.00
4.09
4.04
18.64
7.51
H3C
O
OO
OOH
OO
OH
Ha
Ha
Hb
HcHd
He, Hf, Hg
Hb
Hd
Hc
Ha
Chloroform(Solvent)
He, Hf, Hg
New cyclophanes with possible applications in Self Assembled Monolayers 23
Following a method described by Saiki40 and using the ultra–dilution technique
macrocyclic compounds 9(a,b,c) were obtained in fair to moderate yield (scheme 5).
Scheme 11
Furthermore all macrocylic compounds were separated by column chromatography and
were fully characterized by monodimensional NMR (1H-NMR, 13C-NMR) and bidimensional
NMR (COSY, HETCOR). For exemplifying, the 1H-NMR spectrum of compound 9c was
presented (figure 9) showing the expected number of protons and their assignment was based on
the COSY and HSQC experiments (figure 10). The aromatic region of the 1H NMR spectrum
exhibits two different types of signals, the shielded singlet for the protons of the benzene ring at
6.52 ppm and a singlet (7.33) and two doublet of doublets (7.41 and 8.10) for 1,4-symmetrical
disubstituted naphthalene ring. Protons Hm and Hk appears as doublets of doublets due to the
vicinal coupling (J=6.6 Hz) and a long range coupling (J=3.3 Hz) with Hi protons exhibiting the
classical pattern for 1,4-symmetrical disubstituted naphthalene ring. The methylene protons near
naphthalene unit exhibit a deshielded singlet at 4.95 ppm, while the methylenes from the bridge
appears as multiplets which cannot be solved.
40 Nabeshima, T.; Nishida, D.; Saiki, T. Tetrahedron 2003, 59, 639–647
24 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Figure 12 1H NMR spectrum for compound 9c
3.5 Complexation properties
One of the most important properties of cyclopahanes is the possibility to bind cations or
small molecule inside its cavities. Literature mention already the capacities of several crown
ethers to bind sodium or potassium. 41 Since we notice a binding affinity of raw 9b for different
cations further analysis have been made. A mixture of 9b with different alkaline metals salts
were analyzed on ESI mass spectrometry. A mixture of 9b and sodium thiocyanate was
subjected to an ESI-MS analysis exhibiting the corresponding peak for [M+Na]+at m/z 489.
Repeating the analysis with a mixture of 9b and potassium trifluoromethanesulfonate the
expected [M+K]+ was observed at m/z 505. Using heavier cations such as rubidium or cesium ,
the corresponding complexes were observed at m/z 551 for [M+Rb]+, and m/z 599 for [M+Cs]+,
respectively showing no specific selectivity (figure 14).
41 Montenegro, J.-M.; Perez-Inestroza, E.; Collado, D.; Vida, Y.; Suau, R. Org. Lett. 2004, 6, 14, 2353-2355
ppm (t1)2.03.04.05.06.07.08.0
0
500
1000
1500
2000
2500
3000
8.12
18.
110
8.09
98.
088
7.42
17.
410
7.40
07.
389
7.32
7
7.26
0
6.52
4
4.94
7
3.99
03.
984
3.97
43.
826
3.81
03.
742
3.72
93.
722
3.70
83.
698
3.69
23.
680
3.65
63.
649
3.63
8
2.02
52.00
2.061.96
1.85
4.17
3.9516.68
6.08
4.01
H3C
H3C
O
O
OO
OCH2
O O O CH2
Hi
Hi
Hk
Hk
Hm
Hm
Ha
Ha
Hb Hc Hd He Hf Hg
Ha
CH3
CH2
Hm
Hi
Hk
Hb Hc Hd
He Hf Hg
New cyclophanes with possible applications in Self Assembled Monolayers 25
Figure 13 Mass spectra of the 9b a) with sodium cation; b) potassium cation; c) rubidium cation; d) cesium cation; e) mixture of Na+, K+, Rb+, Cs+ (fragments)
[M+Na]+
[M+Rb]+
[M+K]+
[M+Cs]+
[M+Na]+ [M+K]+
[M+Rb]+ [M+Cs]+
599.2
599.2
[M+H2O]+
26 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
3.6 Conclusions
A series of new podands have been synthesized using literature methods being
investigated by spectroscopic methods in order to elucidate their structures.
Also, three new cyclophanes were obtained and were fully characterized by both
monodimensional (1H and 13C) and bidimensional (COSY and HETCOR) NMR spectroscopy.
Complexation property of one cyclophane to bind alkaline cations (Na+, K+, Rb+, Cs+)
has been investigated using ESI-MS spectrometry showing no selectivity.
An undesired new compound was obtained and was fully characterized by NMR
spectroscopy and mass spectrometry.
New cyclophanes with possible applications in Self Assembled Monolayers 27
SSYYNNTTHHEESSIISS OOFF NNEEWW MMOOLLEECCUULLAARR TTWWEEEEZZEERRSS
PPaarrtt 44
28 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
4.1 Introduction
Automobiles are driven by the conversion of piston action into a rotary motion, for which
a variety of different moving components are integrated and interlocked one with another. Power
transmission involving different interlocked movements via power conversion processes is one
of the essentials elements for the design of movable machines and robots. Molecules that
undergo programmed motions in response to different stimuli are so called molecular
machines.42
Molecular analogues of a variety of mechanical devices such as molecular rocking
chair,43 rudder, wringer,44 shuttles,45 molecular elevator,46 unidirectional rotors,47 and tweezers
have been created. But these “molecular machines” have not yet been used to mechanically
manipulate a second molecule in a controlled and reversible manner.
There is a much interest in molecular switching processes48 as they are crucial to the
realization of devices that operate at the molecular and supramolecular levels.49 Various
approaches have been used in designing bistable systems whose physical behavior can be
modulated by external stimuli Therefore photochromic compounds capable to act as molecular
switches or memories were synthesized. Most photochromic compounds change their color by
photoirradiation and return to their initial state while kept in the dark. Recently thermally
irreversible photochromic compounds, which never return to the initial state thermally but
undergo reversible photoisomerization, have been deve1oped.50 Diarylethenes with heterocyclic
aryl groups are newcomers to the photochromic field. They belong to thermally irreversible (P- 42 Kinbara, K.; Muraoka, T.; Aida, T Org. Biomol. Chem. 2006, 6, 1871-1876 43 Balog, M.; Grosu, I.; Ple, G.; Ramondenc, Y.; Condamine, E.; Varga, R. A. J. Org. Chem. 2004, 69, 13337-1345 44 Bogdan, N.; Grosu, I.; Benoit, G.; Toupet, L. Ramondenc, Y.; Condamine, E.; Silaghi-Dumitrescu, I.; Ple, G. Org. Lett. 2006, 8, 2619-2622 45 Collin, J.-P.; Dietrich-Buchecker, C.; Gaviña, P., Jimenez-Molero, M. C.; Sauvage, J.-P. Acc. Chem. Res. 2001, 34, 477-487 46 Badjic, J. D.; Balzani, V.; Credi, A.; Silvi, S.; Stoddart, J. F. Science 2004, 303, 1845-1849 47 a) Leigh, D. A.; Wong, J. K. Y.; Dehez, F.; Zerbetto, F. Nature 2003, 424, 174-179; b) Koumura, N.; Zijlstra, R. W. J.; van Delden, . A.; Harada, N.; Feringa, B. L. Nature 1999, 401, 152-155 48 P. de Silva, H. Q. N. Gunaratne, C. P. McCoy Nature 1993, 364, 42-44 49 Szaciłowski, K. Chem. Rev. 2008; 108, 9, 3481-3548 50 Darcy, P. J.; Heller, H. G.; Strydom, P. J.; Whittal, J. J. Chem. Soc., Perkin Trans. 1 1981, 202-205
4. Synthesis of new molecular tweezers
Synthesis of new molecular tweezers 29
type) photochromic compounds. Among the compounds, 1,2-diarylethenes with heterocyclic
rings have the potential ability for many applications owing to additional characteristics, namely,
the fatigue resistant property. The compounds continue to display this phenomenon even after
104 times of coloration/decoloration operations.51 Both properties, thermal irreversibility and
fatigue resistance, are indispensable for applications to optoelectronic devices, such as memories
and switches.52
Aida and coworkers reported the design and synthesis of a “light-driven chiral molecular
scissors” where a motion of a photoisomerizable part (azobenzene unit) is transformed into an
open-close motion of other moieties.53 Aida’s device consist of a photochromic (azobenzene)
and ferrocene units designed to interlocked with one another; a motion occurring at the
azobenzene unit can be transmitted to the ferrocene unit.
Ferrocene is a double-decker organometallic compound that has attracted attention as a
component for redox-active modules, catalysts, and chiroptical probes, due to its unique
structural and chemical properties.54 Besides these properties, the rotary motion of ferrocene is
interesting. The two cyclopentadienyl rings, which sandwich an iron(II) center, have been
reported to undergo a friction-free rotation at a rate 109 s−1 even at 154 K.55 Several
supramolecular systems have made use of ferrocene as a flexible hinge, however, ferrocene has
been used as a module for the design of molecular machines only by Aida and coworkers.
Combining the properties of a photochromic 1,2-diarylethenes with the idea of Aida’s
research group a new molecular device has been designed bearing a ferrocene unit linked with a
1,2-diarylethene unit. This type of molecules exhibit as constitutive elements one pivot – a
1,1’,3,3’-tetrasubstituted ferrocene, rods which can be either rigid or flexible, the pedal – a
photochromic moiety – 1,2-diarylethene and the blades – biradicals (figure 1).
The rods between the pivot and ferrocene are rigid (aryl units) and semiflexible between
pedal and ferrocene.
51 Uchida, M.; Irie, M. J. Am. Chem. Soc. 1993, 115, 6442-6443 52 Zheng, H.; Zhou, W.; Yuan, M.; Yin, X.; Zuo, Z.; Ouyang, C.; Liu, H.; Li, Y.; Zhu, D. Tetrahedron Lett. 2009, 50, 1588-1592 53 Muraoka, T.; Kinabara, K.; Kobayashi, Y.; Aida, T. J. Am. Chem. Soc. 2003, 125, 5612-5613 54 a) Rosenblum, M. Chemistry of the Iron Group Metallocenes: Ferrocene, Ruthenocene, Osmocene, Interscience Publishers, New York, 1965, part 1, 40–42; b) Sohn, Y. S.; Hendrickson, D. N.; Gray, H. B. J. Am. Chem. Soc. 1971, 93, 3603-3612 55 Gardner, A. B.; Howard, J.; Waddington, T. C.; Richardson, R. M.; Tomkinson, J. Chem. Phys. 1981, 57, 453-460
30 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Figure 14 Schematic representation of a molecular tweezers
Hence, the cyclopentadienyl rings of the ferrocene unit are able to generate angular
motion in response to the photochemical open-close process of the attached
diarylperfluorocyclopntene. In this case ferrocene unit act as a pivot that can convert the open-
close changes (elongation/contraction) of the photochromic unit into angular motion. The
angular motion of the ferrocene unit induces a shear movement of the blades getting the radicals
in the proximity when pivot is opened, respectively away when the photochromic unit is closed.
The action of the pedal is controlled photochemically by irradiation at different
wavelengths.
pivot
Aryl Terminal reference group
Closed pedal Opened pedal
Synthesis of new molecular tweezers 31
4.2 Retrosynthetic pathway
For molecular design strategy a 1,1’,3,3’-tetrasubstituted ferrocene have been chosen to
be the main core. Several synthetic routes were taken in consideration in order to obtain the
target molecular tweezers. The synthesis of the pivot involves a key precursor bromoderivative
11. Due to its complexity the target compound was considered to be formed from three different
fragments which have to be linked together as final steps of the reaction pathway (figures 2).
Figure 15 Retrosynthetic scheme envisaging the molecular tweezers synthesis
Practically each fragment represents the constitutive elements of the targeting molecule.
Fragment A represents the pivot, fragment B is the rod which is semiflexible (aryl unit is rigid
while the methylene atom can be viewed as a flexible part) and C is the pedal. Due to the blades
instability it was considered as last step the attachment of them in order to achieve the target
molecule.
Synthesis of each fragment starts from commercially available products and follow
methods already described in literature or adapted to the synthetic needs. This molecular device
raise special interest since it has a 1,2-diarylethenes photochromic unit, described in literature
32 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
with several applications in the field of organic memories56 and a biradical57 which can be
stabilized by the entire system.
56 Irie M. Chem. Rev. 2000, 100, 1685-1716 57 a) Barclay, T. M.; Beer, L.; Cordes, A. W.; Oakley, R. T.; Preuss, K. E.; Taylor, N. J.; Reed, R. W. Chem. Commun. 1999, 531-532; b) Beer, L.; Cordes, A. W.; Haddon, R. C.; Itkis, M. E.; Oakley, R. T.; Reed, R. W.; Robertson, C. M. Chem. Commun. 2002, 1872-1873
Synthesis of new molecular tweezers 33
4.3 Synthesis of fragment A
Substituted oxobutanoic acid has been synthesized according to literature procedure58 by
a Friedel Craft acylation starting from toluene as reactant and as solvent as well and succinic
anhydride. An extended reaction time at room temperature permitted the obtaining of 9 with a
high yield and in a completely reactivity reaction (scheme 1).
Scheme 12
Further, compound 9 was transformed into its ester with methanol. Several drops of
thionyl chloride have been added as catalyst giving the ester 10 almost quantitative.
1H-NMR of compound 10 is in agreement with the proposed structure displaying two
triplets for methylene protons, a singlet at 2.4 ppm for methyl protons attached to the phenyl ring
and a singlet at 3.7 ppm corresponding to the protons attached to hydroxyl atom. The aromatic
part exhibits two doublets, from which one is overlapped with the solvent (chloroform) line
(figure 4).
58 Seed, A, J.; Sonpatki, V.; Herbert, M. R. Org. Synth., Coll. Vol. 2004, 10, 125-127
34 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Figure 16 1H-RMN of methyl 4-oxo-4-p-tolylbutanoate (fragment)
Synthesis of the key intermediate 11 following a literature procedure59 failed despite of
good results obtained by Aida’s research group. Pagani and coworkers60 reported very low
yields for achievement of different disubstituted cyclopentadienes. Synthon 11 was obtained
after a series of changes in literature procedures61 with a much larger yield (21%) (scheme 2).
OO
O
10Br
O
+
6
benzeneyield 21% Br
11 Scheme 13
59 Muraoka, T.; Kinbara, K.; Aida, T. Nature 2006, 440, 512-515 60 Greifenstein, L. G.; Lambert, J. B.; Niehuis, R. J.; Drucker, G. E.; Pagani, G. A. J. Am. Chem. Soc. 1981, 103, 7753-7761 61 Rosenblum, M.; Howells, W. G.; Banerjee, A. K.; Bennett, C. J. Am. Chem. Soc. 1962, 84, 2726-2732
ppm (t1)2.503.003.50
0
1000
2000
3000
4000
3.70
4
3.32
23.
300
3.27
8
2.78
02.
758
2.73
6
2.41
0
3.00
1.94
2.03
2.71
ppm (t1)7.508.00
7.89
87.
870
7.27
57.
260
7.24
7
1.96
3.42
O O
O
Ha
Hb
Hc
Hd
CH3OCH3
HdHc
Ha Hb
Synthesis of new molecular tweezers 35
Structure determination of compound 11 was based on NMR analyses and EI mass
spectrometry. EI-MS exhibits a peak at m/z 312 corresponding to [M+H]+. NMR spectrum
exhibit a singlet at 2.35 ppm for the methylenic protons attached to the phenyl ring. A singlet
corresponding to the methylenic protons Ha form cyclopentadiene ring was observed. NMR
shows at 6.87 and 6.93 ppm two broad singlets which appear to be protons Hb and Hc (figure 5).
Three pairs of protons attached to aryl units cannot be solved due to overlapped signals.
Figure 17 1H-RMN of synthon 11
Synthesis of simple ferrocene has long been known62 its synthesis involves the reaction
of a cyclopentadienyl salt with ferrous chloride. Ferrous chloride was freshly obtained from iron
and ferric chloride under argon. Derivative 11 was treated with a base under Ar and has been
refluxed overnight to achieve fragment A in 42% yield (scheme 3).
62 Wilkinson, G. Org. Synth., Coll. Vol. 1963, 4, 473-475
ppm (t1)6.907.007.107.207.307.40
0
50000
100007.45
8
7.43
6
7.41
2
7.39
0
7.26
07.
249
7.16
47.
144
6.92
8
6.87
1
2.23
6.91
1.01
0.99
ppm (t1)2.503.003.50
-50000
0
50000
10000
15000
3.72
7
2.35
1
4.01
2.26
Br
Hb Hc
Ha Ha
Ha
Hb Hc
CH3
36 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Br
11
FeCl2
N2THF
yield 42%
FeBr
BrA
Scheme 14
The NMR spectrum exhibits a broad signal at 4.72 ppm and a triplet at 4.44 ppm for the
corresponding protons of cyclopendienyl ring showing the disappearance of corresponding
singlet from 3.72 ppm characteristic to compound 11. Due to the iron influence the aromatic
protons are more shielded.
Figure 18 1H-RMN of fragment A (pivot)
ESI-MS is in accordance with NMR analyses, showing the molecular ion at m/z 677 as
[M+H]+, being easily recognized from the bromine and iron isotopic patterns (figure 7).
ppm (t1)6.9006.9507.0007.0507.1007.1507.2007.250
-100
0
100
200
300
400
500
600
7007.26
0
7.24
5
7.21
7
7.18
4
7.15
6
7.06
6
7.03
9
7.01
3
6.98
4
6.96
6
6.94
3
6.91
5
4.42
6.19
5.43
ppm (t1)4.4004.4504.5004.5504.6004.6504.7004.750
4.72
0
4.50
6
4.44
5
4.39
8
2.00
4.01
ppm (t1)2.3002.350
2.34
5
6.11
FeBr
Br
Ha Ha
Hb
Hd
Hc HeHfCH3
HaHb
Synthesis of new molecular tweezers 37
Figure 19 ESI-MS of pivot A (fragment)
Scheme 15
4.4 Synthesis of rods
Derivative B has been previously synthesized63 from commercially p-bromo-phenol and
commercially available propargyl alcohol, in acetone using sodium hydroxide as base.
Compound B was used later as intermediate for the construction of the molecular tweezers
(scheme 6).
63 Punna, S., Meunier S., Finn, M. G. Org. Lett. 2004, 6, 2777-2779
[M+H]+
38 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Scheme 16
A longer rod was synthesized starting from compound B by a Sonogashira coupling
reaction following a literature procedure in presence of “tetrakis” and cuprous iodide as
catalysts.64 It is very important to have a well deoxygenated solution since oxygen can decrease
dramatically the yield of the reaction. Thus compound 17 was obtained in very good yield
(scheme 7).
Scheme 17
The aromatic region of the 1H-NMR spectrum of 17 exhibits the expected number and
pattern of resonances and their assignment was based on COSY, and HSQC experiments (figure
10).
64 a) Zhang, H.-C.; Huang, W.-S.; Pu, L. J. Org. Chem. 2001, 66, 481-487; b) Firth, A. G.; Fairlamb, I. J. S.; Darley, K.; Baumann, C. G. Tetrahedron Lett. 2006, 47, 3529-3533
Synthesis of new molecular tweezers 39
Figure 20 1H-RMN of 17 (fragment)
The methylic protons appear at as singlet at 2.6 ppm as while the Hc proton shift
downfield as singlet at 4.9 ppm. The aromatic proton Hb shifts as doublet with a coupling
constant 3J=9 Hz due to the vicinal coupling with proton Ha. Proton Hd shifts as doublet at 7.5
ppm, with a coupling constant 3J=8.1 Hz due to the vicinal coupling with He which is more
deshielded due the greater influence of acetyl moiety.
13C-NMR was also used to characterize compound 17. Aliphatic carbons C3, C1 and C2
shift in the range 26-87 ppm , with C1 and C2 downshielded at almost the same value.
ppm (t1)7.007.50
0
1000
2000
3000
40007.91
27.
885
7.52
07.
492
7.43
47.
404
7.26
0
6.93
16.
924
6.90
86.
901
2.00
1.96
1.93
1.97
ppm (t1)4.900
4.91
0
2.05
ppm (t1)2.6002.650
2.59
7
2.99
OBr
O
Ha Hb
Ha Hb
Hd He
Hd He
Hc HcHc CH3
HbHdHe Ha
40 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
Figure 21 Fragment of the 13C-NMR spectrum (75 MHz) of compound 17
The assignment of the carbons for 17 was possible using HSQC bidimensional spectrum.
4.5 Synthesis of pedal C
Synthesis of pedal starts from commercially available methyl-thiophene following a
method already described in literature by Xu65 and Park.66 Methyl thiophene and freshly
recrystallized NBS were stirred in acetic acid overnight affording compound 18 in good yield
(scheme 8).
S S
BrBr
NBSacetic acidyield 48%
3 18 Scheme 18
65 Yang, T.; Pu, S.; Chen, B.; Xu, J. Can. J. Chem. 2007, 85, 12-20 66 Lim, S.-J.; An, B.-K.; Park, S. Y. Macromolecules 2005, 38, 6236-6239
ppm (t1)50100150200
-10.0
-5.0
0.0
5.0
10.0
197.
240
156.
693
136.
667
132.
338
131.
909
128.
189
126.
817
116.
759
113.
867
86.6
1786
.583
77.4
2377
.000
76.5
77
56.6
89
26.6
48
OBr
O5" 123
41'
2' 3'
4'
5'6'1"
2"3"
4"
6"
C C
CH3
C3
C=O C1" C4'C4"C1'
C6"C3'
Synthesis of new molecular tweezers 41
1H-NMR of compound 18 is in agreement with the proposed structure displaying one
singlet at 6.86 ppm corresponding and one singlet for methylic protons at 2.33 ppm (figure 13).
Figure 22 a) 1H-RMN and b) 13C-RMN of 18 (fragment)
Compound 4 was obtained by two different approaches following literature data. 67 S S
Br
yield 41%
H2OCH3COONa
1) Br2
2) Zn
S
BrBr
184
1) BuLiTHF/pentane
N22) MeOH3yield 87%
Scheme 19
Compound C was already described in literature and was prepared according to Lehn and
Tsivgoulis’s procedure.68 Monobromothiophene 4 was treated with nBuLi and THF/pentane
67 Halberg, A.; Liljefors, S.; Pedaja, P. Synth. Commun. 1981, 11, 25-28 68 Tsivgoulis, G. M.; Lehn, J.-M. Chem. Eur. J. 1996, 2, 1399-1406
ppm (t1) 5.06.07.0
7.26
6.86
1.00
ppm (t1)2.3002.350
2.33
4
3.06
CH3
ChloroformH
S
BrBr
H
ppm (t1)100
136.
083
132.
015
108.
712
108.
507
ppm (t1)0.05.010.015.020.025.030.0
14.7
12
CCH3 1
2
34
5
S
Br
Br
C3, C5C4
C2
a) b)
42 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
mixture affording white crystals of pedal C in moderate yield after the workup of the reaction
(scheme 10).
S
Br
1) BuLiTHF/pentane
FF
FF
FF
FF2)
yield 39%
S S
FF
FF
FF
N2
4
C
Scheme 20
All the spectral data confirm the proposed structure. The characterization in solution
(NMR) is also in agreement with the drawn structure, exhibiting in aromatic region at 7.16 ppm
for Ha a doublet with coupling constant 3J=8.6 Hz due to vicinal coupling with Hb.
Figure 23 1H-RMN of pedal C (fragment)
ppm (t1)7.0507.1007.1507.2007.250
0
1000
2000
3000
4000
7.26
00
7.17
22
7.15
07
7.07
10
7.04
95
1.00
0.95
ppm (t1)1.8601.8701.8801.890
1.87
30
2.93
S S
F
F F F
F
F
HaHa
Hb Hb
CH3
Hb
Ha
Synthesis of new molecular tweezers 43
4.6 Conclusions
To conclude, three building blocks have been synthesized which will be further
assembled to obtain the target molecular tweezers. All the compounds were investigated by
characteristic spectroscopic methods in order to elucidate their structures. Three new
intermediates were prepared using modified literature procedures.
The synthesis of the pivot involves a series of reactions, which undergo in fair yield.
Using modified methods the yields were improved by approximately 10%.
44 Design, synthesis and structural analysis of some new spirans, macrocycles and molecular
devices. Supramolecular chemistry to the new frontiers
The efficient synthesis of some new spiro and trispiro-1,3-dithianes is reported. The first
single crystal X-ray molecular structure for compounds with 2,4,8,10-tetrathia-
spiro[5.5]undecane shows the chair conformers for the 1,3-dithiane rings and the zigzag
disposition of the molecules in the lattice. The NMR studies reveal flexible, semiflexible and
anancomeric structures in correlation with the substituents located at the extremities of the
spirane skeleton. The barriers (ΔG# = 10.95-11.83 kcal/mol) for the flipping of the heterocycles
in the flexible and semiflexible compounds were calculated by variable temperature NMR
experiments.
A series of new podands have been synthesized using literature methods being
investigated by spectroscopic methods in order to elucidate their structures.
Also, three new cyclophanes were obtained and were fully characterized by both
monodimensional (1H and 13C) and bidimensional (COSY and HETCOR) NMR spectroscopy.
Complexation property of one cyclophane to bind alkaline cations (Na+, K+, Rb+, Cs+)
has been investigated using ESI-MS spectrometry showing no selectivity.
An undesired new compound was obtained and was fully characterized by NMR
spectroscopy and mass spectrometry.
Three building blocks have been synthesized which will be further assembled to obtain
the target molecular tweezers. All the compounds were investigated by characteristic
spectroscopic methods in order to elucidate their structures. Three new intermediates were
prepared using modified literature procedures.
The synthesis of the pivot involves a series of reactions, which undergo in fair yield.
Using modified methods the yields were improved by approximately 10%.
5 General remarks
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