DESIGN, SYNTHESIS AND STRUCTURAL ANALYSIS OForganica/abstracturi/andrei.pdf · Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro‐1,3‐ dithiane derivatives

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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

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3Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro1,3dithiane derivatives

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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


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.



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


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



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


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.



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.


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.



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)


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



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.


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.



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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



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


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



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


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



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


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



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


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]+



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.


SSYYNNTTHHEESSIISS OOFF NNEEWW MMOOLLEECCUULLAARR TTWWEEEEZZEERRSS

PPaarrtt 44



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



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


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



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


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



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


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



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


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]+



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


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



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'


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)



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


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%.



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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DESIGN, SYNTHESIS AND STRUCTURAL ANALYSIS OForganica/abstracturi/andrei.pdf · Design, Synthesis and Structural Analysis of Some new Spiro and Polyspiro‐1,3‐ dithiane derivatives