Electrochemical Thiocyanation of Organic Compounds by Anna Gitkis

Home , Acetyl group, Thiocyanate, Thiocyanogen

Electrochemical Thiocyanation of Organic Compounds

Thesis submitted in partial fulfillment of the requirements for the degree of “DOCTOR OF PHILOSOPHY”

Anna Gitkis

Submitted to the Senate of Ben-Gurion University of the Negev

September 2010

Beer Sheva

Electrochemical Thiocyanation of Organic Compounds

Thesis submitted in partial fulfillment of the requirements for the degree of “DOCTOR OF PHILOSOPHY”

Anna Gitkis

Submitted to the Senate of Ben-Gurion University of the Negev

Approved by the advisor Prof. James Y. Becker: ______

Date: ______

Approved by the Dean of the Kreitman School of Advanced Graduate Studies: ______Date: ______

September 2010

Beer Sheva

This work was carried out under the supervision of

Professor James Y. Becker

In the Department of Chemistry

Faculty of Natural Sciences

Acknowledgments

I wood like to thank my supervisor, Prof. James Y. Becker, for providing me with consistent stimulus and inspiration to proceed and for his valuable support and assistance in all aspect of my scientific work.

I want to especially mention my colleagues, Ph.D. students Natalie Geinik, Alex Shtelman, and Efrat Korin; new members of our laboratory Libi Brakha, Anna Rakovchic, and Tatyana Golub; and technical assistant Mrs. Ethel Solomon, who helped me in solving scientific and technical problems and, most importantly, ensured an unforgettable atmosphere of friendship and joy.

I am thankful to my family for supporting and encouraging me on the way towards the Ph.D. degree, for their patience and understanding when this thesis was being written.

I am sincerely grateful to my mother Ekaterina who since childhood has instilled in me a desire to study. I am honored to receive my Ph.D. degree.

This work is dedicated to my amazing children, Daniel and Liron, whose love in them I am carrying in my heart.

Table of Contents

Abstract………………………………………………………………………………………... i

1. Introduction……………………………………………………………………………….. 1

1.1. Electroorganic synthesis……………………………………………………………... 1

1.1.1. Advantages of electrochemical synthesis……………………………………….. 4

1.1.2. Disadvantages of electrochemical synthesis…………………………………….. 5

1.1.3. Electrochemical methods………………………………………………………... 5

1.1.3.1. Controlled potential electrolysis (CPE)………………………………. 5

1.1.3.2. Constant current electrolysis (CCE)………………………………….. 6

1.2. Organic thiocyanates………………………………………………………………… 7

1.2.1. Chemical preparation of organic thiocyanates…………………………………... 8

1.2.1.1. Formation of organic thiocyanates by reaction between thiocyanate

anions and organic compounds………………………………………………... 8

1.2.1.2. Preparation of organic thiocyanates by using thiocyanogen or related

reagents……………………………………………………………………….... 13

1.2.1.3. Reactions of thiocyanogen……………………………………………. 15

1.2.1.4. Common methods for thiocyanation of organic compounds ………… 15

1.2.1.5. Methods of preparing thiocyanogen ……………..…………………... 16

1.2.2. Identification of organic thiocyanates……………………….…………………... 19

1.2.2.1. IR spectroscopy……………………………………………………….. 19

1.2.2.2. 1H- and 13C-NMR……………………………………………………… 19

1.2.2.3. Detection of isothiocyanate and thiocyanate groups by feature

reactions……………………………………………………………………….. 20

2. Objectives of the proposed research……………………………………………………… 21

3. Results and discussion……………………………………………………………………... 22

3.1. Choosing “optimal” conditions for good yield and selective electrolysis…………. 22

3.2. Mechanism……………………………………………………………………………. 31

3.2.1. Does the mechanism involve 1e- or 2e- oxidation?...... 31

3.2.2. A step-wise heterolytic or concerted thiocyanation mechanism?...... 33

3.3. Electrochemical thiocyanation of aromatic compounds…………………………... 37

3.3.1. Controlled potential electrolysis (CPE)…………………………………………. 37

3.3.2. Constant current electrolysis (CCE)…………………………………………….. 46

3.4. Electrochemical thiocyanation of alkenes………………………………………….. 49

4. Conclusions…………………………………………………………………………………. 60

4.1. Electrochemical thiocyanation of aromatic compounds…………………………… 60

4.2. Mechanism of electrochemical thiocyanation of aromatic compounds…………… 61

4.3. Electrochemical thiocyanation of alkenes…………………………………………… 61

4.4. Mechanism of electrochemical thiocyanation of alkenes…………………………… 62

5. Experimental………………………………………………………………………………... 63

5.1. General: instruments, techniques and procedures…………………………………. 63

5.2. Characterization of products………………………………………………………… 65

6. References…………………………………………………………………………………... 74

7. Appendix ...... 78

7.1. Basic principles in "organic electrochemistry"…………………………………….. 78

7.1.1. Electrochemical experimental conditions……………………………….………. 78

7.1.1.1. Electrochemical cells…………………………………………………. 78

7.1.1.2. Solvent systems………………………………………….……………. 78

7.1.2. The effect of different parameters on electrochemical reactions………………... 79

7.1.2.1. Type of electrode……………………………………………………... 80

7.1.2.2. Factors affecting the mechanism of electrolysis……………………… 80

7.1.2.3. Effect of solvent………………………………………………………. 81

7.1.2.4. Electrolyte……………………………………………….……………. 82

7.1.2.5. Electrochemical parameters…………………………………………... 83

7.1.2.6. Electricity consumption (charge) passed through electrochemical cell. 84

7.1.2.7. Temperature…………………………………………………………... 85

7.1.2.8. Stereochemistry of substrate………………………………………….. 86

List of Figures

Page

1 Divided electrochemical cell………………………………………………………..... 6

2 Undivided electrochemical cell………………………………………………………. 6

3 Electronic structure of thiocyanogen…………………………………………………. 14

4 Dimensional structure and torsion angles of thiocyanogen by theoretical calculations…………………………………………………………………………… 14 5 Cyclic voltammogram of anion SCN- in acetonitrile, scan rate 50 mV/sec...... 22

6 Cyclic voltammogram of anion SCN- and anisole in acetic acid; scan rate 50 mV/sec………………………………………………………………………………… 24 7 A graphical illustration of data from Table 7 with extrapolation to zero yield……... 29

8 Cyclic voltammogram of anion SCN- with ferrocene in acetic acid……..…………… 32

9 A coulometry experiment with extrapolation to zero current in acetic acid..………… 32

10 Specific adsorption of N,N-dimethylbenzylamine on electrode surface ...... 87

List of Tables

Page

1 Yields of 4-thiocyanatoanisole from CPE …..……………………………………….. 25

2 Effect of electrolyte on the yield of 4-thiocyanatoanisole……………………………. 26

3 Effect of anode material on the yield of 4-thiocyanatoanisole……………………….. 27

4 Effect of thiocyanate salts on the yield of 4-thiocyanatoanisole……………………… 27

5 Effect of NH4SCN concentration on the yield of 4-thiocyanatoanisole……………… 28

6 Effect of NH4SCN/anisole ratio on the yield of 4-thiocyanatoanisole……………….. 28

7 Effect of electricity consumption (NH4SCN, 0.067M)………………………………. 29

8 “Optimal” conditions based on the results described in Tables 1–7…………………. 30

9 Results from constant current electrolysis under the "optimal conditions” (described

in Table 8)…………………………………………………………………………….. 31

10 Electrochemical thiocyanation of substituted anisole, toluene, and aniline

derivatives…………………………………………………………………………….. 38

11 Electrochemical thiocyanation of other aromatic substrates………………………….. 43

12 Constant current electrochemical thiocyanation of anisole and some representative

disubstituted aromatic derivatives……………………………………………………. 47

13 Constant current electrochemical thiocyanation of other disubstituted aromatic

derivatives…………………………………………………………………………….. 48

14 Electrochemical thiocyanation of alkenes by CPE electrolysis………………………. 50

List of Schemes

Page

1 Electrochemical transformation of functional group……………………………….. 3

2 Charge distribution in thiocyanate anion…………………………………………… 8

3 Substitution reaction of dicarbonyl compounds with thiocyanate anion…………… 10

4 Suggested mechanism for electrochemical thiocyanation in two-phase

solution…………………………………………………………………………….... 18

5 Electrochemical thiocyanation of anisol as a model substrate…………………….. 23

6 A step-wise mechanism of thiocyanation of aromatic compounds………………… 33

7 A concerted mechanism of thiocyanation of aromatic compounds……………….... 34

8 Aromatic substrates…………………………………………………………………. 37

9 Products distribution from electrochemical thiocyanation of 2,3-dimethyl-2- 52 butene……………………………………………………………………………….

10 Mechanism of thiocyanation of alkenes to yield an addition product……………… 53

11 Products distribution from electrochemical thiocyanation of 2,3-dimethyl-1- 54 butene………………………………………………………………………………..

12 Products distribution from electrochemical thiocyanation of cyclohexene………… 55

13 The product from electrochemical thiocyanation of styrene……………………….. 55

14 The product from electrochemical thiocyanation of stilbene……………………..... 56

Abbreviations

AN acetonitrile

CAN cerium(IV) ammonium nitrate

CCE constant current electrolysis

CPE controlled potential electrolysis

CV cyclic voltammetry

DCM dichloromethane

DME dropping mercury electrode

DMF dimethylformamide

DSA dimensionally stable anode

F Faraday (1 F = ~96500 Coulombs)

GC glassy carbon

GLC gas chromatography

NBS N-bromosuccinimide

NMR nuclear magnetic resonance

NTS N-thiocyanatosuccinimide

THF tetrahydrofuran

Abstract

Organic thiocyanates are useful precursors for agrochemicals, dyes, insecticides, and drugs. In organic synthesis, they are also used as a convenient source of ArS- for introducing functional sulfur groups in various organic molecules. Chemical synthesis of aryl thiocyanates can be performed via both electrophilic and radical reactions. In the radical process, the thiocyanate radical is produced by N-thiocyanatosuccinimide (NTS, an analog of NBS), followed by an attack on the aromatic nucleus. However, this reaction is accompanied by by-products that are difficult to remove from the reaction mixture. The electrophilic reaction involves initial oxidation of the thiocyanate anion and its recombination to the thiocyanogen dimer (SCN)2.

Polarization of the S-S bond is then required to generate a positive charge on one of the sulfur atoms, in order to allow an electrophilic attack on the aromatic ring. Oxidation of the thiocyanate anion has been carried out by various oxidizing reagents, such as halogens, metal oxidants, and many other organic and inorganic oxidants. The common drawback in all these reactions stems from the use of large quantities of the oxidizing agent or toxic metal thiocyanate.

Furthermore, the chemical thiocyanation reaction is far from being selective because usually a mixture of isomers is formed, e.g., para- and ortho-isomers by thiocyanation of aromatic derivatives, and thiocyanate and isothiocyanate isomers by addition to alkenes and subsitutions of alkyl bromides and aromatic diazonium salts. In comparison, the electrochemical method affords a “green” oxidizing agent – a non-sacrificial anode.

To accomplish our first goal, we studied a direct, one-pot, electrochemical thiocyanation of methoxybenzene (anisole) as a model for aromatic compounds (Scheme I). The sole product obtained is 1-methoxy-4-thiocyanatobenzene, indicating a high regio- and isomer-selectivity.

OMe OMe

anode (~ 80%) AcOH, SCN- SCN

Scheme I. Electrochemical thiocyanation of anisole as a model substrate

Preparative electrolysis was carried out by both controlled potential and constant current techniques, for comparison. The formation of 1-methoxy-4-thiocyanatobenzene by controlled potential electrolysis (CPE) was found to be more efficient than by constant current technique.

The effects of various parameters, such as: anode material, solvent, electricity consumption, current density, electrolyte, and concentration of the substrate on the outcome of the electrolytic processes were studied.

We have concluded that under acidic conditions the anodic oxidation of thiocyanate anion to its radical favors dimerization over polymerization to parathiocyanogen, (SCN)n. In addition, the electrochemical thiocyanation of anisole affords good yield of both regio- and isomer-selective electrochemical thiocyanation product (Table I).

Table I. “Optimal” conditions for selective preparation of 4-thiocyanatoanisole

Experimental condition Acetic acid

Supporting electrolyte LiClO4 0.5M

Thiocyanate salt NH4SCN

Concentration of thiocyanate salt 0.067M

Charge, Coulombs (F) 426 (2.2 F)

Working electrode Pt foil (area = 5 cm2)

Ratio: salt/substrate 1:2.5

Temperature ambient

Yield of product 4-thiocyanatoanisole 77%

Two suggested mechanisms (a step-wise and concerted heterolytic thiocyanation) can explain the formation of the thiocyyanate products and the electricity consumption of more than 1 F. In both of them, after thiocyanation takes place by electrophilic attack of the electrochemically

ii generated thiocyanogen, the anion thiocyanate was redeveloped and reoxidized. Consequently, the overall process requires more than 1 F/mol electricity consumption.

In the next stage of the present research we expanded the scope of the electrochemical thiocyanation reaction to other aromatic derivatives under similar above-mentioned conditions, with one modification: a mixture of 1:1 acetic and formic acids was used instead of acetic acid only. This change increased the polarity of the medium, allowing more current to pass through and therefore, decreased the duration of electrolysis. Scheme II describes the various mono- and disubstituted aromatic substrates that were investigated for this purpose.

R1 = OMe, Me; R2 = H R1 = OMe, Me; R2 = OMe 1 2 R = NH2, NHEt, NMe2; R = H R2

Scheme II. Aromatic substrates

The thiocyanate products obtained in each case show high regio-selectivity (no ortho isomer was observed) for the mono-substituted aromatics and high isomer-selectivity (no isothiocyanate isomer was detected) for both mono- and disubstituted aromatics (Schemes II and III).

OMe OMe

anode

AcOH, SCN- Me Me SCN

Scheme III. Electrochemical thiocyanation of disubsituted aromatic compounds

Also, we have evaluated the results of electrochemical thiocyanation of different alkenes.

Electrochemical thiocyanation was first implemented on symmetric 2,3-dimethyl-2-butene as a convenient model alkene for which the products were easily analyzed by GLC and NMR techniques. The major product from the thiocyanation reaction is a unique α-formate-β-

iii thiocyanate adduct. In addition, the product mixture contained two minor products, which were characterized as α-isothiocyanato-β-thiocyanate and allylic thiocyanate (Scheme IV). The ratio of the three products is 3:2:1, respectively. Trace amounts of α,β-dithiocyanate were also observed.

HCO SCN

Me CCMe (major product)

Me Me 2,3-dimethyl-3-thiocyanatobutan-2-yl formate

Me CH2SCN CC (minor product)

Me Me Me Me SCN- 2-methyl-3-(thiocyanatomethyl)but-2-ene CC electrolysis Me Me Me Me 2,3-dimethyl-2-butene SCN CCSCN (minor product)

Me Me 2-isothiocyanato-2,3-dimethyl-3-thiocyanatobutane

Me Me

NCS CCSCN (trace)

Me Me 2,3-dimethyl-2,3-dithiocyanatobutane

Scheme IV. Product distribution from electrochemical thiocyanation of 2,3-dimethyl-2-butene

Electrochemical thiocyanation of other alkenes in acetic-formic acids creates α-formate-β- thiocyanate adducts as the major products, in addition to similar to above-mentioned minor products.

In case of alkenes substituted with one or two phenyl rings, the α-formate-β-thiocyanate product was exclusive and selective.

iv In summary, the environmentally friendly electrochemical thiocyanation (that avoids the use of toxic oxidizing agents) was successfully performed by electroorganic methods with various organic substrates under chosen optimal conditions. From a practical point of view, it has been found that the CPE technique employed for the electrochemical thiocyanation process is superior to constant current electrolysis. In addition, the one-pot electrochemical thiocyanation of aromatic compounds, especially those containing at least one methoxy substituent, is more efficient than that of the two-steps thiocyanation of conjugated and non-conjugated alkenes.

1. Introduction

1.1. Electroorganic synthesis

The electrochemistry of organic compounds in the 20th century [1] is based on the work of

Faraday, who was the first to make an electroorganic reaction by electrolyzing an acetate solution and obtaining a gaseous product, ethane. The anodic oxidation of salts of fatty acids to hydrocarbons with loss of carbon dioxide was developed by J. Kolbe to become the first useful electroorganic synthesis:

Pt(anode) - + R-R + 2CO2  2RCOO M

In the middle of the 20th century, electroanalytical methods such as polarography and voltammetry at solid electrodes were developed to study many organic molecules. Those techniques made it possible to investigate more details and understand the intermediate steps in electrochemical reactions. The polarography technique, where current-voltage curves are obtained at the dropping mercury electrode (DME), was invented by J. Heyrovsky [2]. Many examples of inorganic and organic compounds were studied by this polarographic method.

Lingane [3] demonstrated that potentials found by polarography could be used for selective electrolysis at a controlled potential at a macroelectrode, and that preparative electrolysis at the potential of the limiting polarographic current could establish the electrode reaction in polarography. The introduction of potentiostats made it easier to perform electrochemical reactions at controlled potentials. The polarographic investigation of many types of organic compounds was continued primarily by Zuman [4]. The results were used for analysis and guidance for controlled potential electrolysis. Later, other electroanalytical techniques became more popular. One of the most widely used techniques is cyclic voltammetry (CV). The method made it possible to obtain a more detailed understanding of the different steps of the mechanism

1 in electrochemical reactions. The electrode reactions were divided into reversible, quasi- reversible, and irreversible according to the rate constant of the heterogeneous electron transfer.

The media for anodic voltammetry were aqueous or aqueous-alcoholic solutions; therefore the experiments were limited by the available potential range. The exploiting of acetonitrile/NaClO4 as the medium was introduced by Lund [5] in the investigation of alcohols and aromatic hydrocarbons, and widely used in various reactions. Development of new instruments, such as the potentiostat that permits conduction of high current for fast reactions during an acceptable time, enabled wide use of electroorganic synthesis.

Another step in the progress of electroorganic chemistry was the invention of indirect electrolysis, where the electrons are not exchanged heterogeneously directly between the electrode and the substrate; rather the electrode exchanges electrons with a compound, a mediator, which then exchanges electrons with the substrate in the solution. Indirect electrolysis can be simple redox catalysis. The first mediators were inorganic compounds, but later organic mediators, mostly aromatic compounds, were developed.

The kinds of electroorganic reactions were extended to the analogues in classical organic reactions, such as coupling, substitution, cycloaddition, elimination, selective fluorination, and multistep reactions.

During the same period, electroorganic reactions were introduced to industrial processes, because many of them were economically favorable and friendly to the environment, so-called

“green chemistry processes”. One of the best-known processes is the cathodic dimerization of acrylonitrile to adiponitrile, which is used as starting material for the manufacture of two main components for Nylon-6,6 production by Monsanto Company, USA:

reduction H2N(CH2)6NH2 cathode 2 H2CCH2CN (-CH2CH2CN)2

HOOC(CH2)4COOH hydrolysis

In organic synthesis, activation of a substrate takes place by heating or irradiation. However, in electroorganic synthesis, activation of the substrate is accomplished by transferring electrons from it to the electrode (oxidation) or from the electrode to the substrate (reduction). Organic electrochemistry takes advantage of electron transfer in its selective introducing or removing electrons from organic molecules and provides numerous opportunities for exploring and developing novel synthetic transformations. Therefore, the electrochemical method can be used when necessary to reverse the polarity of only one functional group in a molecule and trigger reactions. In this way, highly reactive intermediates can be generated and their reactions could be channeled toward the formation of a desired product. The result is a series of reactions that selectively increase the functionality of molecules and reverse the polarity of known functional groups. For instance, electrons can be selectively added to one of the electron-poor functional groups in order to convert it from electrophile to nucleophile or be removed from an electron- rich functional group in order to convert it from nucleophile into electrophile (Scheme 1).

Scheme 1. Electrochemical transformation of functional group [6]

The ensuing reactive intermediates can be trapped in order to complete reactions that involve the net coupling of either two electrophiles or two nucleophiles in ways that would otherwise be impossible. Such reactions are intriguing because their availability creates the potential for the construction of complex molecules [6].

These opportunities arise because the use of electrochemistry enables a chemist to oxidize (or reduce) molecules at controlled potentials while maintaining neutral conditions. Applications of anodic electrochemistry to the construction of complex molecules serve to demonstrate that electrochemical synthetic methods are not just novelties, but rather useful synthetic tools that are capable of opening up entirely new strategies for synthesis. While electrochemical techniques are still far from routine, the utility of simple reaction setups and the availability of commercial power supplies, electrodes, and reaction cells, means that the majority of electrochemical synthetic methods are readily available. As the methodology becomes more and more versatile, the hope is that an increasing number of chemists will choose to use it [7].

1.1.1. Advantages of electrochemical synthesis [8]

 Active intermediates that are difficult or impossible to obtain by common chemical

reactions are achievable by electrochemical methods.

 Selective introduction or removal of electrons to or from organic molecules.

 In some cases, active intermediates generated at the electrode surface cause the reaction

to be regio-, sterio-, or chemo-selective in organic synthesis.

 Sometimes, a multi-step organic synthesis can be shortened by one or two steps by using

electroorganic synthesis.

 In some cases, the use of simple and cheap raw materials can provide complicated and

expensive products.

 Sometimes, electroorganic syntheses produce very clean products or avoid the generation

of some undesired compounds.

 Typically, electrochemical reactions take place at room temperature.

 In a controlled potential method, the electrochemical reaction can be easily tuned to

produce different products from the same substrate.

 In electroorganic synthesis the rate of electrochemical reaction can be easily controlled

by tuning the potential or current of electrolysis.

 Usually, electroorganic reactions avoid the use of toxic organic oxidants and reductants,

which contaminate the environment.

1.1.2. Disadvantages of electrochemical synthesis

 Electrochemical processes need an electric energy source, which is not always

cheaper than thermal energy.

 Electrochemical synthesis requires special tools, such as electrochemical cells,

electrodes, and equipment.

 Electrochemical synthesis requires a special set of solvents and electrolytes that

sometimes are not environmentally friendly.

 Usually, electrochemical synthesis requires extended time for completing the reaction

because of the limitation in transferring sizeable currents in organic media.

1.1.3. Electrochemical methods [8]

Preparative electrochemical reactions can be performed by two main methods:

 Controlled potential electrolysis (CPE)

 Constant current electrolysis (CCE)

1.1.3.1 Controlled potential electrolysis (CPE)

In controlled potential electrolysis, the potential of the working electrode is kept constant relative to a reference electrode.

Advantage: it is possible to obtain selective products by tuning the potential of the working electrode.

Disadvantages: the electrochemical cell (Fig. 1) is more complex. Usually three- compartment cells with adequate membranes are used. The electrolysis requires the use of a reference electrode as the third electrode. In addition, the equipment for controlled potential electrolysis, namely a potentiostat, is complex and more expensive.

Figure 1. Divided electrochemical cell where: W - working electrode; R – reference electrode; C - counter electrode; S - substrate

1.1.3.2 Constant current electrolysis (CCE) [8]

In constant current electrolysis, the current that passes through the electrochemical cell (Fig.

2) is kept constant by employing a galvanostat.

Figure 2. Undivided electrochemical cell

The electricity consumption for a reaction (this term will be used throughout the thesis) can be described by the following equation:

Q = I x t where Q – electricity consumption, total charge (in Coulombs), t – time (sec), I – current

(Ampers).

1 Faraday is the charge required for reduction or oxidation of 1 mole of substrate by transferring one electron per molecule, as determined by:

1 Faraday = 96500 Coulombs

If “m” is the amount of substrate in moles, the charge required for one-electron oxidation or reduction of ‘m’ moles of substrate is determined by the following equation:

Q = 96500 × m = 1F × m

For more than 1e- oxidation/reduction, where, e.g., n =2:

Q = 96500 × m × n = n × F × m

Advantages: it is very easy to maintain constant current with equipment for constant current electrolysis – galvanostat, which is simply designed and inexpensive.

Disadvantages: potential of electrode is not kept constant, which can decrease the selectivity of the electrochemical reaction. Therefore, the technique is mostly useful for rather simple electrochemical processes.

1.2. Organic thiocyanates

Organic thiocyanate (R-S-C≡N) or isothiocyanate (R-N=C=S) as functional groups are useful precursors for heterocycles [9–17] containing nitrogen and sulfur atoms for preparing dyes, insecticides, and drugs:

S ArSCN X C N

They are also useful as a convenient source of ArS- [18–20] for transformation of various organic molecules into those with sulfur functional groups.

1.2.1. Chemical preparation of organic thiocyanates

1.2.1.1. Formation of organic thiocyanates by a reaction between thiocyanate anions and organic compounds

Anion thiocyanate is created from isothiocyanic acid or its salts. The anion is a weak nucleophile. The two resonance structures are [9]:

- - S CN SCN

Calculated charge distribution in the anion is [9]:

-0.7108 +0.1934 -0.4828 SCN

Scheme 2. Charge distribution in thiocyanate anion

From these calculations, it can be concluded that reaction with organic compounds can produce:

 Thiocyanate products (if nucleophilic substitution takes place at the end of the sulfur

atom).

 Isothiocyanate products (if nucleophilic substitution takes place at the end of the

nitrogen atom).

 A mixture of two isomers. 8

The reactivity of the two ends (N- and S-) of the thiocyanate anion is determined by solvent, counter ion, existing catalyst, concentration, temperature, leaving group, and the structure of the organic compounds with which the anion reacts.

Some examples of reactions of organic compounds with the thiocyanate anion include:

 Alkyl and aryl halides [9]

RHal + [SCN]- → RSCN + Hal-

Usually, solutions of sodium, potassium, or ammonium thiocyanate in water, ethanol, or acetone are used. Ethylene glycol and liquid sulfuric dioxide have also been used as solvents.

However, dipolar aprotic solvents such as dimethylformamide, diethylformamide, dimethyl sulfoxide, and tetramethylene sulfoxide have been shown to be superior since they reduce reaction times, lower temperatures, and improve yields. This has been attributed to the formation of onium-type intermediates that react more rapidly than the original halide with the thiocyanato anion:

- + - (SCN) RX + HCONMe2 R- O=C-NMe2 + X RSCN + HCONMe2

Order of reactivity of organic halides:

Hal = I > Br > Cl >> F

Sometimes, alkyl isothiocyanate isomer is formed as a by-product. The yield of this product from substrates is influenced by substituents on the carbon atom on which substitution takes place:

alkyl halides

10 < 20 << 30

and alkyl < aryl < polycyclic aryl

 Lactones

Anion carboxylate does not undergo substitution with the thiocyanate anion, but lactones with small rings can react with this anion [9]:

H2CCH2 - - + (SCN) NCSCH2CH2CO2 O CO

 Carbonyl and dicarbonyl compounds

Benzoate esters have been shown to give thiocyanates by an SN2 process on fusion with a metal thiocyanate mixture.

fusion - ArCO2R + KSCN/NaSCN RSCN + ArCO2

As expected from these reaction conditions, the corresponding isothiocyanates are also formed.

Transformation of β-dicarbonyl compound to α-thiocyanato-β-dicarbonyl compound was

. achieved by using the supported reagent system CuBr2/Al2O3 KSCN/SiO2 [21] (Scheme 3)

K2S2O8/CuSO4 [22] or phenyl iodochloride (C6H5ICl2) [23] in good yields.

O O O O O O

CuBr2 KSCN 2 R R R R2 R R2

R1 Br R1 SCN R1

Scheme 3. Substitution reaction of dicarbonyl compounds with thiocyanate anion

 Alkyl and aryl sulphonates

The thiocyanato anion displaces the sulphonate anion from alkyl [9] and aryl [9, 24] sulphonates under SN2 conditions:

- - ROSO2R' + (SCN) → RSCN + (OSO2R')

[R' = 4-MeC6H4, 4-BrC6H4, Me]

 Diazonium salts

+ - ArN2 + (SCN) → ArSCN + ArNCS

(major)

When catalysts such as CuSCN [25] or Fe(SCN)3 [9] are employed, they cause the reaction to be more selective toward the major product.

 Organometallic compounds [9]

Alkyl and aryl thalium

R-Tl(OAc)ClO4 + Cu(NCS)2 + KSCN→R-SCN + TlClO4 + Cu(OAc)SCN

 Epoxides, aziridines, and oxaziridines [9]

The reactions give a steriospecific product, only the anti isomer was prepared and isomer- selective, only thiocyanate was formed.

SCN H+ C C C C + (SCN)- C C + O O OH anti H

SCN

C C + HNCS C C

N NH2 anti H

SCN

N C + HNCS N C

O OH anti

 Alkenes and alkynes [9]

Isothiocyanic acid behaves as an electrophilic reagent towards alkenes under heterolytic conditions, adding across electron-rich double bonds in the same manner as the hydrogen halides. The additions are regiospecific, yielding the Markovnicov-oriented products.

However, the products are exclusively mixtures of thiocyanates and isothiocyanates.

Aryls Formation of arylthiocyanates from thiocyanate anion can be performed via radical

. reactions [22–29]. In the radical process, (SCN) is produced by N-thiocyanatosuccinimide

(NTS, the analog of NBS) [17] or by reagent containing different N-bromosulfonamides with

KSCN. The process is followed by the reagent’s attack on the aromatic compounds [29].

However, this reaction is accompanied with by-products that are difficult to remove from the reaction mixture.

R R

N-bromosulfonamide + KSCN MeOH, reflux 0.5h

SCN

Me Me

N-bromosulfonamides = or S N Br S NCH2 O2 O2 Me Br Me Br 2

Also, (SCN) radical can be generated by oxidation of anion thiocyanate from NH4SCN with

. . 2- Mn(OAc)3 [30], I2O5 [31], oxone (2KHSO3 KHSO4 K2SO4) [32], CAN ([Ce(NO3)6]

+ [NH4 ]2) [33], or NaBO3 [34]. The thiocyanate radical attacks the aromatic ring in the para

position or heteroaromatic compounds such as indoles in the 3-position.

 α, β–unsaturated carbonyl compounds [9]

Isothiocyanic acid adds regiospecifically across the conjugated double bond of α, β–

unsaturated carbonyl compounds yielding thiocyanates, isothiocyanates, or mixtures of the

two according to the degree of substitution in the substrates.

O H OH SCN O +2H+ - + +SCN C C C C C C C C C

1.2.1.2. Preparation of organic thiocyanates by using thiocyanogen or related reagents

The term ‘thiocyanation’ means direct replacement of a hydrogen atom by a thiocyano group through the use of thiocyanogen (SCN)2 or its halide-like thiocyanogen – chloride, bromide, or iodide (XSCN, X=Cl, Br, I) [9, 27, 35, 36].

Thiocyanogen, (SCN)2, (Figs. 3 and 4) is a colorless liquid. At -2 – -3ºC thiocyanogen is a crystalline solid. Thiocyanogen and its halides are pseudohalogen analogues of the halogens and interhalogens. Chemical behavior of thiocyanogen is similar to that of halogens: it attacks noble metals (gold, mercury), and reacts with H2S, NO, HN3, NH3, and HCl. The thiocyanogens feature positions between Br2 and I2 on the “halogen scale”.

N≡C-S-S-C≡N

Figure 3. Electronic structure of thiocyanogen [37, 38]

SS C 108.20 C N 1800 N

0 87.8

Figure 4. Dimensional structure and torsion angles of thiocyanogen by theoretical

calculations [39]

Thiocyanogen is soluble in dry inert solvents such as benzene, bromobenzene, CCl4, CHCl3, ether, ethylenebromide, CS2, petroleum ether, methyl acetate, nitromethane, acetic and formic acids, methanol, and acetone in low temperature.

Thiocyanogen may polymerize in solution at room temperature especially under the catalytic influence of heat, light, moisture, or oxygen. Polymerization takes place rapidly to a reddish orange amorphous mass of indefinite composition known as pseudo- or para-thiocyanogen.

The empirical formula of parathiocyanogen is (SCN)x. It is insoluble in any solvent and acts as a semiconductor [40].

Mechanism of formation of parathiocyanogen and possible structure:

NC S S CN . SCN SCN .

S C N S C N x 14

The monomer of parathiocyanogen is a free radical that is made by homolitical breaking of the S-S bond in thiocyanogen. Polymerization of thiocyanogen to parathiocyanogen is an autocatalytic process whose rate of reaction is affected by the concentration of thiocyanogen.

1.2.1.3. Reactions of thiocyanogen

 Hydrolysis

(SCN)2 + H2O → HSCN + HOSCN

HOSCN is an unstable acid that decomposes in water:

3HOSCN + H2O → 2HSCN + HCN + H2SO4

Total reaction:

3(SCN)2 + 4H2O → 5HSCN + HCN + H2SO4

1.2.1.4. Common methods for thiocyanation of organic compounds

 One step

The substrate is placed in the cell in which thiocyanogen was formed (in situ). This method can be used for decreasing or preventing the polymerization reaction of thiocyanogen.

 Two steps

The thiocyanogen is formed in a cell, isolated, and added to substrate. This method is useful for “thiocyanogen number” analysis and as a synthetic method if reaction with the substrate is carried out slowly, such as in an addition reaction. This method can be exploited when the product is difficult to clean after synthesis. Disadvantages of system are low stability of thiocyanogen and its polymerization with elevated temperature or wetness. For that reason, the solvents used for creating free thiocyanogen are dry organic solvents.

1.2.1.5. Methods of preparing thiocyanogen

 Thiocyanogen generated by chemical oxidants [27].

Thiocyanogen can be prepared in the following reactions: o Thiocyanic acid (for preparing free thiocyanogen) with an oxidizing reagent such as

Pb(OAc)4, PbO2, and MnO2, in organic polar or non-polar solvents. The yield of the reaction is poor. o Metal or ammonium thiocyanates with Cl2, Br2 [24], I2 [43], or reagents that can add halogens, such as to phenyl iodochloride (C6H5ICl2) [23, 44], diacetoxyiodobenzene

(C6H5I(OCOH3)2) [45], sulfuryl chloride (SO2Cl2), or N-chloramide. For example:

Pb(SCN)2 + Br2 → (SCN)2 + PbBr2

C6H5ICl2 + Pb(SCN)2 → C6H5I(SCN)2 + PbCl2

The yield of the reaction is better than with thiocyanic acid. The reaction conditions need to use dry solvents to prevent hydrolysis. High concentration of thiocyanogen, heating, product of hydrolysis, and catalysis by light can promote polymerization. The polymerization of thiocyanogen to parathiocyanogen depends on the nature of the solvent. The non-polar solvent supports the polymerization reaction. Stirring and chilling the reaction mixture retards formation of the polymerization product. o Ammonium thiocyanate with N,N-dichlorourea, N-chloroacetamide, and N- dichloropentamethylenetetramine in acetic acid, acetone, methanol, and diethyl azodicarboxilate

(DEAD) in acetonitrile [46]. Addition of a drop of concentrated sulfuric acid improves the yield of thiocyanogen.

O Dissociation of cupric thiocyanate Cu(SCN)2:

2Cu(SCN)2 → 2CuSCN + (SCN)2

Cupric thiocyanate was prepared from copper sulfate and sodium thiocyanate.

CuSO4 + NaSCN → Cu(SCN)2 + Na2SO4

Equivalent proportions of reagents were added to a solution of the compound in methanol or acetic acid, and the mixture warmed to 35–80ºC until the black cupric thiocyanate has changed completely to the white cuprous thiocyanate. The product was isolated by extraction with ether.

This procedure has the advantage over the others previously described of permitting higher temperatures for thiocyanation. But some organic compounds cannot be dissolved in suitable solvents. Detergents can be used to solve this problem.

 Thiocyanogen generated from thiocyanate salts by electrolysis.

Thiocyanogen is produced when concentrated solutions of alkali or ammonium thiocyanates are electrolyzed. NH4SCN is most commonly used.

The electrolysis takes place by two experimental methods: o One-phase solvent systems: organic polar solvent such as acetonitrile [47, 48], or water with ethanol and hydrochloric acid [27], or concentrated hydrochloric acid [13].

In case of organic solvent [47, 48], electrolysis takes place by controlled potential method. The experimental conditions were: applied potential E=0.7V vs. SCE, LiClO4 as electrolyte, concentration of electrolyte 0.1M, working electrode Pt, electrolysis carried out at -10ºC, and thiocyanate salt was KSCN at a concentration of 5*10-2M.

In the case of water mixture [27], electrolysis takes place by constant current method. An undivided cell was used. Current density was 0.02÷0.03Acm-2. Charge consumption that passed during the reaction was 140% of the theoretical calculations. A graphite anode and copper or platinum electrodes were used. NH4SCN was used as thiocyanate salt. The electrolysis carried out at 0ºC.

In the case of concentrated hydrochloric acid, electrolysis takes place by the constant current method [13]. Undivided and divided cells were used. Current density was 1÷10A*dm-2. Charge consumption during the reaction was 140% of the theoretical calculations. Glassy carbon and

graphite were used as anodes, and stainless steel or nickel were used as cathode. NH4SCN and tetralkylammonium salt were used as thiocyanate salt. The electrolysis was carried out at 0ºC.

The thiocyanate product in all above-mentioned solvents was obtained by one-step electrolysis.

Substrates used in electrolysis were olefins [48] and aromatic compounds (aniline [47], aniline derivatives [27, 41, 47], phenol [47], and alkylindoles [48]). Products of thiocyanation of the olefins were mixtures of isomers and dithiocyanates. The result of thiocyanation of alkylindole was the isothiocyanate isomer. o Two-phase solvent system: water and organic (dichloromethane) [49, 50].

Oxidation of the thiocyanate anion takes place in the water phase. The oxidation product, thiocyanogen, transfers into the organic phase through stirring of the mixture of two-phase solvents. The phases can be separated and the organic layer dried by drying reagent. In this case, the substrate was dissolved in dichloromethane with thiocyanogen [50] as explained in Scheme 4 or was added to electrolysis mixture [51].

- - (SCN)3 (aq) (SCN)2 (aq) + SCN (aq)

(SCN)2 (aq) → (SCN)2 (org)

- + (SCN)2 (org) + R-H (org) → R-SCN (org) + SCN + H

Scheme 4. Suggested mechanism for electrochemical thiocyanation in two-phase solution

Electrolysis takes place by the constant current method [50] using an undivided cell. Current density was 15mA*cm-2. Charge consumption in the reaction mixture was 2÷4 F/mol. Graphite

2 (with an area of 20 cm ) was used as both anode and cathode. H2SO4 0.5N was used as electrolyte. NH4SCN at a 2M concentration was used as thiocyanate salt. The electrolysis was carried out at -5ºC.

Substrates used in electrolysis were aromatic compounds such as aniline [50], aniline derivatives [50], phenol [50], and phenol derivatives [51]. Reaction time with anilines was 0.5 hours; reaction with phenol was carried out for 12 hours. The product of all aromatic compounds was the p-thiocyanate isomer.

1.2.2. Identification of organic thiocyanates

1.2.2.1. IR spectroscopy

Thiocyano group gives a sharp, intensive peak at 2150–2170 cm-1.

Isothiocyano group gives a wide, weak peak at 2050–2090 cm-1.

1.2.2.2. 1H- and 13C-NMR

Range of the proton shift of two different functional groups are [52]:

CH3S- 1.9–3 ppm

CH3N- 2.5–3.5 ppm

Protons situated near the thiocyanate group give peaks in a higher field than protons situated

near the isothiocyanate group [47].

Range of the carbon shift of two functional groups are [52]:

-SCN 110–120 ppm

-NCS 125–140 ppm

1.2.2.3. Detection of isothiocyanate and thiocyanate groups by feature reactions [27]

 The reactions of thiocyanate and isothiocyanate with thiol acids serve to differentiate

products of thiocyanation reactions.

RSCN + HSCOAr → RSCSHNCOAr

RNCS + HSCOAr → RNHCOAr + CS2

 A test for aliphatic dithiocyanates consists of the development of a red color with the

addition of ferric chloride to a solution formed by heating the thiocyanate with

aqueous sodium hydroxide followed by acidification.

 Heating of thiocyanate with alkaline lead tartarate results in the formation of yellow

precipitate.

 Reaction with sodium malonic ester to produce a disulfide has been suggested as a

qualitative test.

 A method for quantitative determination involves heating the compound under reflux

with an ethanolic solution of sodium sulfide Na2S.

2RSCN + Na2S → R2S + 2NaSCN

After removal of the excess sulfide, silver thiocyanate, AgSCN, is precipitated by the

addition of standard silver nitrate AgNO3.

NaSCN + AgNO3 → AgSCN↓ + NaNO3

The excess of silver ion is determined by the Volhard method.

2. Objectives of the proposed research

Our research focused on the following goals:

 To develop “optimal” conditions for electrochemical thiocyanation of anisole as a

model substrate to achieve a selective thiocyanation product in good yields.

 To use the above mentioned “optimal” conditions for electrochemical thiocyanation

of various aromatic compounds and alkenes.

 To investigate the mechanism of the electrochemical thiocyanation of organic

compounds under our electrochemical conditions in comparison to other suggested

mechanisms.

3. Results and discussion

3.1. Choosing “optimal” conditions for good yield and selective electrolysis [53].

To achieve our research goals, we first needed to check the oxidation potential of anion thiocyanate in acetonitrile, the solvent that is most useful for organic electrosynthesis.

4,E-05

2,E-05

0,E+00 00,511,522,5 -2,E-05 -4,E-05 Current, mA Current, -6,E-05 -8,E-05

-1,E-04 Potential, V (vs Ag/AgCl) on Pt

Figure 5. Cyclic voltammogram of anion SCN- in acetonitrile, scan rate 50 mV/sec

We observed one pair of waves corresponding to the one-electron quasi-reversible oxidation step of anion SCN- (Fig. 5). (It should be noted that the Ep is too large here due to the high iR drop inserted by the non-polar solvent). After electrochemical reaction, dimerization of two radical thiocyanates takes place, to generate thiocyanogen:

SCN- - e SCN.

. 2SCN (SCN)2

Initial experiments in our laboratory started with phenol and the electrochemical reaction that takes place is shown below:

OH OH

Anode SCN-

SCN 22

In the literature, thiocyanation of phenol takes place through two electrochemical methods: constant current [49] and controlled potential [46]. Initial conditions for electrolysis were obtained from the literature and under controlled potential conditions the yield of thiocyanated phenol was 70%. Our attempts to further increase the yield of the final product were unsuccessful. For example, increasing the temperature from -10ºC to 25ºC gave less thiocyanation product because the thiocyanogen polymerizes in elevated temperature and does not react with the substrate. For avoiding the polymerization of thiocyanogen we tried to use different mixtures of water and organic solvents, but this also did not increase the yield of the product, until we used solely acidic medium. In this case phenol was not suitable to be used as a substrate because it is highly soluble in the acidic water phase during work-up, making it impossible to be fully extracted, and therefore causing the yield to decrease after the work-up procedure.

Anisole, unlike the acidic water-soluble phenol, was chosen as a model substrate to undergo direct thiocyanation by electrochemically generated (SCN)2:

OMe OMe Anode AcOH, SCN-

SCN

anisole 4-thiocyanatoanisole (1)

Scheme 5. Electrochemical thiocyanation of anisol as a model substrate

It is noteworthy that its chemical thiocyanation affords two isomers: para- and ortho- thiocyanatoanisoles in about a 3:1 ratio, respectively [26]. However, the results in all experiments presented in this work indicate a high selectivity towards the exclusive formation of para-isomer.

1,30E-05 anisole thiocyanate 8,00E-06

3,00E-06

0 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 2 Current, A -2,00E-06

-7,00E-06

-1,20E-05 Potential, V (vs Ag/AgCl) on Pt

Figure 6. Cyclic voltammogram of anion SCN- and anisole in acetic acid; scan rate 50 mV/sec

The CV of anisole does not show any oxidation peak up to 1.7 V (vs. Ag/AgCl), whereas

[SCN]- is oxidized at ~0.95 V (vs. Ag/AgCl) irreversibly (Fig. 6). The applied potential chosen throughout CPE was 1.25 V (vs. the Ag wire quasi-reference electrode that corresponds to 1.1 V vs. Ag/AgCl), enabling the exclusive oxidation of the thiocyanate salt.

The effect of changing the solvents of electrolysis on the yield of the thiocyanation product is summarized in Table 1.

Table 1. Yields of 4-thiocyanatoanisole from CPE*

Solvent system Yield (%)

Acetic acid** 57

Acetonitrile 25

Acetic acid + 10% water 13

Acetic acid + 10% methanol 8

Acetic acid + 1% methanol 40

Acetic acid + 10% methanol +1% acetic anhydride 9

- * [LiClO4] = 0.5M; [NH4SCN] = 0.067M; [SCN] salt; anisole ratio = 1:2.5; Pt anode (foil, ~5 cm2); room temperature; applied potential: 1.25 V vs. Ag wire quasi-reference electrode; ranges of current density run from initial 5mA/cm2 to final 1mA/cm2 for organic solvents and from 25 mA/cm2 to 5mA/cm2 for organic-aqueous solution. Electrolysis was arbitrarily terminated after consuming 1.5 F (300 coul). ** Addition of acetic anhydride to remove residual water gives a similar result within experimental error.

The results in Table 1 indicate that introduction of any polar solvent (aprotic CH3CN or protic

CH3OH, H2O) is not as helpful as employing glacial acetic acid in providing a good yield of product. It is noteworthy that in all cases but one (glacial acetic acid), polymerization of SCN- took place, yielding an orange powder of parathiocyanogen, (SCN)n. This insulating polymer causes passivation of the electrode surface; therefore, pulsing was required throughout each electrolysis.

Table 2. Effect of electrolyte on the yield of 4-thiocyanatoanisole*

Supporting electrolyte Yield** (%)

LiClO4 0.1M 15

LiClO4 0.5M 57

NaClO4 0.5M 33

Bu4NClO4, 0.2M 0

NaOAc 0.5M 0

Et4NHSO4 0.5M 16

Bu4NBF4 0.5M 0

5% concentrated H2SO4 0

* For experimental conditions see a footnote in Table 1. ** When 4-thiocyanatoanisole was not formed, a yellow-orange powder of [SCN]n polymer was generated instead. Entry 2 was also attempted in a non-divided cell and the yield of the desired product was lower (24 %).

Upon examining the data in Table 2 it appears that the use of alkali perchlorate salts affords better yields of (1). However, acetic acid is a weak acid and has a low dielectric constant ( =

~6.2), causing only a slight dissociation of electrolytes. Consequently, a low electrical conductivity is expected. Therefore, a relatively high concentration of electrolyte is required to maintain a reasonable magnitude of current density (1–2 mA/cm2), and indeed, in the presence of

0.5M LiClO4, instead of 0.1M, the yield increased by almost a factor of 4. It is noteworthy that whenever the yield of product (1) is zero in some of the entries, it is due to rapid formation of the polymer, (SCN)n. The reason(s) favoring this competing reaction is not well understood yet, especially in the case of Bu4NClO4. However, in the presence of acetate ions, it is a well-known phenomenon that a strong specific adsorption of these anions on Pt surface (above 0.75V vs.

SCE) can strongly hinder electrochemical reactions [54, 55]. Therefore, in this particular case, it is not surprising that the dimerization of (SCN) radicals at the electrode surface is hindered.

Table 3. Effect of anode material on the yield of 4-thiocyanatoanisole*

Working electrode Yield (%)

Pt (foil, 5 cm2) 57

2 PbO2 (rod, 6 cm )** 16

Glassy carbon (plate, 6c m2) 18

Graphite rod (10 cm2) 41

Carbon felt (6 cm2) 14

Graphite cloth GC-10 (6 cm2) 47

Reticulated carbon (6 cm2) 49

* For experimental conditions see a footnote in Table 1. ** The PbO2 electrode was prepared by procedure described in Ref. 56.

The results described in Table 3 demonstrate the importance of the nature of the anode material on the outcome of the CPE of anisole. It is obvious that a Pt anode was superior to graphite cloth, rod, or reticulated carbon, and much better than glassy carbon or PbO2 or carbon felt in terms of product yield.

Table 4. Effect of thiocyanate salts on the yield of 4-thiocyanatoanisole*

Thiocyanate salt Yield (%)

NH4SCN 57

Bu4NSCN 43

KSCN 28

* For experimental conditions see a footnote in Table 1.

Three thiocyanate salts were examined (Table 4), and in spite of the better solubility of

Bu4NSCN over NH4SCN, the yield of 4-thiocyanatoanisole (1) was greater in the presence of the latter salt, possibly due to a better ionic dissociation in acetic acid.

Table 5. Effect of NH4SCN concentration on the yield of 4-thiocyanatoanisole*

Concentration of salt (M) Yield (%) (F)

0.13 5 (0.7)**

0.10 33 (1.5)

0.067 57 (1.5)

0.033 22 (1.5)

* For experimental conditions see a footnote in Table 1. ** The current reached its background value and no additional electricity could be transferred due to electrode coating by a polymer.

The results in Table 5 indicate that there is an optimal concentration of thiocyanate salt for producing a better yield of product 4-thiocyanatoanisole. It seems that the greater the concentration of NH4SCN the faster the formation of polymer (SCN)n.

Table 6. Effect of NH4SCN/anisole ratio on the yield of 4-thiocyanatoanisole*

Ratio Yield (%)

1:1 25

1:2.5 57

1:5 48

* For experimental conditions see a footnote in Table 1.

As expected, when the salt/anisole ratio is in favor of the substrate the yield of 4- thiocyanatoanisole increases (Table 6) because of the greater probability to trap/react with the electrogenerated thiocyanating agent. The organic substrate must be in excess relative to the thiocyanate salt in order to increase the rate of the reaction between (SCN)2 and the substrate compared with the competing reaction of decomposition/polymerization of the electrogenerated

(SCN)2.

Table 7. Effect of electricity consumption (NH4SCN, 0.067M)

Charge, Coulombs (F/mol) Yield (%)

426 (2.2) 77

305 (1.5) 57

156 (0.8) 19

* For experimental conditions see a footnote in Table 1.

90 80 70 60 50 40

Yield, % Yield, 30 20 10 0 0 100 200 300 400 500 Charge, coul

Figure 7. A graphical illustration of data from Table 7 with extrapolation to zero yield.

Table 7 shows that the greater the electricity consumption the greater the yield of product 4- thiocyanatoanisole. However, the current yield decreases with greater electricity consumption

- because only 1F/1mole of SCN (or 2F/molecule of (SCN)2) is required to generate SCN or

(SCN)2 quantitatively. There was no reason to consume more electricity than what is shown in

Table 7 because the cell current decreased to less than 1 mA. The results in Table 7 are also shown graphically in Figure 7.

Table 8. “Optimal” conditions based on the results described in Tables 1–7

Experimental condition Acetic acid

Supporting electrolyte LiClO4 0.5M

Thiocyanate salt NH4SCN

Concentration of thiocyanate salt 0.067M

Charge, Coulombs (F) 426 (2.2 F)

Working electrode Pt foil (area = 5 cm2)

Ratio: salt/substrate 1:2.5

Temperature ambient

Yield of product 4-thiocyanatoanisole 77%

Table 8 summarizes the “optimal” conditions derived from Tables 1–7 under which CPE of anisole was carried out, increasing the yield of 4-thiocyanatoanisole (1) to about 80%.

Just for comparison, the thiocyanation of anisole was also conducted by constant current electrolysis under the “optimal” conditions described in Table 8, at different current densities. A summary is given in Table 9. Clearly, the lower the current the density the greater the yield of the product; but apparently, this method is less favorable than CPE for making 4- thiocyanatoanisole (1) by preparative electrolysis. It is probable that the constant current method is less efficient than the constant potential one due to a favorable undesired competing reaction of formation of polymeric parathiocyanogene in the former method.

Table 9. Results from constant current electrolysis under the "optimal conditions” (described in Table 8)

Current, mA (on Pt foil, 5 cm2) Yield (%)

50 8

25 14

10 25

5 33

3.2. Mechanism

3.2.1. Does the mechanism involve 1e- or 2e- oxidation?

Since the applied potential for CPE (1.25 V vs. Ag wire) was less anodic than the oxidation potential of anisole (Fig. 6), it is reasonable to assume that the electrochemical process involves the exclusive oxidation of the SCN- salt and not the oxidation of the aromatic ring. It was suggested that heterolytic addition of chemically prepared thiocyanogen, namely electrophilic thiocyanation, to alkenes [57] and aromatics [26] takes place in a variety of organic solvents, whereas homolytic (free radical) thiocyanation takes place upon irradiation of thiocyanogen [58].

Does the mechanism of thiocyanation of aromatic compounds in acetic acid involve 1e- (Eq.

1) or 2e- (Eq. 2) oxidation?

- - . [SCN] - 1e → [SCN] / 1/2[SCN]2 (Equation 1)

[SCN]- - 2e- → [SCN]+ (Equation 2)

To answer this question, we examined the cyclic voltammogram of the oxidation of anion thiocyanate in acetic acid in the presence of ferrocene which is known to undergo one-electron reversible oxidation process. An equivalent amount of ferrocene was added to a solution containing the test compound. Upon comparing the two oxidation peaks (Fig. 8) – although they

31 seemed to be similar in intensity, we could not conclude explicitly that this is a one-electron oxidation process, because the thiocyanate anion oxidation peak is irreversible, unlike that of ferrocene.

1,00E-05 5,00E-06

A 0,00E+00

0 0,2 0,4 0,6 0,8 1 1,2 1,4 -5,00E-06

-1,00E-05 Current, -1,50E-05

-2,00E-05 Potential, V (vs Ag/AgCl) on Pt

Figure 8. Cyclic voltammogram of anion SCN- with ferrocene in acetic acid

To shed further light on this issue, we carried out an experiment in which we checked the changes in the current of electrolysis as a function of charge (Fig. 9). The intersection of the extrapolated line with the x-axis gives us the charge of the system when the current equals zero.

8 7 6 5 4 3 Current, mA Current, 2 1 1.7 F 0 0 50 100 150 200 250 300 350 400

Charge, coul

Figure 9. A coulometry experiment with extrapolation to zero current in acetic acid

We can see from this graph that during electrolysis, the charge needs to exceed ~350 coulombs, which corresponds to 1.7 F/mol, although the formal exhaustive electrolysis requires

1 F/mol. This discrepancy between the two results will be explained later by the suggested mechanism in Section 3.2.2 (Scheme 6), showing that actually more SCN- is available for further anodic oxidation, due to its generation during the thiocyanation process. As a result, more electricity is consumed due to further oxidation of regenerated SCN-.

3.2.2. A step-wise heterolytic or concerted thiocyanation mechanism?

In reactions 1–4 in Scheme 6 we suggest a step-wise heterolytic thiocyanation. Reaction 1 indicates the initial electrochemical process to generate the corresponding radical from the oxidation of the thiocyanate anion, and its dimerization to thiocyanogen. Reactions 2 and 3

+ describe the formation of electrophilic [SCN] from (SCN)2 due to the polarity of the S-CN species, and stabilization of the SCN- through hydrogen bonding due to the ability of acetic acid to coordinate with the thiocyanate. Reaction 4 demonstrates an electrophilic attack on the aromatic nucleus by [SCN]+.

- anode . 2SCN 2[ NCS] (SCN)2 (1) -2e-

+ - ...... NCS S C N HOOCCH3 (2)

- + ...... [ NCS ] + [SCN HOOCCH3] (3)

+ArH H + + + ...... -H [SCN HOOCCH3] Ar Ar-SCN (4) -[HOOCCH ] 3 SCN

Scheme 6. A step-wise mechanism of thiocyanation of aromatic compounds

From the finding that the reaction of thiocyanogen with various phenols is bimolecular [9, pp.

835], we suggest a plausible SE2 mechanism, as represented by reaction 1 in Scheme 7. It shows an alternative electrophilic attack through a concerted mechanism.

- anode . 2SCN 2[ NCS] (SCN)2 (1) -2e-

+ - ...... NCS S C N HOOCCH3 (2)

[ NCS ]- +ArH

H + -H+ Ar Ar-SCN (3) SCN

Scheme 7. A concerted mechanism of thiocyanation of aromatic compounds

As can be seen from Schemes 6 and 7, two mechanisms can explain that after thiocyanation takes place by electrophilic attack of electrochemically generated thiocyanogen, the anion thiocyanate was redeveloped and oxidized. This process needs more then 1 F/mol electricity consumption and in practice 1.5–2 F have passed for oxidation of an initial 1 mole of NH4SCN.

It is noteworthy that both suggested mechanisms explain the observation that considerably more than 1F could be transferred (Table 7).

The step-wise mechanism with a non-bulky electrophile cannot explain either the selectivity towards the exclusive formation of the para-isomer or the lack of formation of any isothiocyanate derivative, Ar-NCS. Likewise, on similar grounds, a homolytic attack by electrogenerated non-bulky radical of type [SCN] is also ruled out.

The exclusive formation of the para isomer without obtaining the ortho isomer is probably due to the steric requirements of the bulky thiocyanogen molecule, especially when it is hydrogen bonded.

As to the isomer selectivity that is expressed by the exclusive formation of Ar-SCN with no

ArNCS present, it is due to the polarization of the species [(+)‘S-C≡N’(-)] within each thiocyanato group. Therefore, electrophilic attack on the aromatic ring occurs via a sulfur atom of the thiocyanogen molecule and thus leads, via a kinetically controlled reaction, to the initial attachment of a thiocyanato group rather than an isothiocyanato group (in spite of the greater

AR-N than Ar-S bond strength).

Previously we have postulated that the reason for the selectivity of the thiocyanation of anisole to be both regio- (no ortho isomer) and isomer- (no isothiocyanate) selectivities could be attributed to its bulkiness and nature (it “blocks” the nitrogen site), respectively, of the thiocyanation species acid-thiocyanate “complex” mentioned in Schemes 6 and 7.

For comparison with other mechanistic schemes, according to literature reports [9, 27], it has been suggested that chemical thiocyanation by thiocyanogen takes place by two main mechanisms – heterolytic and homolytic. In the heterolytic reaction the thiocyanogen reacts like an electrophile under commonly used conditions (temperature: -10ºC ÷ 20ºC, dark or scattered sunlight). Polarization of the S-S bond in heterolytic reactions of thiocyanogen breaks the bond to give anion and cation thiocyanates. Charge distribution in cation thiocyanate produces an electrophilic attack of organic compounds, mostly via the sulfur atom of the thiocyanate cation

[41]:

+ - X: SCN X SCN + (SCN)- SCN

- - X = Cl , Br

As a result, the main products of thiocyanation are the kinetically favorable thiocyanate organic derivatives followed by the thermodynamically less stable isothiocyanate products.

Thiocyanogen can attack aromatic compounds to give aryl thiocyanates. The mechanism of this transformation has not been investigated, but from practical results it can be concluded that 35 electron-donating substituents on the aromatic ring increase the reaction rate and with electron withdrawing groups the reaction rate decreases. From this observation it can be considered that the reaction is bimolecular SE2 type:

R R R

-SCN - -H+ + (SCN)2

H SCN SCN

Under homolytic reactions of thiocyanogen, the S-S bond of thiocyanogen is readily broken homolytically, giving resonance-stabilized thiocyanato radicals:

.S-C≡N ↔ S=C=N.

The thiocyanato canonical form makes the main contribution. The homolysis is readily affected by ultraviolet light from mercury-vapor lamps, by sunlight, or even diffuse light. Furthermore, in the dark, radicals from the breakdown peroxides, present in the reactants or formed in situ by action of atmospheric oxygen, can also affect the homolysis. Thiocyanogen acts as a source of thiocyanato radicals under very mild conditions. Thiocyanato radicals can initiate radical chain reactions by substitution or addition. In this reaction the thiocyanato radical behaves as an electrophilic radical.

3.3. Electrochemical thiocyanation of aromatic compounds [59]

3.3.1. Controlled potential electrolysis (CPE)

In the present study we have examined the direct electrochemical thiocyanation of various aromatic compounds, including substituted methoxybenzenes and anilines in the presence of electrochemically generated thiocyanogen. Scheme 8 describes the various mono- and disubstituted aromatic substrates that have been investigated for this purpose.

R1 = OMe, Me; R2 = H R1 = OMe, Me; R2 = OMe 1 2 R = NH2, NHEt, NMe2; R = H R2

Scheme 8. Aromatic substrates

Note that no thiocyanation products were detected when the substrate contains a deactivating substituent such as Cl, Br, OCOCH3, or NO2.

The thiocyanation products emerging from the mono- and disubstituted aromatic substrates studied are summarized in Table 10. In general, the results indicate that a high isomer-selectivity was achieved because all products are exclusively thiocyanates with no formation of isothiocyanate isomers. This trend is in line with our previous observation in the case of anisole

[53].

Table 10. Electrochemical thiocyanation of substituted anisole, toluene, and aniline derivativesa

b Entry Substrate Ep(ox)/V Product Yield (%)

OMe OMe

1 1.95 (1) 80% c

SCN Me Me

2 2.24 (2) 15% d

SCN OMe OMe

3 1.55 (3) 74%

OMe OMe SCN OMe OMe OMe OMe 4 1.49 (4) 66%

SCN OMe OMe 1.35 (E , 5 1/2 (5) 12%d quasi- reversible) SCN OMe OMe OMe OMe

6 1.74 (6) 38%

Me Me SCN OMe OMe Me Me 7 1.79 (7) 60%

SCN

OMe OMe SCN 8 1.60 (8) 10%d

Me Me Me Me

9 2.15 (9) 13% Me Me

SCN

N(Me)2 N(Me)2

(10) 10 0.80 (E1/2) 42%

SCN NHEt NHEt

(11) d 11 0.83 (E1/2) 15%

SCN

NH2 NHCOH

12 1.36 f (12) 15%e

SCN a The oxidation peak potential of thiocyanate anion is ~1 V (vs. Ag/AgCl). All substrates in entries 1–9 have peak potentials in the range of 1.35–2.2 V (vs. Ag/AgCl), well above the oxidation potential of the thiocyanate anion. As to entries 10–12, see the Discussion section, p. 52. The proper experimental conditions for each entry are described in the Experimental Section, p. 72. The initial current was typically ~5 mA in acetic acid and >20 mA in mixtures of acetic and formic acids. b Oxidation peak potentials (vs. Ag/AgCl) were measured by CV in solutions of acetic and formic acids (1:1) –0.1M LiClO4 on a glassy carbon working electrode; Scan rate: 50 mV/sec. c This result is taken from Ref. 53. d The remainder is mostly unreacted starting material. e A formylation reaction occurred at the amino group converting all the aniline or partially the aniline derivatives to its formamide derivative, prior to thiocyanation. f Value relates to formanilide, formylation product, formed after adding aniline to a mixture of formic and acetic acids.

Previously we have shown [53] that polar acidic solvents promote polarization of the S-S bond in the electrochemically generated thiocyanogen dimer (SCN)2. The partial positively charged species could then attack aromatic substrates to yield the desired thiocyanation products, according to the mechanism outlined in Schemes 7 and 8.

All substrates in entries 1–9 have peak potentials in the range of 1.35–2.2 V (vs. Ag/AgCl), well above the oxidation potential of the thiocyanate anion (~1 V vs Ag/AgCl). As to the aniline derivatives in entries 10–12, see relevant discussion below. In general, the results indicate that a high isomer-selectivity was achieved because all products are exclusively thiocyanates with no formation of isothiocyanate isomers. This trend is in line with our previous observation in the case of anisole [53].

The electron density on the aromatic substituted ring plays an important role in the yield of the thiocyanation product. The presence of a strong electron-donating substituent, such as a methoxy group, strongly activates the aromatic ring to give a good yield of para substituted thiocyanate (Table 10, entry 1). However, the efficiency of the thiocyanation reaction decreases considerably when a weaker electron-donating substituent is employed (a methyl group, entry 2).

This finding could account for the weak electrophilic nature of acid-thiocyanate “complex”

(Schemes 7 and 8).

In the case of disubstituted anisoles, the para position of one of the methoxy groups in 1,3- dimethoxybenzene is activated by both methoxy substituents towards an electrophilic attack.

Therefore, as expected, of the three dimethoxybenzenes, the greatest yield (74%) of thiocyanate product has been obtained for this isomer (entry 3). However, in the case of 1,2- dimethoxybenzene, the para position is now activated by only one methoxy group (and deactivated by the other) and, therefore, the yield of the thiocyanate product decreases (66%)

(entry 4). For 1,4-dimethoxybenzene, the para position is occupied and all available ortho positions for electrophilic attack are activated and deactivated at the same time, in addition to the

steric hindrance applied by the bulkiness of acid-thiocyanate “complex”. As a result, a sharp decrease in the yield of the desired product (12%; entry 5) takes place.

A similar trend should be expected for the three isomers of methylanisoles (entries 6–8); namely, when both substituents exert an inductive effect at different sites of the aromatic nucleus, the more powerful activating group has a dominant influence, and that is why the thiocyanate group occupies the para position to the methoxy rather than to the methyl substituent in the case of m-methylanisole (entry 6). The same argument applies when the inductive effect of the two substituents oppose each other, as in the case of o-methylanisole (entry 7).

Surprisingly, the ortho isomer of methylanisole afforded a greater yield (60%) of the thiocyanate product compared to that obtained from the meta isomer (38%), in contrast to the trend observed for the corresponding dimethoxybenzene isomers. This result could be ascribed to the steric hindrance exerted by the methyl group at its ortho position (in addition to the bulkiness of acid-thiocyanate “complex” described in Scheme 7 and 8), which is not applicable in the case of 1,3-dimethoxybenzene (entry 3). It is noteworthy that the yield from each isomer (entries 6–8) is less than that from the corresponding ones of the dimethoxybenzenes (entries 3–5). This outcome is attributed to the smaller activating effect of the methyl group with respect to the

+ methoxy group (p values for methyl and methoxy groups are -0.31 and -0.78, respectively)

[60].

The observation that m-xylene gave a low yield of a thiocyanate product (13%, entry 9) with a complex mixture of side-chain products and parathiocyanogen (SCN)n suggests that intermediate acid-thiocyanate “complex” is a weak electrophile. In addition, the electrophilic thiocyanation process could be sensitive not only to the electron-donating ability of the substituent, but also to steric hindrance (Me vs. OMe). Therefore, stronger activating groups, or at least as strong as the

+ methoxy substituent, are to be examined. Accordingly, amino substituents (p values for NH2 and NMe2 groups are -1.3 and -1.7, respectively) appear to be good candidates for this purpose.

However, a drawback of their use stems from the fact that aniline, and its N-alkyl and N,N- dialkyl substituted derivatives, are oxidized in the range of 0.7–1 V [61] and therefore, all compete with the oxidation of the thiocyanate anion. Consequently, for this reason and others

(e.g., transformation of the substrates to other types of products [62]), the yield of the thiocyanate products is not expected to be high. Indeed, N,N-dimethylaniline gave only 42% of p-SCN-C6H4NMe2 (entry 10). In the case of aniline and N-ethylaniline (entries 11 and 12), in addition to the competition problem, both substrates undergo hydroformylation (whenever formic acid is present), presumably prior to thiocyanation, which causes the aromatic ring to be less susceptible to an electrophilic attack. This further diminishes the yield of the desired products. Apparently, in both cases the major products were C6H4NHCOH and C6H4N(Et)COH, respectively. N-ethylaniline afforded only 15% of p-NCS-C6H4NHEt, whereas aniline itself yielded 15% of the respective hydroformylated product, p-NCS-C6H4NHCOH (it is likely that the hydroformylation took place after the initial thiocyanation reaction). Notably thiocyanation of N-ethylaniline and toluidines was previously carried out under different experimental conditions (constant current, aqueous ethanol-HCl solution, and low temperature) in a two-step reaction (first electrochemical generation of thiocyanogen and then addition of the substrate) affording good yields (~60%) of the desired thiocyanation products [63].

Finally, it is noteworthy that whenever the yield of the thiocyanation product decreases, the yield of parathiocyanogen increases, as evidenced by the color change in the solution (from colorless to pale yellow to yellow to orange, the actual color of the polymer).

We also examined the thiocyanation of other substrates under similar conditions, but the results are poor, as summarized in Table 11.

Table 11. Electrochemical thiocyanation of other aromatic substrates

Entry Substrate Product Yield (%)

O O (13) 1 8% SCN OH OH

2 (14) 9%

SCN OH OH

3 (15) 7% OCH3 OCH3

SCN

4 No product

(16) 5 8%

SCN

NHCOCH3 NHCOCH3

6 (17) 7%

SCN

SCN (18) 7 N N 8% H H

SCN (19) 8 N N 15% H H

H H N N (20) 9 10%

SCN H H N N (21) 10 2%

SCN

Again, whenever low yields of thiocyanation products were obtained, most of the electricity was consumed to oxidize [SCN]- to its polymer (parathiocyanogen), as reflected by the formation of orange solid as a precipitate.

In general, the reason for the low yield of thiocyanate products could also stem from the competing oxidation of the substrates with the thiocyanate anion (e.g., for phenol, pyrrole and indole) or the weak nucleophilicity of the aromatic nucleous (or both).

It seems that diphenyl ether (entry 1, Table 11) is less reactive toward thiocyanation than anisole, because apparently one of the phenyl rings behaves as an electron-sink causing the other ring to be less nucleophilic.

As to the phenolic derivatives (entries 2 and 3), the low yield of the thiocyanation products could stem from the facile oxidation of the phenol group prior to thiocyanation, yielding other products (e.g., conjugated cyclic ketones, dimers). Indeed, the presence of a carbonyl group in the product mixture was confirmed by IR spectroscopy (1700–1730 cm-1). This explanation is also supported by the fact that both phenol and m-methoxyphenol are oxidized at lower potentials than the thiocyanate anion [62]. By the way, in the case of thiocyanation of cresoles

(o-, m-, and p-), no desired thiocyanate products were detected even in trace amounts, for the same reason as described above.

Aromatic hydrocarbons, such as naphthalenes (entry 4) and anthracene (entry 5) have also been tested for electrochemical thiocyanation. However, whereas naphthalene gave no desired product, anthracene yielded 9-thiocyanatoanthracene in poor yield (8%).

Entry 6 describes the results from electrochemical thiocyanation of acetanilide. Obviously the poor yield of the product stems from the deactivating effect of the N-Acetyl group on the aromatic nucleus towards electrophilic thiocyanation.

A series of aromatic heterocyclic nitrogen-containing compounds have been investigated towards electrochemical thiocyanation (entries 7–10), and again, afforded poor yield of thiocyanation products (2–15%). It is likely that all undergo a partial protonation (e.g., pyridine, entry 8) that hinders further thiocyanation or polymerization (e.g., pyrrole, entry 7).

In comparing the above results with the literature [9, 27], it appears that hydrocarbons such as benzene and naphthalene do not undergo direct heterolytic thiocyanation but do so only with a catalyst such as Friedel-Crafts, which increases polarization of the S-S bond. Polynuclear hydrocarbons such as anthracene and azulene react with thiocyanogen to give dithiocyano derivatives:

SCN SCN

However, primary, secondary, and tertiary amines of benzene, naphthalene, and anthracene react readily and give high product yields. Thiocyanation occurs in the para position to the amino group or ortho if the para position is occupied. In the latter case, the rate and yields are generally lower, probably due to the steric requirement of the bulky thiocyanogen molecule and cyclization to benzothiazoles or benzothiazolines commonly occurs [11, 13]. Phenols of benzenes, naphthalene, and anthracene behave similarly but are not as reactive as the analogous amines [9]. In aminophenol [9] the amino group controls the orientation of attack.

3.3.2 Constant current electrolysis (CCE)

The results from attempts to investigate the electrochemical thiocyanation process by carrying out electrolyses under constant current conditions are described in Table 12 for some selective examples. Whereas similar regio- and isomer-selectivities have been observed as in the use of the CPE technique, the reaction has certainly become less efficient now in terms of yields of the final products. This behavior is not surprising because, unlike the controlled potential technique, the constant current technique is known to be less selective in many cases. Entries 1–3 are confined to anisole at different current densities but with the same amount of electricity consumption. Clearly, the yield of the product p-thiocyanatoanisole increases (from 31% to 64%) with decreasing charge density (from 10 to 1 mA/cm2, respectively). However, the low current density and duration (about 17 hrs) of electrolysis of 2 mmol of thiocyanate anion by consuming just 1.5 F/mol (entry 3) is far from being practical. With greater electricity consumption (entry 4) the product’s yield increases to 75% but, again, about 26 hrs were required to obtain that. Just for comparison with anisole, o-dimethoxybenzene (entry 5) and o-xylene (entry 6) were electrolyzed under the same conditions used in entry 3 for anisole. The results show that the yields of products were 29% (ring-thiocyanation) and 13% (side-chain thiocyanation), respectively, which is considerably less than what was achieved by controlled potential electrolysis for these substrates (Table 11). The lower yields could be attributed to the simultaneous oxidation of the substrate and the thiocyanate anion, which may lead to other types of products besides thiocyanation of the aromatic nucleus.

Table 12. Constant current electrochemical thiocyanation of anisole and some representative disubstituted aromatic derivativesa

Entry Substrate Product Current Charge Yield density (Coul) (%) (mA/cm2) [F] 1 OMe OMe 10 31 300 2 4 58 [1.5] 3 (1) 1 64 4 450 1 75 SCN [2.25] 5 OMe OMe OMe OMe 300 (4) 4 29 [1.5]

SCN

Me CH2SCN Me Me 300 6 4 13 (22) [1.5]

a In a mixture of acetic and formic acids (1:1), 0.1M LiClO4 employing Pt foil electrodes and a divided cell frit membrane; 5mmol substrate and 2mmol NH4SCN were used.

Other aromatic substrates have been investigated for their thiocyanation at constant current, such as phenol and it derivatives (Table 13).

In all cases, the yields of the desired thiocyanation products were low (4 to 24%), probably due to competing electrochemical reactions, such as of the substrates.

Table 13. Constant current electrochemical thiocyanation of other disubstituted aromatic derivativesa

Entry Substrate Product Current Charge Yield density (Coul) (%) (mA /cm2) [F] OH OH

1 (14) 4 300[1.5] 7

SCN OH OH

Me Me 2 SCN or (23) 4 300[1.5] 12 OH NCS

Me OMe OMe

(5) 3 4 300[1.5] 24 SCN

OMe OMe

(3) 4 4 300[1.5] 8 OMe OMe SCN

O O (13) 5 4 300[1.5] 5 SCN

N(Me)2 N(Me)2

(10) 6 4 300[1.5] 4

SCN

*For experimental conditions see a footnote in Table 12.

In addition to what is described in Table 13, we also investigated o-, m- and p-xylenes. The thiocyanation of these substrates gave mixtures of products, including methylthiocyanate derivatives as side-chain products (Table 10).

The low yield of thiocyanation products in table can be explained by competition of thiocyanate anion with solvent in constant current oxidation.

3.4. Electrochemical thiocyanation of alkenes

We have evaluated the results of our electrochemical thiocyanation of different conjugated and non-conjugated alkenes in HCOOH mixtures, as solution in Table 14. Electrochemical thiocyanation was first implemented on the symmetric 2,3-dimethyl-2-butene (entry 1) as a convenient model for alkenes. The products were analyzed by GC-MS and NMR techniques.

Table 14. Electrochemical thiocyanation of alkenes by CPE electrolysisa

Entry Substrate Major product

O Me Me HCO SCN CC 1 Me Me Me CCMe (24)

Me Me SCN Me O Me Me

CC Me C C OCH (25) 2 H H Me Me

O Me Me OCH Me C CH 3 (26) NCSH2C CCH H C 2 Me Me Me

OCH 4 (27)

SCN

C CH2 OCH 5 H

CH CH2-SCN (28)

H OCH C C H 6 H CH C (29)

SCN

a 2 In formic acid-0.1M LiClO4 employing a Pt (foil, ~5 cm ) as the working electrode and a divided cell by frit membrane; 2 mmol of NH4SCN were electrolyzed at room temperature, applying a potential of 1.25 V (vs. Ag wire quasi-reference electrode). After consuming 1,5 F, the electrolysis was arbitrarily terminated. Then 5 mmol of substrate were added to the thiocyanogen solution and allowed to stir for overnight. For the workup procedure see Exp. Sec.

It is known [63] that the oxidation potentials of alkenes are in the range of 1.5–2 V (vs.

Ag/AgCl), well above the oxidation potential of thiocyanate anion (~1V vs. Ag/AgCl, in mixtures of acetic and formic acids). When one-pot electrolysis was carried out, in which both

SCN- and the alkene were present, the yields of the expected products were very low. However, when the alkene was added after electrochemical oxidation of thiocyanate to generate (SCN)2, the yield of products improved. Presumably, such a modified procedure avoids an initial protonation of the alkene and consequent follow-up reactions prior to its reaction with (SCN)2. It is noteworthy that the yields of products were poor (~10%) in mixtures of HOAc-HCOOH (1:1) and increased to ~35% when HCOOH was the only solvent. The total yields is low probably due

+ to the weak elecrophilicity of (SCN)2 or [SCN] , which was also pronounced in the cases of aromatic thiocayanation substituted by weak electron-donating groups.

The major product emerging from the thiocyanation reaction under the above mentioned conditions is a unique α-formate-β-thiocyanate adduct (24) (entry 1). In addition, the product mixture contained two other minor products that were characterized (by GC-MS) as allylic thiocyanate (m/e = 142 (M+), 129, 101, 83, 74, 67, 59) and α-isothiocyanato-β-thiocyanate (m/e

= 200 (M+), 142, 126, 100, 83) (Scheme 9). The ratio of the three products is 3:2:1, respectively.

The isomer of the latter, α,β-dithiocyanate, was observed in a trace amount only.

HCO SCN (major product)

Me CCMe (24)

Me Me 2,3-dimethyl-3-thiocyanatobutan-2-yl formate

Me CH2SCN CC (minor product)

Me Me Me Me SCN- 2-methyl-3-(thiocyanatomethyl)but-2-ene CC electrolysis Me Me Me Me 2,3-dimethyl-2-butene SCN CCSCN (minor product)

Me Me 2-isothiocyanato-2,3-dimethyl-3-thiocyanatobutane

Me Me

NCS CCSCN (trace)

Me Me 2,3-dimethyl-2,3-dithiocyanatobutane

Scheme 9. Products distribution from electrochemical thiocyanation of 2,3-dimethyl-2-butene

It is noteworthy that the formation of the major product in each entry in Table 14 is an isomer-selective process towards thiocyanation because the isothiocyanation products were detected in low amounts.

The fact that the major product of the reaction of the electrochemically generated thiocyanogen with 2,3-dimethyl-2-butene is an addition of thiocyanogen to alkene, followed by a nucleophilic attack on the carbocation intermediate by a formate anion can be explained by a two-step heterolytic mechanism. The first step involves an initial electrophilic attack on the alkene by an electron-deficient sulfur atom of the thiocyanogen molecule (due to polarization of the S-S bond by hydrogen bonding, Scheme 10) with the formation of a cyano-sulphonium ion; the second step takes place when the sulphonium ring is opened at either of the ring carbon

52 atoms (in case of symmetric 2,3-dimethyl-2-butene) by the formate anion that is in excess

(compared to thiocyanate or isothiocyanate anions). In addition, as explained in the Introduction

Section, although both thiocyanate and isothiocyanate anions can be formed, only a trace amount of this products was formed because the concentrations of these anions decrease during electrochemical reaction in comparison to concentration of formate anion present.

O N

+ - HCO H N S S N S Me Me -SCN- Me Me CC H Me Me Me Me O O

HCO SCN

Me CCMe

Me Me

(24)

Scheme 10. Mechanism of thiocyanation of alkenes to yield an addition product

The formation of allylic thiocyanate could be explained by an attack of [SCN]. radical at the allylic site of the alkene. The source of [SCN]. radical could stem either from the direct anodic oxidation of the thiocyanate anion (before recombination to its dimer) and/or from a homolytic breaking of the S-S bond in thiocyanogen.

The major product from the electrochemical thiocyanation of a trisubstituted alkene, 2- methyl-2-butene, is also an α-formate-β-thiocyanate adduct (25) (entry 2, Table 14). As expected. This product shows a high isomer-selectivity because it stems from a tertiary

53 carbocation intermediate. As a minor product, an allylic derivative was also formed (m/e = 127

(M+), 100, 87, 69, 59, 41). The ratio between the two products is 4:1, respectively. This result is similar to our previous observation for the case of 2,3-dimethyl-2-butene. However, in this case, no α-isothiocyanato-β-thiocyanate or α,β-dithiocyanate were observed even in trace amount.

We continued our investigation by studying the addition of electrochemically generated thiocyanogen to a non-conjugated alkene with a terminal double bond, namely 2,3-dimethyl-1- butene (entry 3, Table 14), which behaved like both previous alkenes. The thiocyanation took place at the less substituted carbon, affording α-thiocyanate-β-formate (26) adduct. The second detected minor product (at a ratio of 3:1) involved allylic substitution of the alkene at the tertiary carbon, with retention of the double bond (m/e = 141 (M+), 116, 87, 67, 55) (Scheme 11).

OCH Me

NCSH2C CCH (major product) Me Me Me Me (S and R)-3-methyl-2-(thiocyanatomethyl)butan-2-yl formate SCN- C CH electrolysis (26)

H2C Me

Me 2,3-dimethylpent-1-ene Me

C C SCN (minor product)

H2C Me 2,3-dimethyl-3-thiocyanatobut-1-ene

Scheme 11. Products distribution from electrochemical thiocyanation of 2,3-dimethyl-1-butene

The electrochemical thiocyanation of a cyclic non-conjugate alkene, cyclohexene (entry 4,

Table 14) was also investigated. The results were similar to what has been observed for the tetra- substituted 2,3-dimethyl-2-butene. The major product was characterized as the α-formate-β- thiocyanate (27) adduct. However, in addition, two other minor products were characterized as

α-isothiocyanato-β-thiocyanate (m/e = 198 (M+), 140, 81, 67, 53) and an allylic thiocyanate (m/e

= 139 (M+), 111, 81, 53) (Scheme 12), in a ratio of 4:2:1, respectively.

OCH (major product) SCN (27) 2-thiocyanatocyclohexyl formate

SCN SCN- (minor product) electrolysis NCS cyclohexene 1-isothiocyanato-2-thiocyanatocyclohexane

SCN

(minor product)

3-thiocyanatocyclohex-1-ene

Scheme 12. Product distribution from electrochemical thiocyanation of cyclohexene

The electrochemical thiocyanation reaction of an unsymmetrical conjugated alkene like styrene (entry 5, Table 14) was examined too, affording a highly selective result due to an exclusive formation of α-formate-β-thiocyanate (28) in 30–50% yield (Scheme 13):

OCH

SCN- PhCH=CH2 Ph C CH2-SCN electrolysis H styrene 1-phenyl-2-thiocyanatoethyl formate

(28)

Scheme 13. The product from electrochemical thiocyanation of styrene

As expected, the thiocyanate group was added only at the terminal carbon, and the formate group is situated at the benzylic position. This result could be explained by the Markovnikov rule, by which alkene reacts with a positively charged sulfur moiety to form the most stable carbocation intermediate. In the case of styrene, the carbocation at the benzylic position is strongly stabilized by the aromatic ring.

To gain a better understanding of the electrochemical thiocyanation process, the scope of the reaction has been expanded to another conjugated alkene, trans-1,2-diphenyl-1-ethylene (trans- stilbene) (entry 6, Table 13) under the same experimental conditions. Again, as in the styrene case, a selective adduct product (29) with 20–30% yield was observed (Scheme 14).

OCH

SCN- H PhCH=CHPh CH C electrolysis 1,2-diphenylethene SCN (trans-stilbene) 1,2-diphenyl-2-thiocyanatoethyl formate

(29)

Scheme 14. The product from electrochemical thiocyanation of stilbene

We also investigated electrochemical thiocyanation of a conjugated diene, 2,3-dimethyl-1,3- butadiene, in a mixture of formic and acetic acids (1:1). From GC-MS spectra we can conclude that the addition reaction is not selective in this case. A complex mixture of products contained, among other unidentified products, two adducts of aceto-thiocyanate (m/e = 199(M+), 169, 139,

127, 99, 85, 67, 43) and formato-thiocyanate (m/e = 185 (M+), 139, 126, 99, 67, 43), (could be either 1,2- or 1,4- addition). The latter is similar to what was obtained in the case of the non- conjugated 2,3-dimethyl-2-butene, but not as a major product.

In the case of a cyclic conjugated diene, such as 1,3-cyclopentadiene, the results of GC-MS spectra show 5 products in about the same ratios. According to the molecular ions and fragments,

one of them seems to be a formato-thiocyanate adduct (m/e = 185 (M+), 139, 126, 99, 67) (either

1,2- or 1,4- adduct). Other products were difficult to analyze but contain hydroxyl, thiocyanate and acetate groups.

Finally, activated alkenes have been examined for electrochemical thiocyanation. For example, n-butylvinyl ether afforded the formato-thiocyanate adduct selectively, but decomposed after column separation.

In addition, cyclohexene and 2,3-dimethyl-2-butene were investigated under different experimental conditions, such as in mixtures of acetic and formic acid and in formic acid alone.

Obviously, in the latter case, the product mixtures become more selective because the formation of adducts of aceto-thiocyanate type are prevented. Certainly, more work has to be done in this direction.

In comparison to the above results, it has been reported [9] that chemical thiocyanation of alkenes affords addition products, yielding the corresponding α,β-dithiocyanates. However, this reaction can occur by both homolytic and heterolytic mechanisms. Here are few examples for the homolytic process:

Alkenes [9, 42]

h C C C + (SCN)2 C C C + C C C

H H SCN SCN SCN

major product

Terminal alkenes yield only dithiocyanate product. However, alkenes of type RCH=CHR give, in addition, also an isomer (involving an isothiocyanato group) that depends on the nature of the

R group and solvent of reaction [42].

Allenes [9]

R H R SCN R CH2SCN CCC h CC + (SCN)2 + CC

H H H CH2SCN H SCN

Alkynes [9]

H H H SCN HC CH h + (SCN)2 CC + CC

NCS SCN NCS H

In the absence of an olefinic double bond the hemolytic thiocyanation can take place at the benzylic site of a suitable aryl derivative::

hν ArCHR'R" + (SCN)2  ArC(SCN)R'R" + HNCS

Different substituents of aryl alkanes afford different isomers: if R'=R"=H or R'=H, R"=alkyl, the product is thiocyanate derivatives. If R'=alkyl and R"=alkyl, the result is a mixture of the corresponding thiocyanates and isothiocyanates or isothiocyanates exclusively.

In the case of heterolytic thiocyanation of alkenes by electrochemical methods, two reports are known. Cauquis and Pierre [48] investigated the reaction between electrogenerated thiocyanogen and unsaturated hydrocarbons in acetonitrile. The ambidextrous nature of the the thiocyanate anion was revealed due to the formation of two isomeric products in similar yields: dithiocyanate and -thiocyanato--isothiocyanate products.

The second report by Klein [64] also demonstrated the addition of electrochemically generated thiocyanogen to olefins but under different solvents, and with or without irradiation.

He found that no thiocyanation took place in acetonitrile or methanol unless irradiation during electrolysis was employed. However in acetic acid, thiocyanogen added smoothly to the double bond to produce the vicinal dithiocyanate. In methanol-HCl addition of both SCN and OMe took

place. Indeed, this result is similar to what we have obtained with formic acid. Also, in both above reports, an ionic mechanism analogous to halonium type addition reactions was proposed to account for observed results. However, no explanation was given for the necessity of photoinitiation or the mechanism in the non-acidic solvents.

4. Conclusions

4.1 Electrochemical thiocyanation of aromatic compounds

An environmentally friendly electrochemical thiocyanation (that avoids the use of toxic oxidizing agents) of various aromatic compounds has been described. The one-pot electrochemical thiocyanation of anisole as a model substrate has been found to be highly selective in acetic acid towards the formation of 1-methoxy-4-thiocyanatobenzene (1) exclusively. It is both regio-selective (no ortho isomer was observed) and isomer-selective (no isothiocyanato isomer was detected). Chemical thiocyanation affords a mixture of isomer products. In the acidic media and at room temperature, the yield of 1-methoxy-4- thiocyanatobenzene increased to about 80% and no observable parathiocyanogen due to polymerization of thiocyanogen was found. Previous work by other groups used polar solvents at

-15º or 0ºC to diminish (but not to eliminate) the quantity of parathiocyanogen.

The use of controlled potential (CPE) technique for the formation of anisole thiocyanate was found to be more efficient than constant current (CCE) technique, possibly due to a favorable competing reaction of formation of parathiocyanogen in the CCE method.

Electrochemical thiocyanation of other monosubstituted aromatic compounds was regio- selective (no ortho isomer was detected) and isomer selective (no isothiocyanate isomer was detected).

With electrochemical thiocyanation of disubstituted aromatic compounds, a high isomer- selectivity was found because no isothiocyanate isomers were detected. If the para position in the substrate was occupied, the electrochemical thiocyanation took place at the ortho position of the more activated substituent; however, the product yield was low.

The electrochemical thiocyanation reaction has been found to be efficient when at least one methoxy group is the substituent. Apparently, [SCN]+ is a weak electrophile and therefore,

requires an aromatic nucleous with a relatively high electron density with which to react.

Therefore, no thiocyanation products were detected when the substrate contains a deactivating substituent such as, Cl, Br, OCOCH3, or NO2. However, a stronger electron-donating substituent such as NH2, N-alkyl- or N,N-dialkyl amines, causes the substrate to compete favorably with the oxidation of the thiocyanate anion, and as a result, the yield of the desired thiocyanation product decreases.

Some substrates such as phenols and indoles give poor yield of thiocyanation product because they are oxidized prior to the thiocyanate anion and can undergo other routes of reactions, e.g., dimerization.

Aromatic hydrocarbons, such as naphthalene, gave no desired product; anthracene yielded 9- thiocyanatoanthracene, but in a poor yield.

4.2. Mechanism of electrochemical thiocyanation of aromatic compounds

Electrochemical thiocyanation involves the formation of thiocyanogan, (SCN)2, which undergoes S-S polarization by the acidic media via hydrogen bonding. Two suggested mechanisms (a step-wise heterolytic thiocyanation and a concerted one) could explain the formation of aromatic thiocyanates. After thiocyanation takes place by electrophilic attack of electrochemically generated thiocyanogen on the aromatic nucleus, the anion thiocyanate is redeveloped and reoxidized to consume more electricity than the anticipated amount.

Consequently, the overall process requires more than 1 and less than 2 F/mol electricity consumption.

4.3. Electrochemical thiocyanation of alkenes

Unlike the one-pot electrochemical thiocyanation of aromatic compounds, in the case of alkenes a step-wise process is proposed. The alkene substrate was added after the

electrochemical generation of (SCN)2. However, the yields of adduct products are considerably lower than the aromatic thiocyanates, ArSCN. For the more exact, this means that thiocyanation of aromatic compounds (bearing at least one methoxy group) is more efficient than that of alkenes.

In general, electrochemical thiocyanation of alkenes in acetic and formic acids affords α- formate-β-thiocyanate adduct as the major product, in addition to two minor products: α- thiocyanato-β-isothiocyanato adduct and allylic thiocyanate with retention of the double bond.

4.4. Mechanism of electrochemical thiocyanation of alkenes

Initially, the polarized (SCN)2 reacts with an alkene, following the Marcovnicov rule to generate the more stable carbocation intermediate, which then further reacts with a formate anion to afford a final product of type α-formate-β-thiocyanate alkanes.

5. Experimental

5.1. General: instruments, techniques and procedures

Organic compounds were supplied by Aldrich and Alfa and used without further purification.

Analytical grade glacial acetic (supplied by Frutarom Co.) and formic 97% (supplied by Gadot

Co.) acids were used without further purification. For electrochemical measurements and electrolyses, a Princeton Applied Research (PAR) Potentiostat/Galvanostat Model 173 and PAR

Universal Programmer Model 175, or a computerized PAR Potentiostat/Galvanostat Model

273A, were employed. Cyclic voltammetry (CV) measurements were performed in a conventional three-electrode cell. The working electrode was a platinum disk (ca. 1 mm diameter), the reference electrode was Ag/AgCl (in 3M NaCl), and the auxiliary electrode was a

Pt cylindrical gauze or wire.

For controlled potential electrolysis (CPE), an H-type two-compartment cell equipped with a medium glass frit as a membrane was used. The anode compartment contained a polished silver wire quasi-reference electrode (commonly used in organic electrochemistry, ~+0.15 V vs. SCE), immersed in electrolyte solution in a glass cylinder equipped with a fine glass frit at its end. Both compartments contained either glacial acetic acid and 0.5M LiClO4 (for entries 1, 10, 11, Table

10) or a mixture of formic and acetic acids (1:1) and 0.1M LiClO4 (for entries 2–9 and 12, Table

10) The choice of solvent-electrolyte medium depends on the optimized final outcome. Glacial acetic acid does not conduct electricity well unless a greater concentration of electrolyte was

o used. The aromatic substrates and thiocyanate salt, NH4SCN (dried at 80 C under vacuum, for 24 h), were added to the anode compartment. A magnetic stirrer stirred the mixture during electrolysis (1–3 days) and for an additional 24 h. Electrolysis was terminated after passing 1.5–

2.2 F/mol.

CPE was conducted by controlling the potential at 1.25 V (vs. Ag wire, which corresponds to

~1.05 V vs. Ag/AgCl). This applied potential was based on the observation that the thiocyanate anion is oxidized at ~1 V (vs. Ag/AgCl) in acetic acid [53]. At the cathode was observed a

2 release of H2 due to proton reduction. A platinum foil (5 cm ) working electrode and a stainless steel counter electrode were used. The anode compartment contained 5mmol of aromatic substrate and 2mmol of NH4SCN, both dissolved in 30 ml of solvent-electrolyte solution. Initial current was typically ~5 mA in acetic acid or >20 mA in mixtures of formic and acetic acids; at the end of electrolysis it reached a value of ~1 mA. Pulsing (to 0 V for 0.5 sec, every 50 sec) was required during electrolysis to avoid passivation of the working electrode surface, probably due to the formation of the insulating polymer, parathiocyanogen. The reaction mixture was filtered and treated twice with 30 ml of saturated aqueous NaCl and 30 ml of CH2Cl2. After phase separation, the organic layer was washed with three portions of saturated NaHCO3 solution, then dried over MgSO4, and filtered. The solvent CH2Cl2 was evaporated by a rotavapor until reaching a final volume of ~1 ml. A sample of the residue was checked by glc and the yield of the product was determined by a calibration curve of an external standard consisting of 1- methoxy-4-thiocyanatobenzene [53].

CPE for alkenes was carried out under a modified two-step procedure in order to avoid an initial protonation of the alkene and consequent follow-up reactions prior to its reaction with

(SCN)2. At first, 2 mmol of NH4SCN were electrolyzed at room temperature, applying a potential of 1.25 V (vs. Ag wire quasi-reference electrode). After consuming 1,5 F the electrolysis was arbitrarily terminated. Then 5 mmol of a substrate were added to the thiocyanogen solution and allowed to stir for overnight. The yields of products were poor

(~10%) when mixtures of HOAc-HCOOH (1:1) were used and increased to ~35% when

2 HCOOH was the only solvent. In all cases, 0.1M LiClO4, a Pt (foil, ~5 cm ) as the working electrode and a divided cell (by a medium frit membrane) were employed.

Constant current electrolyses for aromatic substrates were performed in a divided H-type two- compartment cell equipped with a medium glass frit as a membrane. Both electrodes were made of Pt foils (5 cm2) and distant from each other by 3–5 mm. The volume of the electrolyte solution

(1:1 AcOH-HCOOH and 0.1M LiClO4) in each compartment was 20 ml and the ratio between substrate (5mmol) and NH4SCN (2mmol) was 5:2. After passing the desired Coulombs, the solution mixture was treated as before.

Purification by column chromatography was performed on Davisil chromatographic silica media (40−60 μm). TLC analyses were performed using Merck pre-coated silica gel (0.2 mm) aluminum [backed] sheets.

NMR spectra were recorded on Bruker DPX200 or DMX400 instruments; chemical shifts, given in ppm, are relative to Me4Si as the internal standard, or using the residual solvent peak.

MS data were obtained using an Agilent 6850 GC equipped with an Agilent 5973 MSD working under standard conditions and an Agilent HP5-MS column, a Bruker Daltonics Ion Trap

MS Esquire 3000 Plus equipped with APCI (atmospheric pressure chemical ionization) analyzed by Xcalibur software (Thermo Fisher Scientific), He gas flow 30 mL min-1, column temperature from 100 to 270°C.

5.2. Characterization of products

1-Methoxy-4-thiocyanatobenzene (4-thiocyanatoanisole) (1)

Solid, m.p.40–41ºC, (m.p. 43–44ºC [26]); IR: a sharp peak of thiocyanate group at 2155 cm-1; 1H

NMR (in CDCl3, 200 MHz) [21] δ: 3.83 (s, 3H, OCH3), 6.95 (d, J = 8.9 Hz, 2H, 2-, 6-H), 7.51 (d,

13 J = 8.9 Hz, 2H, 3-, 5-H); C NMR (in CDCl3, 200 MHz) δ: 55.5 (OCH3), 111.6 (SCN), 113.9,

117.4, 132.1, 135.4 (4 different aromatic carbons); MS: m/z (%): M+ 165 (100), 150 (75), 139

(15), 122 (50), 95 (13), 63 (18).

1-Methyl-4-thiocyanatobenzene (4-thiocyanotoluene) (2)

Solid (m.p. 40–41ºC [65]); IR: a sharp peak of thiocyanate group at 2155 cm-1; 1H NMR (in

+ CDCl3, 200 MHz) δ: 2.50 (s, 3H, CH3), 7.05–7.23 (m, 4H, ring protons); MS: m/z (%): M 149

(100), 116 (75), 91 (90), 65 (18).

1,3-Dimethoxy-4-thiocyanatobenzene (3)

Oil [18]; IR: a sharp peak of thiocyanate group at 2153 cm-1, 3013, 2938, 2838, 1595, 1481,

1 1306, 1205, 1166, 1071; H NMR (in CDCl3, 200MHz) δ: 3.77 (s, 3H, OCH3), 3.85 (s, 3H,

OCH3), 6.46 (s, 1H, 2-H), 6.48 (d x d, J = 8.2, 2.5 Hz, 1H, 6-H), 7.38 (d, J = 8.2 Hz, 1H, 5-H);

13 C NMR (in CDCl3, 200 MHz) δ: 55.6 (OCH3), 56.1 (OCH3), 111.3 (SCN), 97.8, 101.1, 104.5,

107.9, 132.1, 135.3 (6 aromatic carbons); MS: m/z (%): M+ 195 (100), 180 (45), 152 (25), 95

(10), 69 (12).

1,2-Dimethoxy-4-thiocyanatobenzene (4)

Solid m.p. 48–50ºC, (m.p. 49–50ºC [66]); IR: a sharp peak of thiocyanate group at 2155 cm-1,

1 3007, 2933, 2830, 1600, 1502, 1453, 1238, 1170; H NMR (in CDCl3, 200 MHz) δ: 3.90–3.92

(s+s, 6H, OCH3), 6.88 (d, J = 8.4Hz 1H, 6-H), 7.05 (d, J = 2.2Hz, 1H, 3-H), 7.15 (d x d, J =8.4,

13 2.2Hz, 1H, 5-H); C NMR (in CDCl3, 200 MHz) δ: 55.9 (OCH3), 56.0 (OCH3), 111.3 (SCN),

111.9, 113.7, 114.3, 125.1, 149.9, 150.7 (6 aromatic carbons); MS: m/z (%): M+ 195 (100), 180

(45), 152 (15), 125 (12), 94 (30).

1,4-Dimethoxy-2-thiocyanatobenzene (5)

Solid m.p. 67–69ºC, (m.p. 68–69ºC [66]); IR: a sharp peak of thiocyanate group at 2155 cm-1,

1 3002, 2935, 2830, 1600, 1502, 1450, 1240, 1166, 1037; H NMR (in CDCl3, 200 MHz) δ: 3.80

13 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.87–6.88 (m, 2H, 2-, 6-H), 7.12 (d, J = 1Hz, 1H, 5-H); C

NMR (in CDCl3, 200 MHz) δ: 55.0 (OCH3), 55.8 (OCH3), 110.3 (SCN), 111.6, 113.0, 113.9,

114.7, 149.4, 153.3 (6 aromatic carbons); MS: m/z (%): M+ 195 (80), 180 (100), 152 (25), 107

(10), 79 (12).

1-Methoxy-3-methyl-4-thiocyanatobenzene (6)

-1 1 Solid m.p. 41–42ºC; IR: a sharp peak of thiocyanate group at 2153 cm ; H NMR (in CDCl3, 200

MHz) δ: 2.51 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 6.78 (d x d, J = 8.6, 2.8 Hz, 1H, 6-H), 6.86 (d, J

13 = 2.8 Hz, 1H, 2-H), 7.54 (d, J = 8.6 Hz, 1H, 5-H); C NMR (in CDCl3, 200MHz) δ: 21.1 (CH3),

55.4 (OCH3), 111.4 (SCN), 114.6, 115.4, 118.6, 134.0, 137.3, 142.8 (6 aromatic carbons); MS: m/z (%): M+ 179 (100), 164 (50), 136 (20), 109 (18), 77 (17).

1-Methoxy-2-methyl-4-thiocyanatobenzene (7)

-1 1 Oil (yellowish [67]); IR: a sharp peak of thiocyanate group at 2155 cm ; H NMR (in CDCl3,

200 MHz) δ: 2.22 (s, 3H, CH3), 3.85 (s, 3H, OCH3), 6.84 (d, J = 8.5Hz, 1H, 6-H), 7.36 (d, J =

13 2.5 Hz, 1H, 3-H), 7.38 (d x d, J = 8.6, 2.5 Hz, 1H, 5-H); C NMR (in CDCl3, 200 MHz) δ: 16.1

(CH3), 55.5 (OCH3), 111.2 (SCN), 111.4, 112.9, 129.6, 131.2, 134.1, 159.4 (6s, ring carbons);

MS: m/z (%): M+ 179 (100), 164 (80), 148 (15), 109 (15), 78 (20).

1-Methoxy-4-methyl-2-thiocyanatobenzene (8)

-1 1 Oil (yellowish [66]); IR: a sharp peak of thiocyanate group at 2155 cm ; H NMR (in CDCl3,

200 MHz) δ: 2.32 (s, 3H, CH3), 3.88 (s, 3H, OCH3), 6.82 (d, J = 8.2Hz, 1H, 6-H), 7.14 (d x d, J

13 = 8.2, 2.0 Hz, 1H, 3- H), 7.36 (d, J = 2.0 Hz, 1H, 5- H); C NMR (in CDCl3, 200 MHz) δ: 18.8

(CH3), 55.5 (OCH3), 113.2 (SCN), 111.3, 113.6, 129.0, 133.5, 136.1, 148.5 (6 aromatic carbons);

MS: m/z (%): M+ 179 (100), 164 (30), 151 (55), 136 (15), 109 (15), 78 (35).

1,3-dimethyl-4-thiocyanatobenzene (9)

Oil, (b.p. 133–134ºC at 12 Torr [67]); IR: a sharp peak of thiocyanate group at 2155 cm-1; 1H

NMR (in CDCl3, 400 MHz) δ: 2.33 (s, 3H, CH3), 2.45 (s, 3H, CH3), 7.06 (d, J = 8Hz, 1H, 6-H),

13 7.11 (s, 1H, 2-H), 7.49 (d, J = 8, Hz, 1H, 5-H); C NMR (in CDCl3, 400MHz) δ: 20.3 (CH3),

23.5(CH3), 110.7 (SCN), 128.3, 129.0, 132.1, 132.6, 139.6, 140.7 (6 aromatic carbons); MS: m/z

(%): M+ 163 (100), 135 (90), 121 (15), 103 (20), 91 (20), 77 (25).

N,N-dimethyl-4-thiocyanatoaniline (10)

-1 Solid m.p. 70–72ºC, (m.p. 72–74ºC [68]); IR: a sharp peak of thiocyanate group at 2147 cm ,

1 3452.5, 3010, 2942.5, 1615, 1510, 1367.5, 1112.5; H NMR (in CDCl3, 200 MHz) δ: 3.02 (s, 6H,

13 N(CH3)2), 6.68 (d, J = 9 Hz, 2H, 2-, 6-H), 7.43 (d, J = 9 Hz, 2H, 3-, 5-H); C NMR (in CDCl3,

200MHz) δ: 40.1 (N(CH3)2), 112.6 (SCN); 111.5, 114.6, 132.8, 136.1 (4 aromatic carbons); MS: m/z (%): M+ 178 (100), 161 (15), 152 (20), 145 (35), 136 (13), 119 (13).

N-ethyl-4-thiocyanatoaniline (11)

Solid m.p. 53–54ºC, (m.p. 52–54ºC [69]); IR: a sharp peak of thiocyanate group at 2155 cm-1; 1H

NMR (in CDCl3, 200 MHz) δ: 1.27 (t, J = 7.1 Hz, 3H, NCH2CH3), 3.16 (q, J = 7.2Hz, 2H,

NCH2CH3), 3.91 (s (broad), 1H, HN), 6.57 (d, J = 8.8 Hz, 2H, 2-, 6-H), 7.37 (d, J = 8.8 Hz, 2H,

13 3-, 5-H); C NMR (in CDCl3, 200 MHz) δ: 14.4 (NCH2CH3), 37.9 (NCH2CH3), 112.4 (SCN);

106.5, 113.4, 134.6, 150.0 (4 aromatic carbons). MS: m/z (%): M+ 178 (45), 163 (100), 152 (10),

138 (10), 105 (15), 63 (10).

N-(4-thiocyanatophenyl)formamide (12)

-1 1 Oil (yellowish); IR: a sharp peak of thiocyanate group at 2155 cm ; H NMR (in CDCl3, 200

MHz) δ: 6.74(m), 7.16(m), 7.36(m), 7.54(m), 7.64(m) (ring H for the two forms), 8.4(m) 8.7(m)

13 (for the two forms NHCHO); C NMR (in CDCl3, 200MHz) δ: 111.9 (SCN), 113.7, 114.4,

114.5, 114.7, 120.0, 120.9, 120.1, 168.3, 169.1 (aromatic carbons, for the two forms); MS: m/z

(%): M+ 178 (100), 150 (30), 118 (40), 106 (10), 80 (12).

1-phenoxy-4-thiocyanatobenzene (13)

-1 Solid m.p. 66–69ºC; IR: a sharp peak of thiocyanate group at 2155 cm , 3012.8, 2923.6, 1608.8,

1 1581.1, 1489.4, 1205.7; H NMR (in CDCl3, 200 MHz) δ: 7.06 (m, 2H), 7.03 (d, J = 10.2 Hz,

2H), 7.20 (t, J = 8 Hz, 1H), 7.44 (t, J = 8.4 Hz, 2H), 7.52 (d, J = 10 Hz, 2H); MS: m/z (%): M+

227 (100), 198 (10), 166 (10), 141 (10), 121 (10), 109 (20), 77(30), 51(10).

1-Hydroxy-4-thiocyanatobenzene (4-thiocyanatophenol) (14)

Solid m.p. 57–58ºC, (m.p. 56–58ºC [34]); IR: a sharp peak of thiocyanate group at 2161 cm-1,

1 3410.5, 3044.8, 3023.5, 1612, 1505, 1434.4, 1367.3, 1152.8; H NMR (in CDCl3, 200 MHz) δ:

4.86 (s, broad, 1H, OH), 6.89 (d, J = 8.6 Hz, 2H, 2-, 6-H), 7.46 (d, J = 8.6 Hz, 2H, 3-, 5-H); MS: m/z (%): M+ 151 (100), 123 (20), 107 (10), 96 (40), 81 (10), 65 (15).

3-methoxy-4-thiocyanatophenol (15)

-1 Solid m.p. 60–63ºC; IR: a sharp peak of thiocyanate group at 2153 cm , 3361.9, 3022.8, 2905.7,

1 1615.7, 1582.1, 1481.4, 1340.3, 1205.9; H NMR (in CDCl3, 200 MHz) δ: 3.89 (s, 3H, OCH3),

6.46 (d, J = 8 Hz, 1H), 7.39 (d, J = 8 Hz, 1H); MS: m/z (%): M+ 181 (100), 166 (30), 153 (20),

138 (25), 120 (10), 69 (15).

10-thiocyanatoanthracene (16)

-1 1 Solid; IR: a sharp peak of thiocyanate group at 2155 cm ; H NMR (in CDCl3, 200 MHz) δ: 7.53

(m, 2H), 7.71 (m, 2H), 8.06 (s, 1H), 8.32 (m, 2H), 8.69 (m, 2H); MS: m/z (%): M+ 235 (100),

203 (20), 190 (10), 178 (15), 151 (10), 117 (10).

N-(4-thiocyanatophenyl)acetanilide (17)

Oil (yellowish); IR: a sharp peak of thiocyanate group at 2155 cm-1, 3450.3, 3035.2, 2934.7,

1 1756.6, 1608.2, 1527.7, 1267; H NMR (in CDCl3, 200MHz) δ: 1.65 (s, broad, NH), 2.1 (s, 3H,

+ OCH3), 7.11 (m), 7.6 (m) (ring H for the two forms); MS: m/z (%): M 192 (10), 135 (30), 93

(100), 77 (10), 66 (15).

Thiocyanatopyrrole (18)

Oil (yellowish); IR: a sharp peak of thiocyanate group at 2160 cm-1, 3336, 3042.2, 2926.1,

1531.9, 1420.5, 1105.7; MS: m/z (%): M+ 124 (100), 97 (20), 92 (10), 71 (15), 45 (10).

Thiocyanatopyridine (19)

Oil (yellowish); IR: a sharp peak of thiocyanate group at 2160 cm-1, 3421, 3025.9, 2917.3,

1521.5, 1433.7, 1207.7; MS: m/z (%): M+ 135 (35), 107 (80), 104 (100), 91 (15), 79 (70), 51

(20).

3-thiocyanato-1H-indole (20)

-1 Solid m.p. 72–74ºC; IR: a sharp peak of thiocyanate group at 2153 cm , 3344.5, 3389.8, 2924.7,

1 1453.7, 1418.1, 1342.7, 1225.9; H NMR (in CDCl3, 200 MHz) δ: 7.08 (m, J = 5.8 Hz, J = 3 Hz,

1H), 7.32 (m, J = 9.9 Hz, J = 6.9 Hz 2H), 7.41 (m, J = 9.8 Hz, J = 7.2 Hz, 1H), 7.48(d, J = 3 Hz,

13 1H), 8.70 (s, broad, 1H, NH); C NMR (in CDCl3, 200 MHz) δ: 91.5, 112.1 (SCN), 112.5,

118.2, 121.1, 123.2, 127.8, 131.7, 136.1; MS: m/z (%): M+ 174 (100), 149 (20), 142 (30), 120

(10), 104(10), 77 (10), 45(10).

3-thiocyanato-1H-indole (21)

-1 Solid, m.p. 95–98ºC; IR: a sharp peak of thiocyanate group at 2149 cm , 3394.7, 2922.7, 1455.8,

1 1428.7, 1228.3; H NMR (in CDCl3, 200 MHz) δ: 2.45 (s, 3H, CH3), 7.22–7.30 (m, 3H benzene

13 ring), 7.69 (d, J = 6.7 Hz, 1H), 8.66 (s, broad, 1H, NH); C NMR (in CDCl3, 200 MHz) δ: 11.7,

88.5, 111.1, 112.5, 118.2, 121.4, 123.1, 127.9, 134.7, 142.6; MS: m/z (%): M+ 188 (100), 161

(20), 155 (30), 118 (10), 77 (15), 51(10).

1-Thiocyanatomethyl-2-methylbenzene (22)

-1 1 Oil; IR: a sharp peak of thiocyanate group at 2147 cm ; H NMR (in CDCl3, 200 MHz) δ: 2.42

13 (s, 3H, CH3), 4.22 (s, 2H, CH2SCN), 7.27–7.28 (m, 4H, ring protons), C NMR (in CDCl3,

200MHz) δ: 18.9 (CH3), 36.4 (CH2SCN), 111.8 (SCN), 126.5, 129.2, 130.1, 131.2, 131.8, 136.7

(6 aromatic carbons); MS: m/z (%): M+ 163 (5), 134 (3), 121 (3), 105 (100), 77 (20).

2,3-dimethyl-3-thiocyanatobutan-2-yl formate (24)

Oil; IR: a sharp peak of thiocyanate group at 2153 cm-1, 3422.4, 2992.5, 2925.4, 1723.1, 1461.2,

1 1380.6, 1199.3, 1152.2; H NMR (in CDCl3, 200MHz) δ: 1.63 (s, 3H, CH3), 1.72 (s, 3H, CH3),

13 8.01 (s, H, HOCO), C NMR (in CDCl3, 200MHz) δ: 25 (CH3), 21.5 (CH3), 62.4, 86.7, 111.2,

159.3; MS: m/z (%): M+ 187(3), 159 (3); 142(3), 129 (5), 101 (40), 83 (100), 74(50), 59(90),

41(50).

2-methyl-3-thiocyanatobut-2-yl formate (25)

Oil; IR: a sharp peak of thiocyanate group at 2155 cm-1, 3405.7, 2989.4, 1726.1, 1455.8, 1359.6,

1 1184.9, 1173.1; H NMR (in CDCl3, 200MHz) δ: 1.54 (s, 3H), 1.56 (s, 3H), 1.63 (d, J = 7 Hz,

13 3H), 3.93 (q, J = 7 Hz, 1H), 7.98 (s, H, HOCO), C NMR (in CDCl3, 400MHz) δ: 17 (CH3), 22.1

+ (CH3), 29.7 (CH3), 52.6, 83.1, 111.9, 159.7; MS: m/z (%): M 172(3); 143(3), 127 (10), 101

(15), 86 (10), 69(20), 59(20), 43(100).

3-methyl-2-(thiocyanatomethyl)butan-2-yl formate (26)

Oil; IR: a sharp peak of thiocyanate group at 2155 cm-1, 2965, 2896.5, 1720, 1480, 1375, 1172.1,

1 1162.9; H NMR (in CDCl3, 200 MHz) δ: 0.87 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H), 1.47

13 (s, 3H), 2.47 (m, 1H), 3.52 (s, 1H, CH2), 3.54 (s, 1H, CH2), 7.94 (s, H, HOCO), C NMR (in

CDCl3, 200MHz) δ: 16.6 (2CH3), 18.9 (CH), 36.8 (CH3), 43.4(CH2), 75.9, 112.1, 159.8; MS: m/z

(%): M+ 187 (3); 141 (40), 126 (5), 116 (30), 99 (10), 87 (100), 83 (80), 69 (40), 55 (30), 41 (40).

2-thiocyanatocyclohexyl formate (27)

Oil; IR: a sharp peak of thiocyanate group at 2155 cm-1, 2996, 2824.5, 1724, 1493, 1354, 1185,

1 1166; H NMR (in CDCl3, 200 MHz) δ: 1.34 (m, 2H), 1.73 (m, 2H), 2.31 (m, 2H), 3.12 (m, 1H),

4.95 (m, 1H), 8.11 (s, H, HOCO); MS: m/z (%): M+ 185 (3); 139 (30), 81(100), 67 (10), 55 (15),

41 (20).

1-phenyl-2-thiocyanatoethyl formate (28)

Solid, m.p. 100–102ºC; IR (KBr): a sharp peak of thiocyanate group at 2155 cm-1, 3429.9,

1 3054.8, 3032.3, 3024.8, 2927.3, 1720, 1495, 1450, 1149.4, 970; H NMR (in CDCl3, 200MHz) δ:

3.29 (d, J = 5.2 Hz, 1H), 3.31 (dd, J = 7.4 Hz, J = 5.4 Hz, 1H), 7.33 (s, 5H, ring protons), 8.09

13 (s, H, HOCO); C NMR (in CDCl3, 200MHz) δ: 38.5 (CH2), 73.2 (CH), 111 (SCN), 126.2,

127.3, 128.8, 129.2 (ring carbons), 159.2; MS: m/z (%): M+ 207 (3); 179 (3), 162 (3), 148 (10),

135 (60), 107 (100), 91(10), 79 (80), 63 (5), 51 (20).

1-phenyl-2-thiocyanatoethyl formate (29)

Solid, m.p. 184–187ºC; IR (KBr): a sharp peak of thiocyanate group at 2155 cm-1, 3392.5.

1 2927.5, 1720, 1502, 1450, 1390, 1150, 700; H NMR (in CDCl3, 400MHz) δ: 4.75 (d, J = 4 Hz,

1H), 6.42 (d, J = 4 Hz, 1H), 7.31 (m, 5H, ring protons), 7.35 (m, 5H, ring protons), 8.02 (s, H,

13 HOCO); C NMR (in CDCl3, 400 MHz) δ: 57.1 (CHSCN), 75.7 (CHOH), 110.3 (SCN), 127.4,

127.3, 127.9, 128.4, 128.8, 128.9, 129.1, 129.4 (ring carbons), 158.9; MS: m/z (%): M+ 255 (3);

237 (5), 224 (3)m 196 (5), 179 (100), 165 (70), 152 (20), 135 (10), 122 (5), 107 (500), 89(10), 77

(15), 63 (3), 51 (5).

6. References

[1] H. Lund, J. Electochem. Soc., 2002, 149(4), S21-S33.

[2] J. Heyrovsky, Polarographie, Springer, Wien, 1941.

[3] J.J. Lingane, C.G. Swain, M. Fields, J. Am. Chem. Soc., 1943, 65, 1348.

[4] P. Zuman, Organic polarographic analysis, 1964, Pergamon Press, Elmsford, NY.

[5] H. Lund, Acta Chem. Scand., 1957, 11, 491, 1323.

[6] R.D. Little, K.D. Moeller, J. of Electrochem. Soc. Interface, winter, 2002, 36.

[7] K.D. Moeller, Tetrahedron, 2000, 56, 9527.

[8] T. Shono, Electroorganic Synthesis, 1991, Academic Press, London,Part 1, 12-68.

[9] R.G. Guy in The Chemistry of Cyanates and Their Thio derivatives, S. Patai (Ed.) , 1977,

Wiley and Sons, Chichester, Part 2, 821–886.

[10] B.W. LeBlanc, B.S. Jursic, Syn. Comm., 1998, 28(19), 3591.

[11] L.D.S. Yadav, R. Patel, V.K. Rai, V.P. Srivastava, Tetrahedron Lett., 2007, 48(44), 7793.

[12] T. Aoyama, S. Murata, I. Arai, N. Araki, T. Takido, Y. Suzuki, M. Kodomari, Tetrahedron,

2006, 62(14), 3201.

[13] B.K. Bandlish, US Patent, Appl. No.:08/423,175, Sandoz Ltd., April 18, 1995.

[14] T. Aoyama, S. Murata, T. Takido, M. Kodomari, Tetrahedron, 2007, 63, 11933.

[15] M. Kodomari, T. Aoyama, Y. Suzuki, Tetrahedron Lett., 2002, 43, 1717.

[16] A.P. Avdeenko, V.V. Pirozhenko, S.A.Konovalova, D.A. Roman`kov, G.V. Palamarchuk,

O.V. Shishkin, Russian J. of Org. Chem., 2009, 45(3), 408.

[17] J.R. Falck, S. Gao, R.N. Prasad, S.R. Koduru, Bioorg. & Med. Chem. Lett., 2008, 18, 1768.

[18] T.R. Kelly, M.H. Kim, A.D.M. Curtis, J. Org. Chem., 1993, 58, 5855.

[19] F.D. Toste, F. LaRonde, I.W.J. Still, Tetrahedron Lett., 1995, 36(17), 2949.

[20] P.A. Grieco, Y. Yokoyama, E. Williams, J. Org. Chem., 1978, 43(6), 1283.

[21] Y. Suzuki, M. Kodomari, Chem. Lett., 1998, 1091.

[22] A. Kumar, P. Ahamd, R.A. Maurya, Tetrahedron Lett., 2007, 48, 1399.

[23] O.Prakash, H. Kaur, R.Pundeer, R.S. Dhillon and S.P.Singh, Syn.Comm., 2003, 33(23), 4037.

[24] I.W. Still, I.D.G. Watson, Synth. Commun., 2001, 31(9), 1355.

[25] I.P. Beletskaya, A.S. Sigeev, A.S. Peregudov, P.V. Petrovskii, Mendeleev. Commun., 2006,

16(5), 250.

[26] A. Khazaei, A. Alizadeh, R.G. Vaghei, Molecules, 2001, 6, 253.

[27] J.L. Wood, in Organic Reactions,1946, Wiley, New York, Vol. 3, 240–266.

[28] R.P. Welcher, P.F. Cutrufello, J. Org. Chem., 1972, 37, 4478.

[29] F.D. Toste, V.D. Stefano, I.W.J. Still, Synth. Commun., 1995, 25, 1277.

[30] X.-Q. Pan, M.-Y. Lei, J.-P. Zou, W. Zhang, Tetrahedron Lett., 2009, 50, 347.

[31] J. Wu, G. Wu, L. Wu, Synth. Commun., 2008, 38, 2367.

[32] G. Wu, Q. Liu, Y. Shen, W. Wu, L. Wu, Tetrahedron Lett. 2005, 46, 5831.

[33] V. Nair, T.G. George, L.G. Nair, S.B. Panicker, Tetrahedron Lett. 1999, 40, 1195.

[34] V.K. Jadhav, R.R. Pal, P.P. Wadgaonkar, M.M. Salunkhe, Syn.Comm., 2001, 31(19), 3041.

[35] H.P. Kaufmann, W. Oehring, Ber., 1926, 59B, 187.

[36] V.S. Pilyugin, Yu. E. Sapozhnikov, E.V. Klimakova, G.V. Kiseleva, S. L. Kuznetsova, T.P.

Vorob`eva, G.E. Chikisheva, L.V. Yakovleva, Russian J. of App. Chem., 2008, 81(3), 459.

[37] C.E. Vanderzee, A.S. Quist, J. Inorg. Chem., 1966, 5, 1238.

[38] D.C. Frost, C. Kirby, W.M. Macdonald, C.A. McDowell, P.C. Westwood, Chem. Phys.

Letters, 1980, 69(1), 1-6.

[39] J.O. Jensen, Theochem, 2005, 714(2-3), 137.

[40] F. Cataldo, J. Inorg. Org. Polymers, 1997, 7(1), 35.

[41] R. Loos, S. Kobayashi, H. Mayr, J. Am. Chem. Soc., 2003, 125, 14126.

[42] R.J. Maxwell, L.S. Silbert, J.R. Russell, J. Org. Chem., 1977, 42(9), 1510.

[43] J.S. Yadav, B.V.S. Reddy, S.Shubashree, K. Sadashiv, Tetrahedron Lett., 2004, 45, 2951. [44] O. Prakash, H. Kaur, N. Rani, S.P. Singh, R.M. Moriarty, J. Org. Chem., 2001, 66, 2019.

[45] N.N. Karade, G.B. Tiwari, S.G. Shirodkar, B.M. Dhoot, Syn. Comm., 2005, 35(9), 1197.

[46] N. Iranpoor, H. Firouzabadi, D. Khalili, R. Shahin, Tet. Letts., 2010, 51, 3508.

[47] G. Cauquis, G.Pierre, C.R. Acad. Sci., Ser. C, 1971, 272, 609.

[48] G. Cauquis, G.Pierre, Tet. Letts., 1978, 34, 1475.

[49] G. Palmisano, E.Brenna, B.Danieli, G.Lesma, B.Yodopivec, G.Fiori, Tet. Letts., 1990,

31(49), 7229.

[50] P. Krishnan, G.Gurjar, Syn. Comm., 1992, 22(19), 2741.

[51] P. Krishnan, G.Gurjar, J. App. Electrochem., 1993, 13, 268.

[52] E. Breitmaier, “Structure elucidation by NMR in organic chemistry”, 2002, Wiley and Sons,

Chichester, Part 1, Chap. 2.1, pp. 11–12.

[53] A. Gitkis, J.Y. Becker, J. Electroanal. Chem., 2006, 29, 593.

[54] J. Malyszko, S. Michalkiewicz, D. Goral, M. Scendo, J. Appl. Electrochem., 1998, 28, 107.

[55] S. Michalkiewicz, M. Mechanik, J. Malyszko, Electroanalysis, 2004, 16(7), 588.

[56] J.Y. Becker, T.A. Koch, Electrochimica Acta, 1993, 38(2/3), 357.

[57] R.J. Maxwell, L.S. Silbert, J.R. Russell, J. Org. Chem., 1977, 42, 1510.

[58] R.G. Guy, J.J. Thompson, Chem. Ind. (London), 1970, 1499.

[59] A. Gitkis, J.Y. Becker, Electrochimica Acta, 2010, 55, 5854.

[60] M.B. Smith, J. March, Advanced Organic Chemistry, 2007, Wiley and Sons, New York, 6th

Ed., p. 403.

[61] N.L. Weineberg, Technique of electroorganic synthesis, 1975, Wiley and Sons, New York,

Vol. V, part II, pp. 807–812.

[62] M.M. Baizer, in Organic Electrochemistry, 1973, M. Dekker, New York, p. 515.

[63] N.L. Weinberg, H.R. Weinberg, Chem. Revs., 1968, 68, 449, 739.

[64] W.J. Klein, Electrochimica Acta, 1973, 18, 413.

[65] M. Hosseini-Sarvari, M. Tavakolian, J. Chem. Res., 6 (2008) 318.

[66] Y. Kita, T. Takada, S. Mihara, B.A.Whelam, H. Tohma; J. Org. Chem., 1995, 60, 7144.

[67] R.G.R. Bacon, J. Chem. Soc., 1961, 2428.

[68] D.S. Bhalerao, Synlett, 2007, 19, 2952.

[69] J.S. Yadav, B.V.S. Reddy, B.B.M. Krishna, Synthesis, 2008, 23, 3779.

7. Appendix

7.1. Basic principles in "organic electrochemistry"

7.1.1 Electrochemical experimental conditions [8]

Organic electrolysis can be performed under the following experimental conditions:

 Using a divided or undivided electrochemical cell

 Using one or two phase solvent systems

 Using a flow cell (divided and undivided) system, especially in industrial

electrochemical processes.

7.1.1.1. Electrochemical cells

Reduction and oxidation in electroorganic reactions can be executed in a cell-like beaker.

This cell is called undivided because both anode and cathode compartments are sited in the same vessel. But sometimes, the product of an electrochemical reaction can be reduced or oxidized at the counter electrode. In this case, the reaction can be performed in a divided cell where the anolyte and catholyte are in two different compartments separated by a membrane. The membrane can be made of porous ceramic materials or from polymers such as Teflon or even glass frit.

7.1.1.2. Solvent systems

 A one-phase solvent system

Organic solvents that dissolve both substrate and electrolyte can be used for electroorganic syntheses. This method is very simple and inexpensive.

Conventionally, polar organic solvents such as acetonitrile (AN), dimethylforamide (DMF), methanol, and acetic acid are used, but dichloromethane (DCM) and tetrahydrofurane (THF) can also be used.

A mixture of two miscible solvents (co-solvents) can also be used for dissolving of substrate and/or electrolyte.

 A two-phase solvent system

Sometimes, for organic electrolysis it is possible to use solvents consisting of two immiscible solvents – organic and water phases. Electricity is passed through the water phase in which electrolyte and substrate are dissolved. The solvents are stirred and the product extracted into the organic phase. The method can be used when the substrate (or inorganic catalyst) is unable to dissolve in organic solvents or when stopping electrolysis between some stage and the next stage is not required.

Some factors of the two-phase solvent system method are essential: effective stirring of the immiscible phase and type of electrolyte, which should be soluble mostly in the desired phase.

7.1.2. The effect of different parameters on electrochemical reactions [8]

Organic electrolysis is influenced by different parameters, such as:

 Type of electrode

 Effect of solvent

 Electrochemical parameters

 Electrolyte

 Potential/current

 Electricity consumption (total charge)

 Temperature of reaction

 Stereochemistry of substrate

7.1.2.1. Type of electrode

Electrodes must be inert to oxidation and reduction processes.

 For anodic oxidation electrodes such as: Pt, Ti coated with Pt, Au, graphite, GC (glassy

carbon – amorphic carbon, similar to glass, more dense than graphite, less reactive than

graphite, can be polished to a mirror surface), DSA (dimensionally stable anode – Ti

metal coated with transition metal oxide such as IrO2 and RuO2, which is very stable to

oxidation), and lead dioxide (PbO2) can be used.

 For cathodic reduction, electrodes such as: Fe, Al, Ni, Pt, Pb, Hg, Zn, graphite, and GC

can be used.

The type of electrode affects the mechanism of the electrochemical reaction. In some electrochemical conditions the electrolysis product could be significantly different, for different electrodes.

7.1.2.2. Factors affecting the mechanism of electrolysis [8]

 Adsorption

Sometimes, different adsorption of the substrate or electrolyte on the surface of different electrodes gives different products of electrolysis. This phenomenon can be explained by a parameter named overpotential. The term was defined as the excess potential required for releasing, e.g., hydrogen, by reduction of acid on the surface of the electrode compared with a

80 spontaneous reaction. Release of hydrogen from a black platinum (Pt/Pt) electrode occurs spontaneously and the overpotential equals 0.

The order of electrodes by overpotential for reduction of hydrogen:

Pt, Pt < Pd < Au < Fe < Pt < Ag < Ni < Cu < Cd < Sn < Pb < Zn < Hg

Order of electrodes by overpotential for oxidation of oxygen:

Ni < Fe < Pb < Ag < Cd < Pt < Au

 Catalytic reactions

Chemical interactions of active intermediates on the surface of the electrode affect the results of electrolysis. This reaction can produce organometallic compounds. For instance, reduction of alkyl halides (RX) on a mercury electrode produces a compound such as R2Hg.

 “History” of the electrode

Contamination on the surface of the electrode can be caused by previous use of the electrode, affecting the electrochemical function of the electrode and influence the results of organic electrolyses.

 Degree of digestion of electrode (corrosion)

7.1.2.3. Effect of solvent

Solvent effect on electrooganic reactions is similar to the effect of solvent in chemical organic reactions, but there are some special requirements for electroorganic solvents:

 Electrolytes and substrates must be well dissolved in solvent.

 Good ability of solvent to dissociate molecules of electrolytes to ions.

 Fine electrical conductivity.

 High electrochemical stability (wide potential windows without electrochemical

degradation of solvent).

Solvents suitable for electrochemical oxidation

CH2Cl2, CH3CN, CH3COOH, CH3OH, CH3NO2, CH3OCH2CH2OCH3, THF, tetramethylene sulfone, propylene carbonate, pyridine.

Solvents suitable for electrochemical reduction

CH3CN, DMF, (CH3)2NCOCH3, DMSO, THF, 1,4-dioxane, CH3OH, CH3COOH, NH3,

CH3OCH2CH2OCH3, propylene carbonate.

It is possible to use one of the given solvents or a mixture when solvents are mutually soluble.

In a two-phase solvent system the organic phase may not be conductive because the electrochemical reaction takes place in the water phase. Therefore, in this case, it is possible to use nonpolar organic solvents such as: n-hexane, toluene, benzene, and dichloromethane.

7.1.2.4. Electrolyte

Parameters that determine the electrolyte choice in electroorganic synthesis

 Dissolving in organic solvents that are used in electroorganic reactions.

 High electrochemical stability.

 Ability to perform interactions with reaction intermediates.

 Easy to prepare and clean (inexpensive materials of high quality).

 Easy to remove after performing electrolysis.

In electrochemical oxidation, the nature of the anion is important. For preventing competition with oxidation of the substrate, it is preferable to use a salt with a very stable anion for oxidation.

It is possible to use salts with following the anions as electrolytes in oxidation:

------ClO4 , PF6 , BF4 , CH3COO , CF3COO , NO3 , p-toluene sulfonate. Alkali metal salts of

- perchlorates (ClO4 ) can be dissolved in polar organic solvents such as acetonitrile and DMF.

Otherwise, tetraalkylammonium salts are used.

In electrochemical reduction, the nature of the cation is important. It is possible to use salts with an alkali metal cation (Li+, Na+) because they are very stable to reduction conditions. When

+ a non-polar solvent is used for electrolysis, the cation of the electrolyte can be R4N (R=Me, Et,

Pr, Bu). The ability to dissolve salts in non-polar solvents can be controlled by the size of the R group. Acceptable concentration of electrolyte is 0.1–1M. Larger quantity of electrolyte can enlarge the current of electrolysis and lower the resistance of the solution; as a result, the time of electrolysis decreases.

7.1.2.5. Electrochemical parameters

Potential of working electrode

Usually, the potential of the working electrode is suited to the oxidation or reduction potential of substrate. It can be measured by cyclic voltammetry. Only a controlled potential method makes it is possible to maintain a constant potential of electrolysis that gives a high degree of selectivity of electroorganic products.

The effect of changing electrode potential on products of electrochemical reactions

 Controlling oxidation or reduction states.

In case of substrates that have more than one oxidation (or reduction) peak that all establish one electron transfer, it is possible to perform electrolysis at the potential of one of the peaks.

The selectivity of the products can be controlled in this way. The constant current method is not necessarily selective; the same substrate could give a mixture of products.

 Intermolecular selectivity.

If the reaction mixture has two compounds with oxidation (or reduction) potential close to each other, the constant current method oxidizes (or reduces) them together, giving a mixture of products. In contrast, in a controlled potential method it is possible to tune the potential toward one of the products with lower oxidation (or reduction) potential, following that with the mechanism (chemical sequential reaction) that takes place with other compounds.

 Intramolecular selectivity.

If a substrate has two functional groups with oxidation (or reduction) potential close to one another, the constant current method oxidizes (or reduces) them together, giving a mixture of products. In contrast, with the controlled potential method it is possible to tune the potential toward one of the functional groups with lower oxidation (or reduction) potential. After that, the potential of electrolysis can be increased toward the potential of another group.

Although the controlled potential method usually gives high selectivity, it is not useful in the manufacture of chemicals in industry because of the disadvantages of this method (paragraph

1.1.1). The constant current method is more useful for producing organic compounds by an electrochemical process, but controlling the process requires keeping a constant density of current in order to increase the selectivity of the product. The constant current method, which is not direct control of the potential of working electrodes in electrochemical reactions, is performed during manufacturing processes by a constant current supplier, which is not as expensive, such as a potentiostat.

7.1.2.6. Electricity consumption (charge) passed through electrochemical cell

The parameter “electricity consumption” relates to one of the reagents of an electrochemical reaction. Electricity consumption is calculated as the number of electrons per molecule of

84 substrate that is required for completing the reaction. Units of electricity consumption are coulombs or Faraday/mol. The yield of the electroorganic reaction can be calculated in two ways:

 Chemical yield: calculation of the yield of isolated product, such as the yield of organic

reactions.

 Current yield: calculation of the yield of current (or efficiency of current):

P Current yield = *100% T where P – quantity of product (in mol) that was made when some amount of electricity was passed through a reaction mixture; T – theoretical quantity of product (in mol) that could be made when the same amount of electricity was passed.

Usually, electroorganic synthesis requires enlarging electricity consumption over the needs determined by theoretical calculations to provide a high yield of product, because part of the electricity goes to oxidation or reduction of other compounds such as impurities, solvent, and electrolyte.

7.1.2.7. Temperature [8]

Most electroorganic synthesis takes place at room temperature, which is one of the advantages

(paragraph 1.1.1) of electroorganic synthesis. Generally, the solution temperature does not affect the rate of electrochemical reactions but does affect the rate of follow-up chemical reactions. But sometimes, electroorganic reactions require external chilling of the electrochemical cell, which warms during electrolysis as a result of passed electricity or sequential exothermic chemical reactions after the electrochemical reaction affects the temperature of the mixture.

7.1.2.8. Stereochemistry of substrate

Stereochemistry of the substrate results in specific adsorption of molecules on the surface of the working electrode. The phenomenon depends on the distribution of charge on the molecule and the charge of the electrode, which can affect formation of a specific product that is difficult or impossible to make by chemical organic reactions. For example, the main product of chemical oxidation of N,N-dimethylbenzylamine differs from main product of electroorganic reaction

(Equations 3 and 4, respectively):

OMe chemical oxidation PhCH2NMe2 Ph C NMe2 MeOH H

Equation 3. Chemical oxidation of N,N-dimethylbenzylamine

electrochemical CH2OMe oxidation PhCH2NMe2 PhCH2N MeOH Me

Equation 4. Electrochemical oxidation of N,N-dimethylbenzylamine

The difference between two products can be explained by the stereochemistry of the substrate and absorption on electrode (Fig. 10). If the anode is positively charged and the nitrogen has one pair of electrons, it can be assumed that the molecule adsorbs on the surface of the electrode in this manner:

+ + Me Me + N + + H2C + + + + + + + +

Figure 10. Specific adsorption of N,N-dimethylbenzylamine on surface of electrode

In this case, the position of one of the methyl groups is closer to the surface of the electrode; therefore, oxidation of methylic carbon (not benzilic as in the case of chemical reaction) takes place.

87 מועדפת מבחינת ביצוע תיוציאנציה אלקטרוכימית יעילה על פני שיטת הזרם הקבוע. באופן כללי, כל אחת מהתרכובות

הארומאטיות שנבדקו, במיוחד אלה שמכילות לפחות מתמיר מטוקסי אחד, נתנה תוצר תיוציאנציה יחיד, בניצולת טובה,

בתהליך חד-שלבי. כמו כן, נמצא שתיוציאנציה של תרכובות ארומטיות יעילה יותר מבחינת ניצולת התוצרים מזו של אלקנים

אליפטים (כולל מצומדים), כאשר האחרונים עוברים תהליך סיפוח בשני שלבים.

ה O

HCO SCN

Me CCMe (major product)

Me Me 2,3-dimethyl-3-thiocyanatobutan-2-yl formate

Me CH2SCN CC (minor product)

Me Me Me Me SCN- 2-methyl-3-(thiocyanatomethyl)but-2-ene CC electrolysis Me Me Me Me 2,3-dimethyl-2-butene SCN CCSCN (minor product)

Me Me 2-isothiocyanato-2,3-dimethyl-3-thiocyanatobutane

Me Me

NCS CCSCN (trace)

Me Me

2,3-dimethyl-2,3-dithiocyanatobutane

סכימה IV. תוצרי תיוצאנציה אלקטרוכימית של סובסטרט ארומאטי די-מותמר.

חקרנו גם אלקנים אליפטים אחרים ונמצא שתוצר עיקרי של תיוציאנציה אלקטרוכימית שלהם בתערובת חומצות אצטית

ופורמית הוא גם תוצר סיפוח מסוג α-פורמט-β-תיוציאנט, כאשר בנוסף לו התקבלו גם תוצרים משניים דומים לאלה שהוזכרו

בדוגמה לעיל.

במקרה של אלקנים מותמרים בטבעת ארומאטית אחת או שתיים, התיוציאנציה האלקטרוכימית הייתה סלקטיבית כלפי

תוצר α-פורמט-β-תיוציאנט בלבד.

לסיכום, ביצענו בהצלחה תיוציאנציה ידידותית לסביבה (מונעת שימוש בריאגנטים חמצון רעילים) בשיטה אלקטרוכימית

עם סובסטראטים אורגניים שונים בתנאים 'אופטימאליים' שמצאנו. בתנאים חומציים הצלחנו למנוע תגובה מתחרה לקבלת

פאראתיוציאנוגן ולכן גם הניצילות של תוצרי התיוציאנציה היו טובות יותר. הסתבר גם ששיטת ה CPE (בקרת מתח) ד כממס בלעדי עברנו לתערובת 1:1 של חומצה אצטית וחומצה פורמית. השינוי הזה גרם לסביבה יותר פולארית שאיפשרה

להעביר זרמים גבוהים יותר בתמיסה וכתוצאה מכך - להקטין משך אלקטרוליזה באופן משמעותי.

R1 = OMe, Me; R2 = H R1 = OMe, Me; R2 = OMe 1 2 R = NH2, NHEt, NMe2; R = H R2

סכימה II. סובסטרטים ארומאטיים.

תוצר התיוציאנציה שהתקבל עבור כל סובסטרט הראה גם כאן רג'יו-סלקטיביות (לא נוצר איזומר אורתו) במקרה של

סובסטרטים ארומאטיים מונו-מותמרים, ואיזומר-סלקטיביות במקרה של סובסטרטים ארומאטיים די-מותמרים (סכימה III).

OMe OMe

anode

AcOH, SCN- Me Me SCN

סכימה III. דוגמה של תיוצאנציה אלקטרוכימית של סובסטרט ארומאטי די-מותמר.

נוסף לכך, חקרנו תוצאות תיוציאנציה אלקטרוכימית של אלקנים (אולפינים) שונים. כללית, התגובה הייתה פחות יעילה

מתיוציאנציה אלקטרוכימית של תרכובות ארומטיות כי הניצולות היו נמוכות יותר בכל המקרים שבדקנו. תחילה ביצענו

תיוציאנציה אלקטרוכימית של -3,2דימתיל-2-בוטן כדוגמה לאלקן סימטרי. את התוצרים שהתקבלו ניתן היה להפריד בקלות

מתערובת התגובה ולזהות ע"י שיטות כמו GLC ו-NMR. התוצר העיקרי היה של מונו-תיוציאנציה ע"י סיפוח מיוחד שנתן

α-פורמט-β-תיוציאנט. נוסף לכך, תערובת התוצרים הכילה שני תוצרים משניים: α-פורמט-β-איזותיוציאנט ותוצר של

תיוציאנציה אלילית (סכימה IV). היחס בין שלושת התוצרים האלה היה 1:2:3, בהתאמה. תערובת התוצרים הכילה גם

עקבות של תוצר β,α-דיתיוציאנט.

ג סכימה I. תיוצאנציה אלקטרוכימית של אניזול, כמודל לסובסטרט ארומאטי.

לצורך השוואה, בוצעה אלקטרוליזה פרפרטיבית בשתי שיטות אלקטרוכימיות: בקרת מתח ובקרת זרם. על פי תוצאות

של תיוציאנציה אלקטרוכימית של אניזול, שיטת בקרת מתח נמצאה כשיטה יותר יעילה לקבלת ניצולת גבוהה של תוצר

תיוציאנציה מאשר שיטת זרם קבוע. כמו כן, חקרנו השפעה של פרמטרים שונים, כגון השפעת החומר ממנו עשויה האנודה,

ממסים שונים, כמות החשמל שעוברת דרך התמיסה, צפיפות הזרם, סוג האלקטרוליט וריכוזים שונים שלו, מלחים שונים של

תיוציאנט ובריכוזים שונים, ועוד. התוצאות שהתקבלו מתוארות בטבלה I:

טבלה I. תנאים "אופטימאליים הנבחרים לתיוציאנציה אלקטרוכימית של אניזול

ממס Acetic acid

אלקטרוליט LiClO4 0.5M

מלח תיוציאנט NH4SCN ריכוז של מלח תיוציאנט M 0.067 מטען, (2.2F/molecule) Coulombs (F/molecule) 426 אלקטרודת עבודה (Pt (area=5cm2 יחס מלח/סובסטרט 1:2.5

ניתן לסכם שתגובת התיוציאנציה האלקטרוכימית יעילה בתנאים חומציים (למשל, חומצה אצטית במקרה שלנו). בשלב

ראשון מתרחשת דימריזציה כתוצאה מחמצון אניון תיוציאנט לרדיקל ונוצר תיוציאנוגן שאינו עובר פולימריזציה לפולימר

פאראתיוציאנוגן בתנאים חומציים, אפילו בטמפרטורת החדר. בנוסף לכך, נתקבלה ניצולת טובה של תוצר תיוציאנציה

אלקטרוכימית של אניזול ובסלקטיביות גבוהה מבחינת רג'יו (תוצר פארא בלבד, ללא אורתו) ואיזומר (תוצר תיוציאנט בלבד,

ללא איזותיוציאנט) (סכימה I).

ניתן להסביר את תגובת התיוציאנציה האלקטרוכימית ע"י שני מגנונים, האחד – בשלבים, והשני – קונסרטי. בשניהם,

אחרי תיוציאנציה אלקטרופילית על טבעת ארומאטית ע"י תיוציאנוגן, נוצר שוב תיוציאנט אניון והוא יכול עוד פעם להתחמצן

אלקטרוכימית. עובדה זו מסבירה מדוע שלמרות שבשני המנגנונים נדרש תיאורטית מעבר של אלקטרון אחד פר מולקולת

סובסטרט, בפועל, שניהם דורשים מעבר של יותר מ- 1Fכמות מטען חשמלי.

בשלב הבא של המחקר בדקנו תגובת תיוציאנציה אלקטרוכימית של נגזרות של אניזול וחומרים ארומאטיים אחרים

(סכימה II) בתנאים האופטימאליים שנבחרו קודם לכן עבור אניזול, עם שינוי אחד קטן – במקום להשתמש בחומצה אצטית

ב תקציר

תיוציאנטים ארומאטיים הן תרכובות ביניים חשובות בהכנת תרכובות הטרוציקליות המכילות אטומי חנקן וגופרית

לשימוש בתעשיית תרופות, צבעים וככימיקלים בחקלאות. כמו כן, תיאוציאנטים אורגניים הם גם מקור לאניון מסוג

-ArS שניתן להשתמש בו בסינתזה אורגנית להכנת תרכובות ארומאטיות המכילות גופרית.

תיוציאנציה כימית של תרכובות ארומאטיות ואליפטיות מתרחשת דרך התקפה אלקטרופילית או רדיקלית. בתגובה

רדיקלית ניתן להכין תיוציאנטים אורגניים כתוצאה מתגובה בין סובסטרטים ארומאטים לבין N-תיוציאנטוסוקסינימיד

(TNS, אנלוג של NBS) או מקורות אחרים של רדיקל תיוציאנט, ולאחר מכן, התקפה רדיקלית על גרעין ארומאטי.

תגובה רדיקלית אינה סלקטיבית ונוצרים הרבה תוצרים שקשה להפריד ביניהם מתערובת התגובה. לעומת זאת,

המנגנון האלקטרופילי קצת יותר סלקטיבי מהרדיקלי. בהתחלה מתרחש חמצון של אניון תיוציאנט לתיוציאנט רדיקל,

אחר כך מתרחשת דימריזציה של שני רדיקלים ליצירת תיוציאנוגן, SCN)2). כתוצאה מפולריזציה של קשר גופרית-

גופרית (S-S), נוצר מטען חיובי על אחד מאטומי גופרית וכתוצאה מכך מתרחשת התקפה אלקטרופילית על טבעת

ארומאטית. חמצון של אניון תיוציאנט נעשה ע"י מחמצנים שונים כמו הלוגנים, מתכות מחמצנות וריאגנטי חמצון

אורגניים ואי אורגניים שונים. החיסרון של תגובות החמצון הכימיות נובע מהשימוש בכמויות גדולות של חומרי חמצון

רעילים. נוסף לכך, בדרך כלל נוצרת תערובת של תוצרים כמו למשל, איזומרים של פארא- ואורתו- בתיוציאנציה של

תרכובות ארומאטיות, ותיוציאנטים ואיזותיוציאנטים בתגובות עם אלקנים או בתגובת התמרה של אלקיל ברומידים או

מלחי דיאזונים ארומאטיים. לעומת זאת, מצאנו שתיוציאנציה בשיטה אלקטרוכימית היא יותר סלקטיבית (ראה

בהמשך) בהשוואה לתיוציאנציה כימית, וגם מאפשרת תגובה "ירוקה" יותר כי מתבצעת בעזרת אנודה אינרטית

הנחשבת כריאגנט חמצון "ירוק" במקום השימוש בריאגנטי חמצון רעילים.

כדי לבצע המטלות שהצבנו לעצמנו, ביצענו תיוציאנציה אלקטרוכימית ישירה של מתוקסיבנזן (אניזול) כדוגמא-

מודל לתרכובות ארומאטיות (סכימה I). כתוצאה מכך התקבל תוצר יחידי, -1מתוקסי-4-תיוציאנטובנזן. התוצר מראה

הן סלקטיביות מסוג "regio" (תוצר פארא בלבד, ללא אורתו) והן סלקטיביות מסוג – "isomer" (תוצר תיוציאנט

בלבד, ללא איזותיוציאנט).

OMe OMe

anode (~ 80%) AcOH, SCN- SCN א

העבודה נעשתה בהדרכת

פרופ' ג'מס בקר

במחלקה לכימיה

בפקולטה מדעי הטבע

תיוציאנציה אלקטרוכימית של תרכובות אורגניות

מחקר לשם מילוי חלקי של הדרישות לקבלת תואר "דוקטור לפילוסופיה"

מאת

אנה גיטקיס

הוגש לסינאט אוניברסיטת בן גוריון בנגב

אישור המנחה פרופ' ג'מס בקר ______

אישור דיקן בית הספר ללימודי מחקר מתקדמים ע"ש קרייטמן ______

אלול תש"ע ספטמבר 2010

באר שבע

תיוציאנציה אלקטרוכימית של תרכובות אורגניות

מחקר לשם מילוי חלקי של הדרישות לקבלת תואר "דוקטור לפילוסופיה"

מאת

אנה גיטקיס

הוגש לסינאט אוניברסיטת בן גוריון בנגב

אלול תש"ע ספטמבר 2010

באר שבע