Chapter I

1

CHAPTER I N-BROMOSUCCINIMIDE (NBS) IN IONIC LIQUID:

A GREEN SYSTEM FOR RAPID OXIDATION OF 1,2-DIOLS, α-HYDROXYKETONES AND ALCOHOLS

I.1: INTRODUCTION I.1.1: Ionic Liquids Ionic liquid is the name given to a liquid that consists only of ions and is different from a molten salt in a way that molten salt is generally referred to a high melting, highly viscous and corrosive medium whereas ionic liquids are already liquids at low temperatures (<100°C) and have relatively low viscosity. The first reported ionic liquid was ethyl ammonium nitrate which is a liquid at room temperature [m.p. 12°C].1 The application of ionic liquids (ILs) as a new reaction media and catalyst for organic synthesis appeared at the end of 1980s. Acidic ionic liquids with chloroaluminate ions were used for the Friedel-Crafts catalysis2 and phosphonium halide melts were used successfully in nucleophilic aromatic substitution reactions.3 Their first application as the solvent for biphasic catalysis was reported by Chauvin et al. for the dimerization of propene by nickel complexes dissolved in acidic chloroaluminate melts.4 The concept of ionic liquids received a substantial boost when synthesis of a series of air and moisture stable imidazolium salts based on anions such as [BF4]– and [PF6]– was reported in 1992.5 Since then, there has been significant expansion in the variety of ionic liquids reported. The utility of ionic liquids has been exercised not only within the field of biphasic catalysis and organic synthesis, but also covers diverse applications such as separations,6 electrochemistry7 and photochemistry.8 A brief review on ionic liquids is presented below: Composition of Ionic Liquids The most commonly used cations in ionic liquids are alkylammonium, alkylphosphonium, N,N′-dialkylimidazolium, and N-alkylpyridinium cations. The most commonly utilized alkyl chains are methyl, ethyl, butyl, hexyl, octyl and decyl. The most commonly investigated IL cations and anions are shown in Figure I.1.

Chapter I

2

NN

R2

R1

R1

R2NR1

R4

R3R2 P

R1

R4

R3R2

PhoshoniumAmmonium

Cl- , Br- , I- , Al2Cl7- , NO3- , HSO4

- , PO43-

PF6- , BF4

- , SbF6- , CF3SO3

- , CF3COO- , N(CN)2 -, (CF3SO2)2N-

, SO42- , ClO4

- ,

CationsImidazolium Pyridinium Pyrazolium

R1 = alkylR2 = H, alkyl

R1, R2, R3, R4 = alkylR1, R2 = alkylR1, R2 = alkyl

Anions, CB11H12

- , (MeO)2PO2- , (CF3CF2)3PF3

-

Figure I.1

N NR1 R2

R1, R2, R3, R4 = alkyl

Properties of Ionic Liquids Melting Point and Vapour Pressure: The key criterion for the evaluation of an ionic liquid is, by definition its melting point. The melting points are influenced both by cations and anions. The interest for ILs has been centered on their possible use as ‘‘green’’ alternatives to volatile organic solvents, mainly because ILs are considered as non-volatile and consequently non-flammable at ambient and higher temperatures. ILs have no vapour pressure. This is a great advantage from a process engineering viewpoint, since separation by distillation of a reaction mixture becomwes more effective as a method of product isolation. The well known problem of azeotrope formation between the solvent and the product does not arise. Solubility in Water: The solubility of ILs in water is an important factor for the industrial application of these solvents. The solubility of ILs in water depends on the nature of anion, temperature and the length of alkyl chains. For the [bmim] cation, the anions like [BF4]–, [CF3COO]–, [NO3]–, [NMs2]– and halide salts display complete miscibility with water at 25°C. However, upon cooling the [bmim]BF4 aqueous solution to 4°C, a water rich phase separates out. Butylmethyl imidazolium [bmim] based ILs of other anions such as [PF6]–, [SbF6]– and [Tf2N]– show low solubilities in water.9-12

Density and Viscosity: The density of a material depends on how closely the ions can pack together and, hence on the size and shape of the ions and ion-ion interactions. A

Chapter I

3

considerable amount of data on the density of ILs is available in the literature.13 ILs are generally denser than either organic solvents or water, with typical density values ranging from 1.0 to 1.6 gcm-3. The viscosity is dependent on the ion-ion interactions, such as Van der Waals interactions and hydrogen bonding, with greater interactions leading to higher viscosities. The viscosity of many ILs is generally one to three orders of magnitude higher compared to conventional solvents. Environmental Aspects: Ionic liquids have often been discussed as promising solvents for “clean processes” and “green chemistry”.14 Ionic liquids have no measurable vapour pressure and so there is no loss of solvent through evaporation unlike the volatile organic solvents. With respect to the efforts to reduce catalyst consumption, two aspects of ionic liquids are important. Firstly, the special solubility characteristics of an ionic reaction medium enable a biphasic reaction procedure in many cases. Exploitation of the miscibility gap between the ionic catalyst phase and the products allows the catalyst to be isolated effectively from the product and be reused many times. Secondly, the non-volatile nature of ionic liquids enables more effective product isolation by distillation. Synthesis of Ionic Liquid Ionic liquids can be synthesized by quaternization of an amine or phosphane.15-16 In cases where quaternization to form the desired ion is not possible, it can be achieved by treatment with some Lewis acid MXn or by anion exchange. Synthesis of ILs using non conventional activation method (microwaves or ultrasounds) has also been described.17 However, ILs can decompose under sonochemical conditions.18

Ionic Liquids as Reaction Media (A) Transition metal catalyzed reactions in ionic liquids Ionic liquids are able to dissolve organometallic compounds and therefore can be used as possible solvents for reactions involving homogeneous catalysts. The use of ionic liquids often allows a combination of solvent properties like water or common organic solvents. Some of the transition metal catalyzed reactions are discussed below:

Chapter I

4

(i) Suzuki coupling: Suzuki cross coupling of aryl halides with phenyl boronic acids in presence of palladium-bis(carbine)complex in [bmim]BF4 has been reported under ultrasonic irradiation (eq. 1).19

X

R+

R1

B(OH)2

R

R1

...(1)Pd(PPh3)4

[bmim]BF4, Na2CO3 (ii) Stille Coupling: Stille coupling is used for the preparation of polyarenes, diaryl and aromatic carbonyl compounds. Stille coupling reactions with Pd(0) and Pd(II) catalyst precursors have been reported in [bmim]BF4 (eq. 2).20

OI

+ RSn(Bu)3Pd(II)/CuI/Ph3PAs

[bmim]BF4

OR

...(2)

(iii) Hydrogenation: de Souza et al. have reported rhodium catalyzed hydrogenation of cyclohexene in [bmim]BF4.21 Hydrogenation of 1-pentene by “Osborn complex” [Rh(nbd)(PPh3)2]PF6 (nbd = norbornadiene) as catalyst in ionic liquids has been reported (eq. 3).22

H2, [Rh(nbd)(PPh3)2][bmim]A, A = BF4

-, PF6-, SbF6

- ...(3) Rhodium and cobalt catalyzed hydrogenation of butadiene and 1-hexene23 and Ru-catalyzed hydrogenation of aromatic compounds24 and acrylonitrile-butadiene co-polymers25 have also been reported to be successful in ionic liquids. (iv) Hydroformylations: The hydroformylation of 1-hexene to heptanal using Rh(OAc)4 and PPh3 as catalyst in phosphonium tosylate as ionic liquid has been described.26 The platinum catalyzed hydroformylation of 1-octene in [bmim]Cl/SnCl4 has been reported to give high n-/iso- selectivities (eq. 4).27

CO/H2[PtCl2(PPh3)2]

[bmim]Cl/SnCl2

CHO

CHO

+ ...(4)(>95%)

Chapter I

5

(v) Alkoxycarbonylation: Palladium catalyzed alkoxycarbonylation of aryl halides has been carried out in [bmim]BF4 and [bmim]PF6 (eq. 5).28

Br+ CO + ROH + NEt3 Pd(II)/PPh3

[bmim]BF4 /[bmim]PF6OR

O

+ [HNEt3]Br ...(5)

(B) Other Organic Reactions in Ionic Liquids Ionic liquids have been used in a number of other synthetic organic transformations, some of which are discussed below briefly. Welton29 et al. and Seddon30 et al. reported that ionic liquids such as [bmim]BF4, [bmim]ClO4, [emim]CF3SO3 and [emim]PF6 are effective solvents for Diels-Alder reaction between cyclopentadiene and methyl acrylate. Reactions in these ionic liquids showed significant strong endo selectivities (eq. 6).

+ Ionic Liquid

COOMeCOOMe ...(6)CH2 CHCOOMe +

The self-condensation of propanal to form 2-methylpent-2-enal has been carried out in non-coordinating imidazolium ionic liquids.31 The reaction proceeded through an aldol intermediate. The highest selectivity was observed in [bmim]PF6. S-Proline catalyzed asymmetric direct aldol reaction of aromatic aldehydes with acetone and other ketones in ionic liquid [bmim]PF6 gave good yields of aldol products with reasonable enantioselectivities even when 1-5 mol% of S-proline was used as a catalyst (eq. 7).32

HO

XS-Proline, acetone[bmim]PF6 / r.t. X

O

...(7)

OH

Michael addition of acetylacetone to methyl vinyl ketone has been described by Nobile et al. in [bmim]BF4 in presence of Ni(acac)2 (eq. 8).33

Chapter I

6

O O+

ONi(acac)2[bmim]BF4

O

O

O...(8)

A number of other reactions like Friedel-Crafts reaction,34 Wittig reaction,35 Baylis-Hillman reaction36 and olefin metathesis37 have been successfully carried out in ionic liquids. Epoxidation of olefins and allylic alchols with UHP (urea hydrogen peroxide) in presence of methyltrioxorhenium (MTO) as catalyst has been reported in [bmim]PF6.38 Epoxidation of olefins with NaOCl using Jacobsen’s chiral Mn(III) salen complex immobilised on [bmim]PF6 proved to be an efficient and recyclable method (eq. 9).39

O

NCMn(salen), NaOCl[bmim]PF6/ CH2Cl2

O

NC O...(9)

Yadav et al. have reported the oxidation of alcohols to the corresponding carbonyl compounds (eq. 10) using hypervalent iodine reagents in ionic liquids.40 They have also reported conversion of olefins to halohydrins using N-halosuccinimides in [bmim]BF4-H2O (eq. 11),41 α-halogenation of β-dicarbonyl compounds and cyclic ketones using N-halosuccinimides in ionic liquids (eq. 12)42 and synthesis of thiiranes from epoxides in [bmim]PF6-H2O (2:1, v/v) at room temperature (eq. 13).43

R R1

OH

[bmim]BF4, r.t.

OI OHO

O R R1

O...(10)

RR1

N-halosuccinimides[bmim]BF4 - H2O

R R1 ...(11)X

OH

R2R1OO

+ N—X

O

O

[bmim]PF6r.t. R2R1

OO..(12)

X

Chapter I

7

ORO + KSCN [bmim]PF6 - H2O

r.t.S

RO ...(13)

A large number of other reactions have been reported in ionic liquids. I.1.2: Reactions of N-bromosuccinimide N-Bromosuccinimide (NBS)44 is a versatile reagent in organic synthesis. A large number of organic transformations have been reported with this reagent. The reagent is a convenient source of bromine for both radical substitution and electrophilic addition reactions. The first application of this reagent for allylic bromination of alkenes was reported by Wohl (eq. 14).45a It is a free radical substitution catalyzed by dibenzoyl peroxide or irradiation with visible light or both to effect initiation. The general mechanism of this Wohl-Ziegler reaction45 is given in Scheme I.1.

CH CH C CCl4, hv C CH CBr

NBS ...(14)

CH2 CH CH2 CH CH CH2 HBr

CH CH CH2 Br2 CH CH CH2Br

Scheme I.1

Br

.

Br

.

+

+

+

+

.

.

Mechanism

N

O

O

Br HBr NH

O

O

Br2

Br2Peroxide or

Ultraviolet2Br

.

+

The formation of HBr is the result of a side reaction and the formation of Br2 is the fast ionic reaction between NBS and HBr. High level of regioselectivity operates during the hydrogen-abstraction step of the chain mechanism, such that allylic methylene groups are attacked much more rapidly than allylic methyl groups (eqs. 15, 16).46

C4H9CH CHCH3 C3H7CHCH CHCH3BrCCl4, Reflux

NBS...(15)

Chapter I

8

CCl4, RefluxNBS

Br...(16)

Bromination of α,β-unsaturated esters (eq. 17)47 and lactones (eqs. 18-20)48-50 using NBS, has been achieved in high yields.

COOMeNBS, SunlampCCl4, Reflux

CH2BrBrH2C

COOMe ...(17)

OO

NBS, (PhCOO)2CCl4, Reflux

OO

Br

...(18)

O

ONBS, CCl4

RefluxO

O

Br

...(19)

OO

C5H11

NBS, CCl4hv

OO

Br

...(20)

Benzylic bromination is one of the most extensively studied reaction of NBS (eq. 21).51-53

O

ONBS, Reflux

hv, CCl4O

O

Br

...(21)

Hauser and Prasanna54 have reported the oxidative aromatization of polycyclic compounds including steroids and anthraquinone precursors (eq. 22). Phenols, anilines and other electron rich aromatic compounds can be mono-brominated with NBS in dimethylformamide in high yields and with high para selectivity (eq. 23).55 Bromination of quinoline, isoquinoline, quinazoline and quinoxaline could be achieved in presence of a strong acid (eq. 24).56

Chapter I

9

OH

OH

O

NBSaq. acetone

O

O

...(22)

OHNBSDMF

OH

Br

...(23)

N N

Br

i) H2SO4, 0oC

ii) -25oC, NBS, 5 h...(24)

Carreno and co-workers57 have reported NBS as a mild and regiospecific nuclear brominating reagent for methoxybenzenes, naphthalenes, phenols, naphthols and activated pyridines in acetonitrile. Oxidation of aldehydes and hydrazines to acid bromides and azo compounds respectively (eqs. 25, 26)58,59 has been reported with NBS. Regeneration of carbonyl compounds from tosyl hydrazones (eq. 27)60 has also been reported.

OHR

NBSCCl4, hv

OBrR ...(25)

Me3COCNHNHCOCMe3O O

Me3COCNO

NBSPyridine

NCCMe3O

...(26)

C NR1

RN TsH NBS CR

R1O

MeOH, H3O+....(27)

NBS has been used for oxidative cleavage and oxidation reactions in different media. Aliphatic α-hydroxy acids undergo reaction with NBS in water to give aldehydes or ketones with loss of one carbon atom (eq. 28).61

RR1C(OH)COOH 2 NBS H2O RR1CO

R1 = H, Alkyl

...(28)+

Chapter I

10

Oxidative degradation of phenyl acetic acid to benzaldehyde, polycarboxylic acids to aldehydes or ketones and citric acid to acetone with NBS have also been reported.62 NBS is reported to bring about bond scission in tertiary amines with the formation of aldehydes and secondary amines in good yields (eq. 29).63 The results suggest that a methyl or methylene group attached to nitrogen is required and N-CH2 linkage is cleaved preferentially under these conditions. This carbon-nitrogen cleavage also occurs in α-aminoacids to give aldehydes64 (eq. 30), while β-amino acids give acids with loss of two carbon atoms (eq. 31).65

(C6H5CH2)3NNBS

Dioxane-H2O(C6H5CH2)2NHC6H5CHO ...(29)

C6H5CHCOOHNH2 NBS

H2O C6H5CHO ...(30)

C6H5CHCH2COOHNH2 NBS

H2OC6H5COOHC6H5CHCBr3

NHBr i) KOHii) HCl

...(31)

Benzyl ethers react with NBS to give favorable yields of the corresponding benzaldehydes (eq. 32).66 Oxidation of sulfides to sulfoxides has also been reported with NBS in either aqueous medium or in methanol (eq. 33).67

RC6H4CH2OR1 NBSCCl4 Br

RC6H4CH O R1 RC6H4CHO ...(32)

SPh PhNBS, 5-10oC Ph S

OPh ...(33)

MeOH The conversion of olefins to α-bromohydrins and subsequent dehydrohalogenation to epoxides is an excellent method for indirect epoxidation (eq. 34).68 Reactions with polyalkenic compounds have also been reported.69,70

C CNBS

aq. DMF/ THF C COH

Br-Br HO -H+ O ....(34)

Chapter I

11

Khurana et al.71a have reported a simple procedure for the synthesis of benzils and aliphatic 1,2-diketones of cyclic and open chain compounds from the corresponding hydrobenzoins and 1,2-diols by refluxing with NBS in CCl4 in the presence or absence of pyridine (eq. 35). They have also reported microwave accelerated oxidation of hydrobenzoins, benzoins and alcohols with NBS adsorbed on neutral alumina.71b

CHOH

CHR1

OHR2 C

OCR1

OR2NBS, CCl4

Pyridine, Reflux

R1, R2 = Aryl, Alkyl

...(35)

Ionic liquid promoted regioselective monobromination of aromatic substrates (eq. 36)72 and α-monohalogenation of 1,3-diketones, β-ketoesters and cyclic ketones (eq. 37)73 with NBS has been reported in excellent yields in the absence of a catalyst. The ionic liquid could be recycled with consistent activity.

N

O

O

BrArH[bmim]BF428oC

N

O

O

H ArBr ...(36)+ +

OR1

OR2

OR1

OR2N

O

O

Br[bmim]PF6

r.t.Br

N

O

O

H ...(37)+ +

Three component reactions of aldehydes, amines and diethyl phosphite catalyzed by NBS leading to the corresponding α-aminophosphonates under solvent-free conditions have been reported by Wu et al. (eq. 38).74

ArCHO + + HPO(OEt)2 Solvent-freeNBS NHR

Ar PO

OEtOEt

...(38)RNH2

A novel procedure for the synthesis of 14-aryl-14H-dibenzo[a,j]xanthenes through one pot condensation of 2-naphthol with aromatic aldehydes in presence of NBS as catalyst under solvent-free conditions (eq. 39)75 and synthesis of 2-substituted 1,4,5,6-

Chapter I

12

tetrahydropyrimidine derivatives catalyzed by NBS using ultrasonic irradiation in aqueous medium (eq. 40)76 have been reported.

ArCHO + Solvent-free, 110oCNBS ...(39)

OH

O

Ar2

RCHO + H2O, 70oCNBS ...(40)H2N NH2 HN N

R I.1.3: Oxidation of Hydrobenzoins, Benzoins and Alcohols Carbonyl compounds including benzoins and benzils have received a great deal of attention because of their potential industrial applications. Benzils, in particular, have gained lot of importance because of their applications as photosensitive agents in photocurable coatings,77 as starting materials in organic and pharmaceutical synthesis,78 as precursors for heterocyclic moieties79 and also as biologically important compounds.80 Oxidation of hydrobenzoins to benzoins as well as benzils and oxidation of benzoins to benzils (eqs. 41, 42) has been reported by a wide variety of reagents.

CHOH

CRO

R CO

CRO

R

CHOH

CRO

RCO

CRO

RCHOH

CHROH

R and/ or ...(41)

...(42) Some of the literature reported methods use CuSO4/Py,81 Bi2O3/H+,82 aq. HNO3 solution,83 4-MeO-Tempo,84 (4-AcNH-Tempo)-OTs-TsOH,85 4-PhCO2-Tempo-electrolysis,86 n-Bu4N[MoO(O2)2C5H4N(O)CO2]87 and H2O2-[C5H5N-(CH2)15CH3]3 {PO4[W(O)(O2)2]4}88 and bromamine-T using RuCl3.xH2O as catalyst in alkaline acetonitrile/ water (1:1) medium.89 Oxidation of benzoins with zeolite A, without any oxidizing agent under solvent-free conditions and microwave irradiation,90 silica gel supported Bi(NO3)3.5H2O under microwave irradiation in a solvent-free system91 and aerial oxidation in presence of aluminium oxide92 has been reported (eq. 42). Oxidation of benzoins to benzils with

Chapter I

13

catalytic amount of triarylstibanes under aerobic conditions has also been reported.93 This catalytic oxidation is heteroatom-specific for the antimony compound as no reaction takes place with other group 15 reagents such as triphenylphosphane, -arsane and -bismuthane. Oxidation of alcohols to carbonyl compounds is one of the most fundamental functional group interconversion and has been achieved by an array of reagents.94 Oxidation of a variety of activated and non-activated secondary alcohols to their corresponding ketones has been reported with molecular oxygen using cobalt phthalocyanine as catalyst in the presence of powdered KOH (eq. 43).95

CHOH

R1 R2 CO

R1 R2Cu(II) phthalocyanine,O2Xylene, KOH, Heat

...(43)

Oxidation of secondary alcohols with DMSO/N2H4.H2O/I2/H2O/CH3CN gives ketones. This system selectively oxidizes secondary alcoholic groups in the presence of primary alcoholic groups.96 Oxidation of various electron rich alcohols has also been reported with I2O5/KBr.97 Secondary alcohols could be efficiently oxidized to ketones with H2O2 using n-hexadecyltrimethyl ammonium heteropoly phosphatotungstate [{n-C16H33N(CH3)3}3{PW4O16}] as catalyst under solvent-free conditions.98 Many of the reported procedures for the oxidation of hydrobenzoins, benzoins and alcohols have drawbacks in terms of expensive reagents, harsh reaction conditions, low yields and use of toxic solvents. The toxic and volatile nature of many organic solvents particularly the chlorinated hydrocarbons have posed a serious threat to environment. Consequently the methods that successfully minimize their use are the focus of much attention. In this respect, ionic liquids are attracting growing interest as alternative reaction media for various chemical and biochemical transformations. Their negligible vapour pressure, wide liquid range, tunable polarity and potential for recycling circumvent many of the problems associated with common organic solvents. In view of the importance of the aforesaid transformations, we decided to investigate the use of ionic liquid as a reaction medium for the oxidation of hydrobenzoins, benzoins and alcohols using NBS as an oxidant.

Chapter I

14

I.2: RESULTS AND DISCUSSION Hydrobenzoin was chosen as the model substrate to optimize the reaction conditions for its quantitative oxidation. A reaction of hydrobenzoin (Ia) and NBS (1:1 molar ratio) was carried out in ionic liquid [bmim]BF4 at 70°C (run 1). TLC analysis of the reaction mixture showed the appearance of two new spots on TLC besides the presence of starting material after 1 h. Both new compounds had Rf higher than the starting material. These two spots were found to correspond to benzil and benzoin by co-TLC with the authentic samples. The reaction was incomplete even after 10 h, and yielded only 60% of benzil after workup (run 1). Therefore, we decided to increase the molar ratio of Ia: NBS. Hence, a reaction of Ia was conducted using 1:2 molar ratio of Ia: NBS in [bmim]BF4 under heating at 70°C. TLC of the reaction mixture showed the complete disappearance of the starting material after 1 h, and presence of two new spots corresponding to benzil and benzoin was confirmed by co-TLC with authentic samples. On continuing the reaction for another 1.5 h, complete oxidation of benzoin to benzil was observed. The reaction was worked up after 2.5 h and 92% of benzil (IIa) was isolated (run 2). A reaction of hydrobenzoin (Ia) and NBS was then attempted in 1: 3 molar ratio at 70°C but no significant improvement was observed in the time of completion of the reaction or yield of the product (run 3). The reaction of hydrobenzoin (Ia) and NBS (1:2) in [bmim]BF4 was also performed at room temperature. The reaction was found to be incomplete even after 10 h. TLC analysis of the reaction mixture showed only a trace amount of benzil along with significant amount of benzoin and starting material (run 4). The oxidation of hydrobenzoin was then attempted in different ionic liquids using NBS as an oxidant. It was observed that the reactions using 1: 2 molar ratio of Ia: NBS in [bmim]Br, [bmim]Cl and [bmim]PF6 at 70°C showed complete disappearance of starting material after 3 h. However, TLC showed the formation of a mixture of benzoin and benzil. The reactions were continued for another 3 h, but low yield of benzil was obtained (runs 5-7). The potential of N-chlorosuccinimide (NCS) and N-iodosuccinimide (NIS) as oxidizing agents instead of NBS was also investigated under identical reaction conditions. Reactions of hydrobenzoin with NCS and NIS in [bmim]BF4 at 70°C gave low yield of benzil (IIa) i.e. 80% and 79% respectively after 4 h (runs 8-9). All these results are listed in Table I.1.

Chapter I

15

Table I.1: Optimization of reaction conditions for the oxidation of hydrobenzoin (Ia) to benzil (IIa)

Run Oxidant Ionic liquid Molar ratio (Ia:Oxidant)

Temp. (°C)

Time (h)

% Yield (IIa)

1. NBS [bmim]BF4 1:1 70 10 60a

2 NBS [bmim]BF4 1:2 70 2.5 92 3 NBS [bmim]BF4 1:3 70 2.5 92

4. NBS [bmim]BF4 1:2 35 10 20a

5. NBS [bmim]Br 1:2 70 6 68 6. NBS [bmim]Cl 1:2 70 6 80

7. NBS [bmim]PF6 1:2 70 6 77

8. NCS [bmim]BF4 1:2 70 4 80 9. NIS [bmim]BF4 1:2 70 4 79

a Reaction incomplete

It can be inferred from Table I.1 that the use of NBS as an oxidant and [bmim]BF4 as the reaction medium was the optimum system for the oxidation of hydrobenzoin (Ia) to benzil (IIa) (eq. 44).

CHPhOH

CHOH

Ph 70oCCPhO

CO

NBS, [bmim]BF4 Ph ...(44)

Ia IIa

Subsequently, oxidation of 4,4'-dichlorohydrobenzoin (Ib), 4,4'-dimethylhydrobenzoin (Ic), 4,4'-dibromohydrobenzoin (Id), 3,3'-dibromohydrobenzoin (Ie), 2,2'-dichloro hydrobenzoin (If), 4,4'-dimethoxyhydrobenzoin (Ig) and α,α'-dihydronaphthoin (Ih) were carried out under similar reaction conditions and the corresponding 1,2-diketones i.e., 4,4'-dichlorobenzil (IIb), 4,4'-dimethylbenzil (IIc), 4,4'-dibromobenzil (IId), 3,3'-dibromobenzil (IIe), 2,2'-dichlorobenzil (IIf), 4,4'-dimethoxybenzil (IIg) and α,α'-naphthil (IIh) were obtained in excellent yields (runs 10-16). All reactions were rapid, clean and no side product was either detected or isolated. Thereafter, we investigated the oxidation of aliphatic 1,2-diols under similar conditions. Aliphatic

Chapter I

16

1,2-diols namely, trans-cyclohexane-1,2-diol (Ii) and 9,10-dihydroxystearic acid (Ij) underwent successful oxidation to give the corresponding 1,2-diketones, i.e. cyclohexane-1,2-dione (IIi) and 9,10-diketostearic acid (IIj) respectively (eq. 45, runs 17-18). All these results are listed in Table I.2.

CHROH

CHOH

R' 70oCCRO

CO

NBS, [bmim]BF4 R' ...(45)

I II (a) R = R' = C6H5 (b) R = R' = 4-ClC6H4 (c) R = R' = 4-MeC6H4 (d) R = R' = 4-BrC6H4 (e) R = R' = 3-BrC6H4 (f) R = R' = 2-ClC6H4 (g) R = R' = 4-MeOC6H4 (h) R = R' = 1-Naphthyl (i) R-R' = 4CH2 (j) R = C8H17, R' = C7H14COOH

In view of successful oxidation of 1,2-diols to 1,2-diketones, we investigated the application of NBS as an oxidant for the oxidation of α-hydroxyketones in [bmim]BF4. Reaction using 1: 1 molar ratio of benzoin to NBS, under otherwise identical conditions resulted in an incomplete reaction with an inferior yield (51%) of IIa. However, α-hydroxyketones namely benzoin (IIIa), 4,4'-dichlorobenzoin (IIIb), 4,4'-dimethylbenzoin (IIIc) and butyroin (IIId) underwent complete oxidation to corresponding 1,2-diketones i.e. benzil (IIa), 4,4'-dichlorobenzil (IIb), 4,4'-dimethylbenzil (IIc) and octane-4,5-dione (IIk) respectively, by using 1: 2 molar ratio of substrate: NBS in [bmim]BF4 at 70°C (eq. 46, runs 19-22).

CHROH

CO

R NBS, [bmim]BF470oC

CRO

CO

R ...(46)

III (a) R = C6H5 (b) R = 4-ClC6H4 (c) R = 4-MeC6H4 (d) R = n- C3H7

Chapter I

17

Table I.2: Oxidation of hydrobenzoins and α-hydroxyketones using NBS in [bmim]BF4 at 70oCa

Run Substrate Product Time (h)

% Yield (II)

10. 4,4'-Dichlorohydrobenzoin (Ib) IIb 2 88 11. 4,4'-Dimethylhydrobenzoin (Ic) IIc 2 88 12. 4,4'-Dibromohydrobenzoin (Id) IId 2 82 13. 3,3'-Dibromohydrobenzoin (Ie) IIe 2 81 14 2,2'-Dichlorohydrobenzoin (If) IIf 2 86 15. 4,4'-Dimethoxyhydrobenzoin (Ig) IIg 2 87 16. α,α'-Dihydronaphthoin (Ih) IIh 2 90 17. Cyclohexane-1,2-diol (Ii) IIi 2.5 85 18. 9,10-Dihydroxystearic acid (Ij) IIj 2.5 70 19. Benzoin (IIIa) IIa 1.5 90 20. 4,4'-Dichlorobenzoin (IIIb) IIb 1 90 21. 4,4'-Dimethylbenzoin (IIIc) IIc 1.5 85 22. Butyroin (IIId) IIk 2.5 80

aGeneral reaction conditions: hydrobenzoin or α-hydroxyketones (1.0 mmol), NBS (2.0 mmol), [bmim]BF4 (5.0 mmol)

The recyclability of the ionic liquid was also investigated. Reactions using hydrobenzoin (Ia) as substrate, showed that the recovered ionic liquid could be used for oxidation upto two runs without any appreciable loss of efficiency by adding 2 equiv. of NBS for each run and afforded 91% and 89% of IIa after 1st cycle and 2nd cycle. However, the yield decreased gradually in third cycle as depicted in Figure I.2.

Chapter I

18

Recycling of Ionic Liquid

92 91 8973

0

20

40

60

80

100

Fresh Cycle 1 Cycle 2 Cycle 3Cycles

% Y

ield

of I

I a

Figure I.2: Recycling Yields: Reaction of hydrobenzoin (1.0 mmol) with NBS

(2.0 mmol) in [bmim]BF4 at 70oC The successful oxidations of 1,2-diols and α-hydroxyketones led us to believe that alcohols could also be oxidized under these conditions. Therefore, we attempted the oxidation of different alcohols using NBS in [bmim]BF4. Variously substituted secondary aromatic alcohols i.e., 9-fluorenol (IVa), diphenylmethanol (IVb), (4-chlorophenyl)phenylmethanol (IVc), (4-bromophenyl)phenylmethanol (IVd), bis(4-chlorophenyl)methanol (IVe), 1-phenylethanol (IVf), 1-(4-bromophenyl)ethanol (IVg), 1-(4-chlorophenyl)ethanol (IVh), 1-(4-nitrophenyl)ethanol (IVi), 1-(4-methylphenyl)ethanol (IVj) and 1-(4-methoxyphenyl) ethanol (IVk) underwent smooth oxidation with NBS using 1: 2 molar ratio of substrate: NBS in [bmim]BF4 at 70oC and afforded the corresponding carbonyl compounds i.e. 9-fluorenone (Va), benzophenone (Vb), 4-chlorobenzophenone (Vc), 4-bromobenzophenone (Vd), 4,4'-dichlorobenzophenone (Ve), acetophenone (Vf), 4-bromoacetophenone (Vg), 4-chloroacetophenone (Vh), 4-nitrooacetophenone (Vi), 4-methylacetophenone (Vj) and 4-methoxyacetophenone (Vk), respectively (runs 23-33). The oxidation reactions of aromatic primary alcohols e.g. cinnamyl alcohol (IVl), (anthracen-9-yl)-methanol (IVm), (naphthalen-1-yl)-methanol (IVn) and phenylmethanol (IVo) gave corresponding aldehydes viz. 3-(phenyl)propenal (Vl), 9-anthraldehyde (Vm), 1-naphthaldehyde (Vn) and benzaldehyde (Vo) respectively in good yields (runs 34-37). All these results are tabulated in Table I.3 and are summarized in eq. 47.

Chapter I

19

Table I.3: Oxidation of alcohols using NBS in [bmim]BF4 at 70oCa

Run Substrate (IV) Product Time (h) % Yield (V) 23. 9-Fluorenol (IVa) Va 1 93 24. Diphenylmethanol (IVb) Vb 1 92 25. (4-Chlorophenyl)phenylmethanol (IVc) Vc 1 84 26. (4-Bromophenyl)phenylmethanol (IVd) Vd 1 87 27. Bis(4-chlorophenyl)methanol (IVe) Ve 1 90 28. 1-Phenylethanol (IVf) Vf 2 83 29. 1-(4-Bromophenyl)ethanol (IVg) Vg 1 82 30. 1-(4-Chlorophenyl)ethanol (IVh) Vh 1 82 31. 1-(4-Nitrophenyl)ethanol (IVi) Vi 2 86 32. 1-(4-Methylphenyl)ethanol (IVj) Vj 1.5 78 33. 1-(4-Methoxyphenyl)ethanol (IVk) Vk 1.5 85 34. Cinnamyl alcohol (IVl) Vl 1 80 35. (Anthracen-9-yl)-methanol (IVm) Vm 2 65 36. (Naphthalen-1-yl)-methanol (IVn) Vn 2 60 37. Phenylmethanol (IVo) Vo 2 82 38. Heptan-1-ol (IVp) Vp 2 82 39. Octan-1-ol (IVq) Vq 2 80 40. Cyclohexanol (VIa) VIIa 2 85b 41. Octan-2-ol (VIb) VIIb 2 82b 42. Heptan-4-ol (VIc) VIIc 2 77b 43. Pentan-3-ol (VId) VIId 2 75b

aGeneral reaction conditions: alcohols (1.0 mmol), NBS (2.0 mmol), [bmim]BF4 (5.0 mmol) bIn case of secondary aliphatic alcohols, corresponding bromides were obtained, rather than ketones In view of the successful oxidation of benzylic and allylic alcohols, we investigated the reaction of aliphatic alcohols with NBS in ionic liquids. Reactions of primary aliphatic alcohols like heptan-1-ol (IVp) and octan-1-ol (IVq) with NBS in [bmim]BF4 resulted in the formation of corresponding oxidized product i.e. 1-heptanal (Vp) and 1-octanal (Vq), respectively (Table I.3, runs 38, 39) (eq. 47). There was no further oxidation of these aldehydes to corresponding carboxylic acids.

Chapter I

20

CHROH

R' NBS, [bmim]BF4

70oCCRO

R'

IV V

...(47)

(a) R-R' = 9-Fluorenyl (b) R = R' = C6H5 (c) R = C6H5, R' = 4-ClC6H4 (d) R = C6H5, R' = 4-BrC6H4 (e) R = R' = 4-ClC6H4 (f) R = C6H5, R' = CH3 (g) R = 4-BrC6H4, R' = CH3 (h) R = 4-ClC6H4, R' = CH3 (i) R = 4-O2NC6H4, R' = CH3 (j) R = 4-MeC6H4, R' = CH3 (k) R = 4-MeOC6H4, R' = CH3 (l) R = Cinnamyl, R' = H (m) R = 9-Anthryl, R' = H (n) R = 1-Naphthyl, R' = H (o) R = C6H5, R' = H (p) R = n-C6H13, R' = H (q) R = n-C7H15, R' = H

However, reactions of secondary aliphatic alcohols namely, cyclohexanol (VIa), octan-2-ol (VIb), heptan-4-ol (VIc) and pentan-3-ol (VId) with NBS in [bmim]BF4 at 70°C, resulted in the formation of bromocyclohexane (VIIa), 2-bromooctane (VIIb), 4-bromoheptane (VIIc) and 3-bromopentane (VIId) respectively (Table I.3, runs 40-43) (eq. 48). Cholesterol and triphenyl methanol remained unreacted under our optimized reaction condition, even after continuing the reaction for 24 h.

CHROH

R' NBS, [bmim]BF470oC

CHRBr

R'

VI VII

...(48)

(a) R-R' =

5CH2 (b) R = C6H13, R' = CH3

(c) R = R' = C3H7 (d) R = R' = C2H5 Two different pathways have been proposed for the oxidation of alcohols with NBS.99 In the first approach, oxidation proceeds through α-halogenation of the alcohols followed by rapid loss of hydrogen halide (Path A, Scheme I.2). In this mechanism, the rate determining step is the cleavage of the alpha C-H bond to form the halo intermediate. In the second approach, it has been proposed that the alcohols form a hypobromite which readily loses HBr to form the corresponding carbonyl product (Path B, Scheme I.2).

Chapter I

21

CR2

HR1 O Br C O

R1

R2+ HBr

Scheme I.2

CR2

HR1 OH

CR2

XR1 O H + HBr

N

O

O

Br+

NH

O

O

+

NH

O

O

+

Path A

Path B

C OR1

R2slow

slow

fast

fast

We believe that oxidations are taking place by path B in our reactions by initial formation of hypobromite intermediate followed by loss of HBr to give the carbonyl compound. In order to confirm the reaction pathway, reaction of 2-benzyloxy-naphthalene was carried out with NBS under identical conditions. It was observed that no reaction takes place even after 24 h and 2-benzyloxy-naphthalene was recovered unchanged (eq. 49). This is obviously due to non availability of hydroxyl hydrogen to form hypobromite. Further no evidence was found for the α-halogenation of starting material as reported in case of ethers,66 thereby supporting the fact that reaction proceeds through initial hypobromite intermediate.

ONBS, [bmim]BF4

70oCNo reaction ...(49)

Formation of secondary alkyl bromides in case of secondary alcohols must be proceeding by a different pathway. The work is underway to extend the scope of the reaction and to understand its reaction pathway. In conclusion, the present catalyst free protocol for oxidation of hydrobenzoins, benzoins and alcohols is facile, clean and environmentally friendly. Meanwhile, the method has several advantages such as higher yields, shorter reaction times, easy setup, easy work up, reusable ionic liquid and wide applicability. I.3: EXPERIMENTAL All melting points were recorded on a Tropical Labequip apparatus and are uncorrected. IR spectra were recorded on Perkin-Elmer FT-IR SPECTRUM-2000.

Chapter I

22

NMR spectra were recorded on FT-NMR model R-600 Hitachi (60 MHz) with TMS as internal standard. The products were identified by co-TLC, m.p., IR and NMR spectra. Hydrobenzoins were prepared by reductive coupling of aldehydes by Al- KOH.100 Aliphatic alcohols were prepared by hydroxylation of corresponding olefins. The preparation of acyloins was carried out by acyloin condensation. General procedure for the preparation of hydrobenzoins100 In a 100 mL round-bottomed flask, fitted with a water condenser and mounted over a magnetic stirrer, was placed the aldehyde (n mmol), aluminium powder (2n mmol) and methanol (10 mL/g of aluminium). KOH (6n mmol) was added and the reaction mixture was stirred at room temperature. A vigorous reaction ensued immediately. The progress of the reaction was monitored for complete disappearance of carbonyl compound by TLC. The reaction mixture was filtered to remove unreacted aluminium powder and water was added to the filtrate. A solid precipitated out which was filtered at reduced pressure. The solid product was recrystallized from aqueous ethanol to obtain pure hydrobenzoins. Preparation of [bmim]Cl101 In a typical reaction, 1-methylimidazole (1.0 mmol) and n-butyl chloride (1.10 mmol) were added to a round-bottomed flask fitted with a reflux condenser and mounted on a magnetic stirrer. The mixture was stirred vigorously at 70-80ºC for 72 h under nitrogen. The viscous liquid so obtained was washed well with diethyl ether (3×60 mL) and dried on rotary evaporator to yield [bmim]Cl. Preparation of [bmim]Br102 In a typical reaction, 1-methylimidazole (1.0 mmol) and n-butyl bromide (1.0 mmol) were added to a round-bottomed flask fitted with a reflux condenser and mounted on a magnetic stirrer. The mixture was stirred vigorously at 70-80ºC for 72 h under nitrogen. The viscous liquid so obtained was washed well with diethyl ether (3×60 mL) and dried on rotary evaporator to yield [bmim]Br.

Chapter I

23

Preparation of [bmim]BF4 and [bmim]PF6103

In a typical reaction, NaBF4 (1.0 mmol) was added to a solution of (1.0 mmol) of [bmim]Br in 100 mL of dry acetone. After 48 h of stirring at room temperature, the reaction mixture was filtered through a sintered funnel. The filtrate was concentrated on a rotary evaporator to yield a viscous liquid. Dichloromethane (75 mL) was added to the residue to cause precipitation of any remaining NaBr. The precipitate was filtered through a sintered funnel and the filtrate concentrated again on rotary evaporator to obtain [bmim]BF4. For the preparation of [bmim]PF6, same procedure was followed as above by replacing NaBF4 with KPF6. General Procedure for the Oxidation of 1,2-diols, α-hydroxyketones and alcohols with NBS-[bmim]BF4 using hydrobenzoin (Ia) as representative example In a typical experiment, a mixture of hydrobenzoin (1.0 mmol), N-bromosuccinimide (2.0 mmol) and [bmim]BF4 (5.0 mmol) along with a stir bar was placed in a 50 mL RB flask fitted with a calcium chloride guard tube and mounted over a magnetic stirrer. The reaction mixture was stirred magnetically in an oil-bath maintained at 70°C for the appropriate time (Tables I.2 ). After completion of reaction as monitored by TLC using petroleum ether: ethyl acetate (80:20, v/v), the reaction mixture was cooled to room temperature. The mixture was extracted with diethyl ether (3×10 mL). The combined ether layer was washed with water (3×10 mL) and dried over anhyd. Na2SO4. The solution was concentrated on a rotary evaporator to give a yellow solid, which was identified as benzil (0.19 g, 92%) by m.p., mix. m.p., IR and 1H NMR spectra. The recyclability of the ionic liquid, was examined by repeating the above reaction. On completion of reaction, as monitored by TLC, the reaction mixture was cooled to room temperature. The product obtained was extracted in diethyl ether, leaving behind ionic liquid and the by product of NBS i.e. succinimide as residue. The residue was diluted with ethyl acetate and the insoluble succinimide, was removed by filtration. The ethyl acetate was evaporated under reduce pressure to give ionic liquid which was dried before use at 80°C under vacuum for 30 min. The recovered ionic liquid could be used for oxidation up to two runs without any appreciable loss of efficiency by adding 2 equiv. of NBS for each run and afforded 91% and 89% of benzil after 1st and 2nd cycles. However, the yield of benzil decreased in the third cycle.

Chapter I

24

Representative Example 4,4'-Dibromobenzil (IId): Yellow solid; Yield: 82%; M.p.: 225-226oC (Lit. 224-226

oC);104 IR (vmax cm-1) (KBr): 2980, 1664, 1586; 1H NMR (60 MHz, CDCl3): δ 7.83 (d, J = 8.4 Hz, 4H, Ar), 7.67 (d, J = 8.0 Hz, 4H, Ar). Product-Profile Run Product Physical

State Melting Point (°C) Ref. Obs. Lit.

3. Benzil (IIa) Solid 92-94 92-94 104 10. 4,4'-Dichlorobenzil (IIb) Solid 199-200 198-199 104 11. 4,4'-Dimethylbenzil (IIc) Solid 102-103 103-104 104 12. 4,4'-Dibromobenzil (IId) Solid 225-226 224-226 104 13. 3,3'-Dibromobenzil (IIe) Solid 118-120 120-12 104 14. 2,2'-Dichlorobenzil (IIf) Solid 131-133 128-130 104 15. 4,4'-Dimethoxybenzil (IIg) Solid 122-123 121-122 104 16. α,α'-Naphthil (IIh) Solid 187-189 192-194 105 17. Cyclohexane-1,2-dione (IIi) Solid 32-33 34-38 106 18. 9,10-Diketostearic acid (IIj) Solid 83-85 82-83 107 19. Benzil (IIa) Solid 90-92 92-94 104 20. 4,4'-Dichlorobenzil (IIb) Solid 199-200 198-199 104 21. 4,4'-Dimethylbenzil (IIf) Solid 102-103 103-104 104 22. Octane-4,5-dione (IIk) Liquid - - 108 23. 9-Fluorenone (Va) Solid 82-84 80-83 109 24. Benzophenone (Vb) Solid 46-48 47-49 110 25. 4-Chlorobenzophenone (Vc) Solid 74-76 75-77 110 26. 4-Bromobenzophenone (Vd) Solid 78-80 79-80 111 27. 4,4'-Dichlorobenzophenone (Ve) Solid 142-144 144-145 112 28. Acetophenone (Vf) Liquid - - 110 29. 4-Bromoacetophenone (Vg) Solid 48-51 48-52 110

Chapter I

25

Run Product Physical State

Melting Point (°C) Ref. Obs. Lit.

30. 4-Chloroacetophenone (Vh) Liquid - - 110 31. 4-Nitrooacetophenone (Vi) Solid 76-80 76-78 113 32. 4-Methylacetophenone (Vj) Liquid - - 110 33. 4-Methoxyacetophenone (Vk) Solid 38-41 38-39 114 34. 3-Phenyl-propenal (Vl) Liquid - - 115 35. 9-Anthraldehyde (Vm) Solid 102-104 100-105 116 36. 1-Naphthaldehyde (Vn) Liquid - - 117 37. Benzaldehyde (Vo) Liquid - - 115 38. 1-Heptanal (Vp) Liquid - - 118 39. 1-Octanal (Vq) Liquid - - 118 40. Bromocyclohexane (VIIa) Liquid - - 119 41. 2-Bromooctane (VIIb) Liquid - - 119 42. 4-Bromoheptane (VIIc) Liquid - - 120 43. 3-Bromopentane (VIId) Liquid - - 121

Chapter I

26

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