Indi an Journal of Chemistry Vol. 428, November 2003, pp. 28 14-28 19

Selective and efficient heterogeneous hydration of nitriles to amides using silica supported manganese dioxide

Bhushan M Khadilkar'l' & Virendra R Madyar*

'f' Applied Organic Chemistry Laboratory, University Department of Chemical Technology, Un ivers ity of Mumbai, Matunga, Mumbai 400019. India.

Email: bhushank@vsnl.com, Fax: 91-022-4145619

*Godrej Consumer Products Ltd .. Soaps and Detergent Laboratory , Research Center. Pirojshanagar, Eastern Express Highway. Vikhroli, Mumbai 400 079. Indi a.

Email: l'r.lllad\'or@IIl}(/rejC{I. colII, Fax: 91-022-5188073

Received /6 Jallllary 2002; accepted (revised) 6 January 2003

A highly efficient and selective method for hydration of nitriles to amides without formation of any detectable amount of ac id, under heterogeneous reaction condition using silica supported manganese dioxide is reported . The mechanism of the reaction has becn discussed. Thc reagent preparation is easy and carried out under microwave exposure within 5 min . The silica supported Mn02 reagent has been characterized by DRIFT and XRD techniques. Quantitative yields arc obtained for commercially important heterocyclic amides such as pyridinecarboxamide. nicotinamide and pyrazinamide.

Active manganese dioxide and its various modifica ­tions provide a useful MnO] reagent to carry out mild, selective conversions under heterogeneous conditions for diverse classes of organic compounds. I In our laboratory we had successfully carried out preparation of many supported reagents, such as si lferc2

, silzic3,

silfen4, si lchromes, 6 to carry out various organic trans­

formations under heterogeneous reaction conditions. Our continued interest in preparation and use of sup­ported reagents for heterogeneous organic synthesis prompted us to study the preparation and use of si lica supported MnO].

In literature,7. 8 there are different methods reported to prepare active manganese dioxide reagen t. But all of them are time consuming with elaborate proce­dures. We have developed an easy and fast method to prepare silica supported Mn02 reagent9 under micro­wave itTadiation. The reagent was prepared in just 5 minutes as against the methods requiring 10 to 48 hr reported in the literature IO.12a.c. it was then decided to focus our attention to study the scope of this reagent for nitrile hydration under heterogeneous conditions.

Hydration of nitrile to amide can be achieved by many different methods such as refluxing in presence of strong acidic l3 or basic conditions l4

, Ritter reac­tion l s

, use of H20 2 in DMSO l 6 under basic or H20 2-

alkal i under PTC conditions 17, microbial 18 or cnzy­

mntic routes. 19 All these methods involve homogene­ous reaction conditions. These methods suffer from

some drawbacks like use of strong acids or bases, possibility of amide hydrolysis to acid, or problems in isolation in case of DMSO and PTC conditions, long reaction time up to 72 hr in case of microbial and en­zy matic routes.

Recen tly supported reagents have become popular due to the well known advantages of eas ier separation and work up, better regeneration and recycling pro­perties, improved selectivity and faster reactions. Other advantages are that the solid reagents can be safer, less toxic, more stable, easier to handle and hence, face more ecological acceptance. Possibility of developing large scale or continuous process exists with the use of solid reagents.

A very first report by Cook et al. 20 have described the use of Mn02 for selective hydrolysis of nitriles to amides at room temperature using Mn02 with envi­ronmentall y undesired dichloromethane as a solvent. The procedure in volves long reaction time with low yie lds for amide, and the substrate to reagent ratio has been as high as 1 :20 by weight, and also the reagent is not reusable. Cheng-Ting Liu et al. II have reponed the use of Mn02 deposited on silica gel by coprecipi­tat ion method to catTy out hydration of nitriles to am­ides using hydrocarbons as solvent with only mode­rate yields. But the reagent preparation requires elabo­rate and multistep procedure with long process time. They have used this reagent in proportion of 1.5 to 2 times that of the substrate nitrile.

KHADILKAR el al.: SELECTIVE HETEROG ENEOUS HYDRATION OF NITRJLES TO AMIDES 281 5

Results and Discussion We have calTied out an ex tremely effic ient, rapid,

microwave assisted synthes is of Mn02 supported on silica. MnCO) and NH4NO) were mi xed thoroughly with silica gel by co-grinding in an agate mortar. This mixture was then decomposed in a modifi ed domestic microwave oven9 to g ive silica supported Mn02 in the form of black free flowing powder. The method is easy, manageable though vigorous and requires just 5 minutes as compared to 10 to 48 hr required in con­ventional procedures, which in volve lengthy pre­treatment of the precursor. The SiOr Mn02 reagent was characteri zed by BET, FfIR (DRIFf) and XRD techniques . The reagent possessed no storage and handling problems. The reagent has shelf life of at least two years.

I I L

R-CN Mn02/S i0 2 -----:.~ R-CONH2

Chlo ro benzene Stir, Reflux

Scheme I

Pel elher

Chlorobenzene

p-X ylene

Toluene

'" C EDC

" > "0 Vl

Chloro[onn

Dioxan J

Acetone ==:J

Melhanol :::J Water

o 20 40 60 80 Benzamide yield %

Figurc I- Nitrile hydra tion us ing silica supponed with man­ganese dioxide in different solvents at renux temperature

100 !;11 80 • -0

l 60 • " -0 40 • 'E '" 20 N c: " • CXl 0

0 50 100 150

Reaction temperature °c

I I I

We report here a study of the nitrile hydration reac­tion with respect to the nature of solvent, time, and temperature(Scheme I). We have also examined the conversion by unsupported manganese dioxide pre­pared by similar method and also with commercially available Mn02 (s .d . fine chemicals, Ind ia).

We fo und that the choice of the solvent was impor­tant in the nitrile hydration reaction using silica sup­ported manganese diox ide. We studied nitrile hydra­tion of benzonitrile by keeping the substrate to re­agent mol ar ratio equal to 1: 1. Various polar and non polar sol vents were examined. It can be seen fro m the (Figurc 1) that the yields fo r benzamide fo rmation are very low in polar solvents when compared to the non po lar solvents. It was also observed that the yield for benzamide was lower in p -xy lene than in chloroben­zene though the reaction temperature was higher in case of p -xylene than the latter.

Chlorobenzene was found to be best solvent. We observed that in chlorobenzene benzamide fo rmation took place within 5 hr at reflu x temperature. Yields of benzamide were lower at lower reaction temperatures. Optimi zati on with respect to reaction time was al so calTied out. We have observed that 5 hr of refl ux wa optimum ti me and thereafter there was no increase in the y ield of benzamide (Figurc 2).

Hydration of various nitriles using silica supported Mn02

The reactions of various nitriles under conditions optimized for benzonitr ile were c3ITied out. Complete selecti vity and good yields of amides for aromatic and heterocyclic nit!i les were obtained (Table I). However pentanen itrile, steareon itrile (heptadecyl nitrile) and sterica lly hindered l -cyanostilbene were recovered back completely even after 48 hr of reflux . In case of phthalonitrile, quantitati ve y ie ld of phthalimide on hydrati on was obtained though the

100 90

"'" • • • • 80 • '0 70 • • U

":>- 60

" 50 • '0

.~ 40 30

C

" 20 co 10 0

0 10

Reaclion time in hrs

Figurc 2--Optimi zation of reac tion ti me and effect of reac tion temperature fo r benzoni trile hydra ti on in chl orobenzene using sil ica supported wi th Mn0 2

2816 INDIAN .I . CHEM., SEC B, NOVEMBER 2003

Table 1- Nit rile hydrati on reac ti on usi ng si li ca supported manganese dioxide

Entry Substrate Yi eldd m.p./("C) No. (%) fo r amidc (Lit)l)

l. Benzonitrile 86 126-128 ( 127-2R)

2. 2-Ami nobcilzoni trile 20 110- 11 2 ( 11 2- 14)

3. 4-Hydroxybenzonitrile 33 160- 162 ( 162)

4 . 4-Accty lbenzonitri Ie 40 188- 189 ( 190-9 1 )

5 . 2-Chlorobenzollitri Ie 83 138- 140 (142)

6. 2.6-Di nuorobenzollitri Ie 4 1 145- 146 ( 145-46)

7. 4-Cyunobenzaldehyde 36 157-160 ( 16()

8. 2-Cyanopyridine 99 108- 11 0 ( 107-9)

9. 3-Cyanopyridine 100 128 (129- 130)

10. 2-Cyanopi perazinc 100 j 88- 190 ( 192)

a) Substratc = 0.0 I mole: Mn02/SiO~ = 0.0 I mole ~5g) ;

b) Reaction time for all substrates = 5 hr:

c) In all cases ullreacted nitrile were recovered and recycled:

d) % Isola ted yield. All products show ~atisfaclO ry physical ,:nd spectral data.

expected was either o-cyanobenzamide or phtha liamide. With the intention of genera li zing the scope of rcaction, the reaction for diphenylacetonitrile was carried out. However to our surprise the prod uct was not the corresponding amide. The compound was insoluble in aqueous aHCO), so it was not even the carboxy li c acid. The PMR showed a singlet on ly in aromatic region between 97.2-7.5, this eliminated the possibility of tetraphenylethane. The elemental analysis of the compound showed rhe presence of nitrogen (C-86.6, H-6.4, - 6.2) . FflR of the compound showed the presence of peak at 2337 cm-I

corresponding to nitrile streching. The ev idence

Ph I-I

a )Lc N + Ph

b

Ph 1-1

)LCN

Ph

+ O~ -_0 ( I V)

M n -----siO;--

Ph H

)LCN +

Ph

Ph

c 2 ~CN Ph

NC

Ph ) Ph

CN

< Ph Ph

showed the product to be tetraphenylsuccinonitrile (butanedinitriletetraphenyl) which is a good radical initiator. The reported m.p. (223-224°C) of compound tallied with what we had obtaincd (224-226°C). The PMR and IR were also in agreement with the structure.

The first step (a) involves adsorption of di­phenyl acetonitrile molecule to the su rface of silica supported Mn02 (b) transfer of a hydrogen atoms takes from two molecules to give an intermedi ate sta­ble cyanodiphenylmethyl radical s. (c) cyanodiphenyl­methyl radicals combine to give tetraphenylsuccinoni­tri le product with form ation of Mn02 and water (Scheme II).

During the reaction the formation of stable cyanodiphenylmethyl radical t:lkes pbce by removal of benzylic hyd rogen (a- hydrogen). Replacement of C-H bond by C-C bond would hence prevent the formatio n of such a compound, as the free radical generation wou ld not be possib le. When we carried out the reaction of 2,2-diphenylbutanenitri le and 5-ch loro-2, 2-diphenylpentanenitrile under identical conditions to those used in case of diphenyl­acetonit rile, to our satisfaction the starting material was fully recovered. This is the conv incing ev idence for the mechanism we have proposed.

The synthesis of tetraphenylsuccinonitrile reported in the literature is quite complex. The method reported by Schmidpeter el a/. 21 involves the use of phosphineimide and ketene adduct to give tetra­pheny lsuccinon itr ile. Russell et a /.22 have described a method in which li thiu m acetylenides reacts with 2-chloro-2-nitropropane or 2,2-dinitropropane to give cross coup led product. In yet another method by

Ph H

)Lc

P h

Ph

~CN Ph

+ O~ -0 H

Mil ( III ) ----s;o;----

Ph

~CN H O,---- ....--OH

M Il ( II ) + ~

Ph

+ MilO , +

~ Scheme II

KHADILKAR et al.: SELECTIVE HETEROGENEOUS HYDRATION OF NITRILES TO AMIDES 2817

Russel et al. 23 have can-ied out photolysis of (benzoyl­methyl)mercurials to benzoyl methyl radicals which are then trapped by anions such as Ph2C=C=N- to gi ve tetraphenylsuccinonitrile. A method described by Tsuge et al. 24 involves the reaction between trimethyl­silylcyanide and N-(trimethylsilyl)diphenylmethylene amide to give a-aryl-N-phenylnitrones, wh ich on thermal decomposition in refluxing xylene gives the tetraphenylsuccinonitrile. The compound tetraphenyl­succinonitrile has been used as free radical initiator in polymerization reaction2s-3o. Thus we have developed a very simple process for the synthesis of free radical initiatol , tetraphenyl succinonitrile getting it in 92% yield.

Further work of generalization this reaction is to be done. We had attempted the hydration of benzylcya­nide (phenylacetonitrile) and acrylonitrile as well, the reaction yielded a polymerized product. It must be obviously due to benzylic free radical formation lead­ing to polymeri zed product.

Another most notable observation of our reaction is the reusability of the silica supported Mn02 reagent. We tested the reusability of our reagent for nitrile hy­dration for three runs. The reagent was reused by simply air drying after each run however slight de­crease in yields was observed.

To investigate the role of silica support in the ni­trile hydrolysis reaction unsupported Mn02 was pre­pared by the similar procedure as reported in our ear­lier work9

. Mn02 when used in stoichiometric ratio for the benzonitrile hydrolysis gave only 13% yield of benzamide and surpris ingly fai led to show any reus­ability . This clearly points out the importance of si lica gel as a support in nitrile hydration reaction under these conditions though exact role is difficult to rea­son out. A blank experiment by silica gel alone was unable to induce nitrile hydration under the given ex­perimental conditions, while commercially available Mn02 gave only 5% benzamide.

In conclusion a practical, efficient and selective method for the hydration of nitrile to amide under heterogeneous reaction condition using silica supported with manganese dioxide has been developed by us. The method becomes attractive because of short preparation time of silica supported manganese dioxide. The method gives quantitative yields for commercially important heterocycl ic am ides such as nicotinamide, pyridinecarboxamide, pyrazinamide used in pharma­ceutical industry and in addition the method is interesting due to reusable property for silica supported Mn02 in the nitrile hydration reaction .

Experimental Section Preparation of silica supported with manganese

dioxide. MnC03 (5 .75 g, 0.05 mole), NH4NOJ (4.0g, 0.05 mole) and silica gel (l1.5g, 230-400 mesh, BET surface area 385.6 m2/g, pore volume = 0.65 cm3/g) were accurately weighed and co-ground in an agate mortar until looked homogeneous. The resulting mix­ture was transferred to 100 mL quartz round bottom flask attached with a condenser. The condenser was connected to a scrubber, kept outside the oven. The mixture was ilTadiated in modified microwave oven32

(IFB Neutron, 750W output) for 5 min (5 cycles of 1 min each at full power) to obtain black colored sup­ported Mn02 after a vigorous reaction. The mixture was homogenized before use. The product showed BET surface area = 268.0 m2/g, pore volume = 0.497 cm3/g.

Characterization XRD studies for silica supported with manganese dioxide

X-ray diffraction patterns were recorded on a SIEMENS 0-500 diffractometer with CuKa (a == 1.5405 A) radiation. All diffractograms were scanned at 20 ±1 °C. Nickel filtered Cu radiation was incident on the samples which were scanned at a rate of 1°/min in reflection mode over a range of 28 from 10° to 60°. Few peaks are observed because of large proportions of amorphous silica suppOrt. The samples were ana­lyzed for each cycle of mw irradiatio ll .

Co-grinded mixture (MilC03, NH4 N03 and silica gel) before irradiati on shows XRO peaks with d spac­ing at 2.86, 2.42 and 1.72 corresponding to 31.22, 37.42 and 51.57 on 28 degree axis. The peak at 2.86 was found to be prominent among the three peaks with maximum intensity. As the microwave irradia­tion progresses the peaks at 2.86, 2.42 and 1.72 A starts disappearing in the co-grinded silica supported Mn02 reagent mixture and new peaks at 2.77, 2.72 and 2.49 A appear at 32.20, 32.72 and 35.96 on 28 degree axis respectively at the end of mw irradiation of 5 min . The peak at 2.72 is sharp and strong in com­parison to peaks at 2.77 and 2.49. The peak at 2.72 is also observed for unsupported Mn02 and is persistent in the reused silica supported Mn02 even after 5 run of the nitrile hydration reaction. The peak at 2.72 has also been observed and reported by Suib el 01. 8 in his work on transformation of cryptomelane type of manganese dioxide under microwave heating and has designated this peak as a basal XRO peak for bixybite (Mn20,).

2818 INDIAN J. CHEM., SEC B, NOVEMBER 2003

FTIR studies for silica supported with manganese dioxide

Infrared spectra were recorded on a Shimadzu FfIR-8300 spectrometer. Diffuse reflectance method was employed for a range from 4499 to 351 cm' l and a resolution of 4 cm,l wi th 45 number of scans for each sample,

Peaks at 3750-3903 cm'l revealed the presence of hydroxyl stretching groups and those between 1558-1382 cm'l due to hydroxyl bending. These peaks were absent in case of unsupported Mn02 and in the spectrum of sil ica gel. There was a sharp peak at 2350 cm'l due to CO2 adsorption from air, this peak was absent in samples of unsupported Mn02 and for si lica gel. This may point to the presence of sUlface basicity for si lica supported Mn02. A broad band at 1085 cnfl was observed due to Si-O-Si linkage which was absent in case of unsupported Mn02. Broad peak between 575-675 cm' l and 378 suggested the presence of y-Mn02 and whiie sharp peaks in far IR region at 356, 420 and 450 cm,l also indicated the presence of p-Mn02; the presence of this peaks have been observed for both supported and unsupported Mn02. Thus on the surface a mixture of Mn oxides might be present though the major one was Mn02 which was estimated by standard AS20 3 method.33

Nitrile hydration reaction using silica supported with manganese dioxide. In a typical procedure ben­zonitrile (\.03g, O.Olmole) and 5g of si li ca supported with Mn02 (0.002 mole Mn02 per g of Si02) was stirred in chlorobenzene (25 mL) at reflux tempera­ture for 5 hr. The progress of the reaction was moni­tored by TLC using toluene-ethyl acetate 9: I as eluant. After the completion of the reaction the hot mixture was filtered through sintered G-4 Gooch cru­cible. The reagent mixture was then washed with 25 mL of hot methanol, methanol was di stilled off to ob­tain the mixture of benzamjde and unreacted benzoni­trile. The unreacted benzonitrile was recovered from the mixture by washing with 10 mL of petroleum ether and recycled . The benzamide was obtai ned as pure white crystals (1.04g, 86%) which gave exact melting point 126-128 °C (from MeOH) .

Nicotinamide: IR (KBr): 3368, 3159 (N-H), 1680 (C=O), 161 8- 1423 (C=C, C=N) cm' l; 13C NMR (125 MHz, DMSO-d6): 8 124.66, 130.82, 136.40, 149.80, 153.80, 167.77; IH NMR (300 MHz, DMSO-d6): 7.5 (s, H), 7.1-8.4(d, 2H), 8.2(s, H), 8.7 (s, H), 9.5 (s, H) Pyrazinamide: IR (KBr): 3421,3269, 3151(N-H), 1674 (C=O), 1582, 1522 (C=C, C=N), 1376 cm' l; 'H NMR (60 MHz, DMSO-d6) : 8 8.5-8.6 (d, 2H, NH2), 8.8 (s,

H), 8.85 (s, H), 9.2 (s, H); 13C NMR (125 MHz, DMSO-d6): 8 144.19, 144.93,145.53,148.43,167.27.

4-Acetyl benzamide: IR (KBr): 3402, 3296, 3190 (N­H), 1679 and 1654 (broad, C=O), 1413 (C-N), l357, 1271 cm'l; 'H NMR (300 MHz, DMSO-d6): 8 2.6 (s, 3H, CH3), 7.6-7.8 (s, 2H, NH2), 7.9-8.1 (q, 4 Harom.).

Butanedinitrile tetraphenyl: IR (KBr): 3058, 3031 (C-H stretch), 2237 (C= ) cm' l; IH NMR (60 MHz, CDCh): 87.2-7.5 (s, 20 Harom}

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KHADILKAR et al.: SELECTIVE HETEROGENEOUS HYDRATION OF NITRILES TO AM IDES 2819

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