CA2001689A1 - Process for the production of ortho-nitrobenzonitriles - Google Patents

Abstract

PROCESS FOR THE PRODUCTION OF ORTHO-NITROBENZONITRILES

Abstract of the Disclosure Ortho-nitrobenzonitriles are produced from the corresponding ortho-nitrochlorobenzenes by reaction with cuprous cyanide and an alkali metal bromide, an alkaline earth metal bromide, or zinc bromide or with a combination of lithium cyanide and cuprous bromide, optionally in the presence of a solvent.

Description

20C~1~89 PROCESS FoR THE PRODUCTIoN OF OR~90-NTTRO~ENZOWITRILES

EacXground and Prior Art Oe e Invention m is invention relates to an inproved process for production of ortho-nitrobenzonitriles. Comp~unds of this type have the general fonnula R2 ~ N2 in ~hich R1 and R2 independently represent hydrogen or various electron-withdrawing group6 such as nitro, cyano, halomethyl (particularly trihalo-methyl), lower alkylsulfonyl, an~ halo-(lower alkyl)sulfonyl.

Various processes are known for the production of compounds of this type including the general pro x ss of cyanation of a similarly sub-stituted halobenzene.

One such process is described in U.S. Pat. 2,195,076. Ihat pro-cess uses a combination of cuprous cyanide and a coTpound capable offorming a ~double oompound~ with the cuprous cyanide, pQrticularly oe rtain nitrogenous bases. The patent states that in many cases it is preferable to add inorganic ~alts, preferably copper salts, or also halides of alkali netals, aluminum, zinc, mercury or iron. ~his patent contains a total of 33 examp~es describing production of various oompounds by the general pro-oe ss. Cne of the ccmpounds prepared, in ~xample 18, is 4-cyano-3-nitro-1-trifluoromethylbenzene. In that example the campound is produced using a combination of cuprous cyanide, cuprous chloride and quinoline. An attempt was n~de to repeat this example to determine the yield of the prod w t, as the example did not provide such information. ~o~everv little or no desired product was ob6erved, wi~h tarry products predaminating.
IDwering of the temperature did not result in any significant Lmprovement.

Most of the ex~mples of U.S. Eat. 2,195,076 show ~he use of cuprous cyanide alone or in co~bination wi~h another copper salt, usually cuprous chloride or bramide. The only s lt of any other netal ~hich is .. . ..

201~1~89 disclosed in an example used in combination with cuprous cyanide, is sodium cyanide.

Japanese Patent kpplication 60/47830 (p~blication nu~ber) of Nippoll ~ayaku Company discloses a method for producing ortho-nitrobenzo-S nitrile compounds employing an alkali met 1 cyanide, cuprous chloride ~orcuprous chloride plus a cupric salt) and a polar aptotic or basic solvent.

SummarY of the Invention m e present invention oomprises a process for production of an ortho-nitrobenzonitrile by rea~tion of the corresponding ortho-nitro-chlorobenzene with: (a) cuprous cyanide an~ a met~l bromide selected fram alkali metal bromides, alkaline earth ,~tal bromides and zinc bromide, or (b) cuprous bromide and lithium cyanide, at a temperature of from about 100 to about 200C, opkionally in the presen~e of a solvent.

etailed ~escripkion of the Invention Compound~ produced by the process of this invention can be characterized by the general formula R2 ~N 2X)2 in which R1 and R2 are independently hydrogen or electron~withdrawing groups. Examples of such ele~tron-withdrawing groups are nitro, C1-C4 alkylsulfonyl ~such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, etc.), halo-(C1-C4 aLkyl)sulfonyl (for instance, chloromethylsulfonyl), cyan~, boxyl an~ halomethyl (particularly trLhalome~hyl such as tri-fluoromethyl and trichloro~ethyl).

Some compounds of ~his class are:ortho-nitrobenzonitrile, 2,6-dinitrobenzonitrile, 4-cyano-3-nitro-benzotrifluoride, 4-cyano-3-nitro-benzotrichloride, 2-nitro-4-methylsulfonylbenzonitrile, ~, ~
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4-cyano-3-nitrobenzoic acid, and 2,5-dicyanonitrobenzene.

Such oompounds can be advantageously obkained by reaction of the corresponding chlorobenzene with ouprous cyanide and an alkali metal bro-mide, an alk2line earth metal bromide or zinc bromide, or alternativelyw~th a combination of cuprous bromide and lithi~m cyanide, without the need for a ~double salt ocmpound" of copper as in U.S. Pat. 2,195,076.

When cuprous cyanide is employed, it is preferably used in an approximately stoichiometric amount with respe~t to the starting chloro-benzene. Ihe metal bromide employed together with the cuprous cyanide isused in an amount of from about 0.1 to about 2.0, preferably from about .5 to about 1.0 equivalents, with respect to the chlorobenzene.

In addition to the metal bromide, there nay be used a second bromine-containing substance such as tetraphenylphosphonium bromide or cupric bromide. If a second such bromine-oQntaining substance is used, it is generally used in a minor amount, preferably about 0.1 equivalent with respect to the starting chlorobenzene.

Reaction temperatures generally range from about 100 to about 200C, preferably from about 150 to about 200C. Reaction times may be as short as 3 hours for oomplete or near ccTplete reaction, depending on the starting material, the temperature and the bromude.

The reaction may be conducted without a solvent. ~owever, if a solvent is nok used longer reaction times generally wnll be necessary for more complete reaction in the above temperature range. C~nsequently, the reaction is pre~erably conducted in the presence of a solvent, most pre-ferably a nitrogen-containing solve~t. Preferred solvents are benzo-nitrile, ~methyl-2-pyrrolidinone, dimethylformamide, and 1,4-dicyano-butane. O~her solvents ~hich may be utilized include dimethyl sulfoxide an~ sulfolahe.

30 When a mixture of cuprous brcnide and lithium cyanide is used, the lithium cyanide is used in approximately stoi~hiometric ~m~unts based ,,, : . .
. ~ . , ~0~1689 on the reactant chlorobenzene and the cuprous bronide is used in an amount of $rcm about 0.1 to about 2.0 equivalent based on the chlorobenzene, pre-ferably from about O.S to about 1Ø Tbmperatures and reaction times are as above.

me examples which follow depict the conduct of the process according to this invention, primarily showing the production of 4-cyano-3-nitrobenzotrifluoride (Rl is trifluoromethyl, R2 is hydrogen) as a representative compound. 8Owever, similar conditions, metallic bromides, an~ the like may be used for production of ather compounds of this type such as those mentioned above.

~E 1 PreParation of 4-Cyanc-3-N~trobenzotrifluoride In a flask were placed 1.13 gr~.s (g) (5.0 mm~l) 4-chloro-3-nitrobenzotrifluoride, 0.4478 g (5.0 mm~l) cuprous cyanide, 0.4342 g (5.0 m~l) lithium bromide and 10 milliliters (ml) X~methyl-2-pyrrolidinone, under a nitrogen blanket. The reaction m,ixture was then hRated to a ten~erature of 175-C and reaction was continued at a range of 172-178-C
over a period of 24 hours. At the end of that run, the heat sour oe was removed and the reaction m$xture oooled. Product was recovered by washing with water, 3M HCl, diethyl ether, again with 3M gCl, and again with ether. Ihe ether extract was dried over magnesium sulfate, fil~ered and 20 the solvent striE~?ed, yielding 0.875 g (81% of ~#oretical yield) of an abber, sane~at tarry looking oil, which was identified b~r gas chrnato-grapalic analysis as the desired prcdwt.

me gas chro~atograEihic analysis indi~Led that the final mix-ture contained 62 area % of the desired product, 18 area % of the starting 25 material ana 4 area % 2-nitro-4-trifluorome~ylEhenol by-prodwt.

EXZ~æS 2-8 q~e process as described zibove in ~xanEiLe 1 was carried out using different solvents, or in ~e absenoe of a solvent. In general, the reactions ~here r~ with one equivalen~ each of 4~hloro-~nitrobenwtri-fluoride~ cuprous cyanide and lithium branide. me ~{nount of solvent ~s 30 1 ml/mnol starting ~hloro~enæne in Exa~rEiLes 2 and 6, and 2 mlh~l in the ., ~ .
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20C3~L689 remaining examples. Ihe results in these experiment~ are tabulated in the follownng Iable 1. Product mixture composition was determined by gas chromatography. The distribution of the product nixture is ~how~n as between the desired cyano compound, the starting material and the by-product 2-nitro-4-trifluoramethylphenol.

TA~L~ 1 Product Mixture, Area %
Time, Cyano Starting Ex. 9OlventTemP., C hours compound material Phenol 2 dimethylformamide 165-165 5 70 24 3* CN(CH2)4CN 172-178 3 88 4 4 none 147-152 5 trace 99 5** none 172-178 30 96 4 6*** benzonitrile 195-200 6 91 5 trace 7 dimethyl sulfoxide 160-180 8 44 25 2 8 sulfolane 190-200 7 91 S
* ~brked up after 6 hours to give 49.5% corrected yield of cyano.
** Wbrked up to give 15% yield of cyano compound; reaction run in a heel of the cyano compound.
*** Wbrked up to give 79.2% corrected yield of cyano compoun~.

Cbmparative ~xample 1 qhis ex~,~le illustrates the poor results obkained by the use of lithium chloride instead of lithium bramide.

In a flask were placed 1.13 g (5.0 ,I..~l) 4-chloro-3-nitrobenzo-trifluoride, 0.448 g (5.0 mmol) cuprous cyanide and 0.21195 g (5.0 mm~l) lithium chloride. There was then added 10 nl benzonitrile. The reaction was conducted under a nitrogen blanXet at a temperature of 182-185C for 6 ~ours. ~ chromatographic analysis of the product nuxture at this point showed 72 area % unreacted starting ~aterial and only 27 area % of the desired cyano comFound. Fbr comparison, Example 6, conducted at slightly higher temperature over the same period using lithium bramide rather than lithium chloride, produced 91 area % of the desired compound and only 5 area % unreacted starting ~terial.

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-;-E~ES ~14 m ese examples illustrate produ~tion of 4-cyano-3-nitrobenzokri-fluoride using the metal brom$des as catalyst. The reactions were ried out a~ in Fxamples 2-8 using 1 equivalent of cuprous cyanide per equ$va-lent of starting chlorobenzene and 2 rnl benzonitrile solvent per mnDl S chloroben æ ne. Table 2 below shows the temperatures, reaction times ana equivalent amounts of the various metal bromideq. Ihe product mixture is again given in terms of gas chromatographic analysis by ar~a % in terms of the desired cyano oompound, the starting material and by-product 4-bromo-3-nitrobenzotrifluoride (~brom~ compound~).

TAEL~ 2 (Solvent -- Eenzonitrile) Product Mixture, Area ~
Equi- TL~e Cyano Starting Eromo Ex. Bromidevalents Ibmp. C hrs. compDund Material oom~ound 9 NaEr 1.0 190-193 6 65* 2 trace ~aBr 1.0 188-192 3** 75 22 2 (C6~s)4PBr 0 1 11 ~aBr 1.0 191-193 2** ~3 34 CuBr2 O. 1 12 M~Br2 etherate 0.5 182-184 6 85 12 2 13 ~Rr2 0.5 190-193 7 84 12 3 14 ZnBr2 0.5 189-193 7 77 12 traoe***
* mrNitrobenzotrifluoride also detected.
** Decomposition occurred on further heating.
*** 2,4,6'Triphenyl-s~triazine alSD detected.

Com~arative ~xample 2 Ihis example illustrates the conduct of the reaction using cuprous bromide instead of lithium bromide.

Ihe proGess was run sinilarly to those described above for Examples 9-14. Cuprous bromide wss used in an amount of 1.0 equivalent per equivalent of the starting chlorobenzene. Ihe solvent was benzo-nitrile, reaction temperature wss 180-194UC and the time of the reaction was 3 hours.

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20~689 Gas chromatographic analysis of the product mixture at the end of this tine indicated approximately 52 area % of the desire~
benzonitrile, about 16 area % of starting material and only a traoe amount of the bromD compound. There was al80 detected the presenoe of mrnitro-benzotrifluoride.

This example de~onstrates the use of a combination of lithium cyanide and cuprous bromide for this reaction.

There were placed in a flask 2.26 g (10 mmol~ 4-chloro-3-nitro-benzotrifluoride, 2.869 g ~10 mmol) cuprous bromide and 20 ml of a 0.5 10 molar solution of lithiu~ cyanide in dimethylfonmamide whidh contained 1.0 equivalent of lithium cyanide with resp~ct to the starting chlorobenzene.

Ihe reaction temperature was maintained at 158-159-C; the time of the run ~as 6 hours. At the end of this time, the product mixture was analyzed by gas chromatography. It showed the fol1owing:
15 cyano oompound 81 area starting chloroben æne 12 area dimethylamino-substituked ben æ ne 2 area bromo-substituted ben æ ne trace hydroxy-substituted benzene not detected EX~MPLE 16 Ihis exanple illustrates the production of 2-nitrobenzonitrile by the process of this invention.

m is reaction was oonducted similarly t~ t~ose reported above, using a nixture of cuprous cyanide and lithium bromide. ~he ratios of reactants were (by equivalents) 2-chloronitrobenzene:cuprous cyanide:
lithium bromide = 1:1.1:0.3. Ihe solvent was benzonitrile. Ihe reaction was run for one hour at a tem~erature of 169-190C ana for five additional hours at a temperature of 190-192C. At the end of a tokal six-hour period gas chro~atographic analysis showed the product to oontain R2 area % of the desired produ~t 2-nitrobenzonitrile, 11 area ~ of starting material and 3 area ~ of the brom~-s~bstituted comp~und.

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ZOC)1~89 Additional exa~ples of this type were oonducted, using in one case n;itrobenzene as the solvent, ana in other cases without a ~olvent.
In general, the processes produced the desired product in a predominating amount, Althouqh the reaction was slower and lower temperatures of about 150-165-C were necessary to avoid undue by-product formation.

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Claims (9)

1. A process for the production of an ortho-nitrobenzo-nitrile by reaction of the corresponding ortho-nitrochlorobenzene with:
(a) cuprous cyanide and a metal bromide selected from alkali metal bromides, alkaline earth metal bromides, and zinc bromide, or (b) lithium cyanide and cuprous bromide.

2. A process according to Claim 1 conducted in the presence of a solvent selected from benzonitrile, N-methyl-2-pyrrolidinone, N,N-dimethylformamide, 1,4-dicyanobutane, sulfolane or dimethyl sulfoxide.

3. A process according to Claim 1 or 2 in which the cuprous or lithium cyanide is used in a stoichiometric amount with respect to the ortho-nitrochlorobenzene.

4. A process according to any of Claims 1-3 in which the ratio of bromide compound to ortho-nitrochlorobenzene is from 0.1 to 2.0 equivalent per equivalent.

5. A process according to any of Claims 1-3 in which the ratio of bromide compound to ortho-nitrochlorobenzene is from about 0.5 to about 1.0 equivalent per equivalent.

6. A process according to any of Claims 1-5 in which the temperature is from about 100 to about 200°C.

7. A process according to any of Claims 1-6 in which the ortho-nitrobenzonitrile has the formula wherein R1 and R2 are independently hydrogen or an electron-with-drawing group.

8. A process according to Claim 7 in which R1 and R2 are independently hydrogen, nitro, C1-C4 alkylsulfonyl, halo-(C1-C4 alkyl)sulfonyl, cyano, carboxyl or halomethyl.

9. In a process for production of ortho-nitrobenzo-nitriles by reaction of an ortho-nitrochlorobenzene with cuprous cyanide and an inorganic salt, the improvement comprising utiliz-ing as the inorganic salt an alkali metal bromide, an alkaline earth metal bromide, or zinc bromide.