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PAPER www.rsc.org/greenchem | Green Chemistry

An environmentally benign solvent-free Tishchenko reaction

Daniel C. Waddell and James Mack*

Received 24th June 2008, Accepted 7th October 2008First published as an Advance Article on the web 6th November 2008DOI: 10.1039/b810714a

Herein, we describe the solvent-free ball milling Tishchenko reaction. Using high speed ballmilling and a sodium hydride catalyst, the Tishchenko reaction was performed for aryl aldehydesin high yields in 0.5 hours. The reaction is not affected by the type of ball bearing used and can besuccessful when conducted in a liquid nitrogen environment.

Introduction

Environmental concerns about solvent-based chemistry havestimulated a renewed interest in the study of chemical reactionsunder solvent-free conditions. 13 Although most of the research

conductedin this area hasbeen performedby using a mortar andpestle, high speed ball milling (HSBM) is an attractive solvent-free method that has started to gain attention. In the HSBMmethod, a ball bearing is placed inside a vessel that is shaken athigh speeds. 4,5 The high speed attained by the ball-bearing hasenough force to make an amorphous mixture of the reagentsthat subsequently facilitate a chemical reaction.

The use of commericialball millshave allowed these reactionsto be scaled up to industrial levels, therefore understandingorganic reactions using this methodology can signigantlyreduce solvent waste. 4,69 We recently reported that therateof theBaylisHillman reaction is increased under HSBM conditionsand we developed a safe solvent-free method for the reduction

of esters.10,11

In this work, we describe the Tishchenko reactionunder these novel conditions.

The conversion of aldehydes to their dimeric esters, betterknown as the Tishchenko reaction (Scheme 1) has been knownfor more than a hundred years. 12 This reaction is heavily usedin industry, 13 and it is inherently environmentally benign sinceit utilizes catalytic conditions and is 100% atom economic.Over the years, chemists have looked to develop new reagentsthat are more efcient than the aluminum based catalyststraditionally used. Metal catalysts such as alkali metals, 1417

alkali metal oxides, lanthanides, 1822 and many others have beendeveloped towards the improvement of Tishchenko chemistry.Unfortunately, many of these catalysts react sluggishly with

aromatic aldehydes or provide the ester product in low yield.2325

It was demonstrated that catalytic diisobutylaluminum hydride(DIBAL-H) reacts with aliphatic aldehydes to give the dimericester but it does not give the Tishchenko product with aryl

Scheme 1 Tishchenko reaction.

University of Cincinnati, 301 Clifton Court, Cincinnati, OH, USA.E-mail: james.mack@uc.edu; Fax: +1 513 556 9239;Tel: +1 513 556 9249

aldehydes. 24 Catalysts such as lithium bromide and lanthanidecatalysts undergo the Tishchenko reaction with aryl aldehydesin high yield, but long reaction times (23 days) are required. 25

Oneof the simplest and cheapest catalysts that has been used forthe generation of benzyl benzoate from benzaldehyde has beensodium hydride. Although sodium hydride is generally thoughtof as a non-nucleophilic base, 26 Swamer and Hauser demon-strated in reuxing benzene that benzaldehyde can be convertedto benzyl benzoate in moderate yield. 27 Since benzaldehyde wasthe lone example in this report, the scope and limitations of the Tishchenko reaction using sodium hydride as the catalystare still absent from the literature. Further, the use of benzeneas the solvent under these conditions signigantly increases thehealth risk, especially on large scale. We thought the use of highspeed ball milling under solvent-free conditions would affordus the possibility of using sodium hydride as the catalyst, whileavoiding the use of benzene. Further, we predicted that underHSBM conditions catalytic activity would be very high due tothe high concentration of materials in the reaction vials.

Results and discussion

Our results are summarized in Table 1. We started our processby reacting various aryl aldehydes in the presence of a catalyticamount of sodium hydride. We attempted 1% and 2% molcatalyst but found the reaction was most effective with 10%sodium hydride. Typically, the reactions were conducted in acustom made 1/2 2inch screw-capped stainless steel vialand milled with a 1/8 inch stainless steel ball-bearing in aSpex certiprep mixer/mill 8000M open to the atomospherefor 30 minutes (Scheme 2). At the conclusion of the reactionthe products were recrystallized with 95% ethanol and driedover a Hirsch funnel. Liquid products were isolated fromextraction with the minimal amount of methylene chloride. 28

Upon isolation 1H NMR, 13C NMR andGC-MS were comparedto literature values to conrm product formation. We wereable to convert benzaldehyde to benzyl benzoate in as little

Scheme 2 Conducting the Tishchenko reaction under solvent-free ballmilling conditions.

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Table 1 Tishchenko reaction of aryl aldehydes using 10% sodiumhydride catalyst

Entry SubstrateTime(hrs) % Conversion % Yield TOF

1 2 > 99 91 2.5

2 0.5 > 99 92 10

3 0.5 > 99 98 10

4 0.5 86 80 10

5 2 94 86 2.5

6 2 > 99 93 2.5

7 0.5 > 99 91 10

8 2 > 99 97 2.5

9 2 80 69 2.5

10 2 80 70 2.5

11 16 95 91 1

12 2 86 69 2.5

Table 1 (Contd.)

Entry SubstrateTime(hrs) % Conversion % Yield TOF

13 2 > 99 93 2.5

14 16 > 99 97 1

as 30 minutes under HSBM conditions compared to 5 hrs insolution. 27 The turnover frequencies (TOFs) were determinedfrom complete conversion. 29

Our success with aryl aldehydes led us to investigate the

Tishchenko reaction of aliphatic and a ,b unsaturated alde-hydes. Using sodium hydride as the catalyst we attemptedthe ball milled Tishchenko reaction with 3-phenylpropional,pentanal, and 1,2,3,6-tetrahydro-benzaldehyde. Our resultsshowed that straight chain non-hindered aldehydes such as3-phenylpropional and pentanal gives only a small amountof the dimeric ester with these substrates; with the majorityof the products arising from aldol condensation chemistry.However, when sterically hindered aldehydes are used, such as1,2,3,6-tetrahydro-benzaldehyde the dimeric ester is the majorproduct and we observed no product resulting from the aldolcondensation. a ,b unsaturated systems such as cinnamaldehydeand 2-butenal gave a mixture of products which included the

expected dimeric ester as well as products which arise fromconjugate additon into the double bond. We also examined thereaction with acetaldehyde for the preparation of ethyl acetatebut instead of obtaining ethyl acetate under these conditions thereaction resulted in the formation of a polymer. 30

Since the Tishchenko reaction is catalyzed by various metals,we wanted to investigate the role of the ball material on thisreaction.Using the dimerizationof benzaldehyde to formbenzylbenzoate as the benchmark, we explored the affect of ballmaterial on the Tishchenko reaction under HSBM conditions.Benzaldehyde and 10 mol% sodium hydride was ball milledfor fteen minutes and the % conversion was analyzed by 1HNMR. The reactions were conducted in dupilcate and run

with a 1/8 stainless steel ball, 1/8 brass ball and in theabsence of a ball. In this particular reaction we saw similar% conversion irrespective of the ball material used, each giving~30% conversion. Themost surprising result is that we observedthe reaction was just as sucessful in the absence of a ballbearing. This suggests the high speed movement of the vialprovides enough energy to cause this reaction. We thoughtsince benzaldehyde is a liquid, a ball may not be needed inorder create the proper mixing at the molecular level for thisreaction to take place. To test this hypothesis, we ball milled p-chlorobenzaldehyde, a solid, to determine if the reactionprocedesin theabsence ofa ball.Toour surprise, after 30minutesof milling the reaction proceded in similar yield to reactions

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conductedwithbrass andstainless steel balls ( ~99% conversion).This suggests at least for this particular reaction that theshakingof the vial has enough energy to make an amorphous mixture of the reagents to provide a chemical reaction even without a ball!

On very large scale, ball milled reactions can generate asignigant amount of heat, thus we wanted to conduct thesereactions in the Spex Certiprep freezer mill in a liquid nitrogen

environment to determine the feasibility of the reaction underlow temperature conditions. Using our typical conditions, p-chlorobenzaldehyde and sodium hydride was placed inside areaction vial and cooled to - 196 C. The reaction was milledfor 30 minutes at which point it was allowed to warm toroom temperature. 1H NMR and GC-MS both conrmed thepresence of the expected dimeric ester of p-chlorobenzaldehyde(~5% yield). Thisdemonstrates the ability to conductballmillingexperiments in a low temperature environment which wouldallow this process to be implemented with highly exothermicreactions.

In an attempt to avoid handling sodium hydride, we wantedto generate our catalyst in situ. Sodium formate is known under

certain condtions to break down to sodium hydride and carbondioxide. 26,31,32 We thought we could use sodiumformate, which issafe and very easy to handle as a direct precusor to the sodiumhydride catalyst. Unfortunately, after ball milling benzaldehydeand sodium formate for 16 hours we saw no evidence of thedesired dimeric ester. It has been shown that various metalcatalyst can facilitate the disproportation of sodium formateto sodium hydride and carbon dioxide. 3336 We tested whethera combination of catalytic sodium formate (10 mol%) andpalladium tetrakistriphenylphospine (1 mol%) would lead tothegeneration of the sodium hydride catalyst. Using thismixturealong with benzaldehyde we were able to generate trace amountsof benzyl benzoate after milling for 44 hours (Scheme 3).

Scheme3 Generation of sodium hydridecatalyst fromsodium formateand palladium tetrakistriphenylphosphine.

In addition to sodium hydride, we also investigated otherbenign catalysts that could give high yields of the Tishchenkoreaction usingball milling conditions. Ballmilling benzaldehyde

with catalysts such as lithium bromide and calcium oxidedid not provide the desired dimeric ester but rather gaveunreacted starting material. We custom made vials out of nickeland molybdenum to investgate if these metals would lead toTishchenko products, however, neither of these gave the dimericester product even under long milling times. It was reportedthat benzaldehyde can be converted to benzyl benzoate usingmagnesium metal as the catalyst in reuxing toluene. 37 Weball milled p-chlorobenzaldehyde along with magnesium metaland observed > 95% yield of expected dimeric ester. We arein the process of making magnesium vials to determine if themagnesium vial itself will be a sutiable catalyst under theseconditions.

Conclusions

In conclusion, we report an environmentally benign methodfor the Tishchenko reaction using solvent-free ball millingconditions. We used sodiumhydride as thecatalyst instead of themore traditional aluminum catalyst which allowed the reactionto procede in high yield and short reaction times. We discoveredin this particular reaction the type of ball used has little tono affect on the yield or rate of the reaction and the reactionproceeded equally well without the addition of a ball. We alsoobserved the ball milled Tishchenko reaction can take placewhile the vial is immersed in a liquid nitrogen environment.Currently, we are in the process of creating a magnesium vialthat is expected to act as the catalyst as well. Ball milling is anovel method for conducting organic reactions. With a betterunderstanding of how these reactions procede we will be able tomake signicant strides in the development of various solvent-free reactions.

Experimental

All NMR spectra were recorded on a Bruker Avance 400 spe-ctrometer. Deuterated NMR solvents were obtained fromCambridge Isotope Laboratories, Inc., Andover MA, and usedwithout further purication. p-bromobenzaldehyde, p-chloro-benzaldehyde, p-anisaldehyde, benzaldehyde, p-tolualdehyde, p-(methylthio)benzaldehyde, m-anisaldehyde, napthaldehyde,2-thiophenecarboxaldehyde and sodiumhydride werepurchasedfrom Acros Organics and used without further purication. m-Fluorobenzaldehyde, m-tolualdehyde and 1,2-phthalic carbox-aldehyde were purchased from Sigma-Aldrich and used withoutfurther purication. Ball milling was carried out in a 8000MSpexCertiprep Mixer/Mill. Ball milling under a liquid nitrogenwascarried outin a 6750 SpexCertiprep Freezer/Mill. Ball bear-ings were purchased from Small Parts incorporated. Custommade vials were made by the machine shop at the University of Cincinnati with metal rods purchased from ESPICorp Inc.

Typical procedure

Benzaldehyde (0.22 g, 2.07 mmol), and sodiumhydride (0.004 g,0.2 mmol) were added to a custom-made 2 by 1/2 screwcapped stainless steel vial along with a 1/8 inch stainless steelball bearing. The vial was placed in an 8000M Spex Certiprepmixer/mill and the contents were ball milled for 0.5 h. Theresulting mixture was dissolved in methylene chloride 28 (15 mL)and washed with 10% HCl (15 mL). The organic layer was driedover anhydrous MgSO 4 and the solvent was evaporated underreduced pressure. This afforded benzyl benzoate in > 98% yield.

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