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The solvent 2-methyl tetrahy-drofuran (2-MeTHF) can pro-vide a cost-effective, greenalternative to tetrahydrofuran(THF) chemistry. 2-MeTHF’s

advantages include its origin fromrenewable and price stable resources aswell as beneficial physical and chemicalproperties that can provide increasedyields at reduced costs. The major bene-fits are summarised in table 1.

The solvent 2-MeTHF is obtainedfrom furfural through hydrogenation.In turn, furfural is obtained fromrenewable resources, such as corn cobsand sugar cane, through the intramole-cular cyclisation of the naturally-occur-ring pentoses. In contrast, THF isobtained from 1,4-butanediol, an oil-derived substance.

The incineration of solvents is themain fine chemicals industry contribu-tor to the greenhouse effect. The recentpolitical and legislative drive for reduc-tion of CO2 emissions should make sol-vents derived from renewableresources highly desirable due to theirreduced CO2 emissions impact. Incin-eration of 2-MeTHF does not increasethe CO2 concentration in the atmos-phere as it simply returns the CO2 cap-tured by the previous year’s crop fromthe air.

2-MeTHF is currently the only apro-tic solvent similar to THF that isderived from renewable resources andindustrially available1. The marketshare for 2-MeTHF is growing rapidlydriving the price of the compoundlower. This is in sharp contrast to the

long term trend for oil-derived THF,where prices have increased over thepast decade by approximately 50%.

innovation opportunities The methyl substituted version of THFis not miscible with water. It is compa-rable or even better than THF in termsof its chemical properties. However, 2-MeTHF resembles toluene in terms ofphysical properties and this createshuge innovation opportunities for cut-ting costs both in existing and newprocesses.

The work-up for the THF-based reac-tion is complicated by THF’s miscibil-ity with water. For oily products, THFis distilled first and then the oily crudeis extracted with a saturated salinesolution. For solid products, a nonpolarsolvent such as toluene needs to beadded to achieve phase separation andavoid precipitation. In both cases emul-sions, rag layers at the phase interface-and poor extraction yields are frequentcomplications.

2-MeTHF is not water miscible andprovides easy and clean phase separa-tion during work-up. These advantagesmake the process simpler and morerobust, translating into higher through-put and reduced cost of quality.

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The methyl-substi-tuted THF reducesthe solvent andenergy variable costs.Thus 2-MeTHF hasbetter extractive prop-erties than the classicTHF/ toluene mix-ture2. This means thenumber of extractionsteps can be reducedwhile the recovery ofthe product is simul-taneously increased.

The 2-MeTHF solu-tion of crude product can be driedthrough a simple distillation at atmos-pheric pressure. The water-rich MeTHFazeotrope will create rapidly an anhy-drous solution providing the option toadd a new reagent without product iso-lation. For example, the classic reac-tion sequence carbonyl to alcohol fol-lowed by alcohol to ester is particularlyadequate for MeTHF. The solvent con-sumption is cut by 50% and thethroughput is vastly improved byavoiding isolation of the intermediatealcohol.

Last but not least, 2-MeTHF is mucheasier to recycle and dry than THF.This has important advantages for

Dr Rainer Aul, of Chemetall GmbH, and DrBogdan Comanita, of Penn SpecialtyChemicals propose 2-methyl tetrahydrofuranas a cost-effective alternative to widely usedtetrahydrofuran chemistry

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A green alternative to THF

Table 1: MeTHF vs THFAdvantages Source of savingsRenewable resource CO2 emissions credits; solvent from renewable resources

Decreasing price trend; supply risk decoupled from oil Physical properties Increased throughput; easy aqueous phase separation

Less solvent; more efficient extraction Less solvent; solvent reuse & recycling: azeotrope with water

Chemical properties Less impurities; better solvent stability to acids and baseIncreased throughput; higher reaction yieldsLess solvent; higher saturation concentrationsImproved safety; lower volatility, higher flash point

Figure 1: Degradationof THF and MeTHF,using homogenous50:50 % solutionsTHF/MeTHF with 2 NHCl at 60°C.

manufacturing chemist May 2007 www.manufacturing-chemist.info34

dedicated production capacities con-suming hundreds of metric tons of sol-vent per year. In these capacities THF isrecycled and dried using ‘swing distil-lation’. In contrast 2-MeTHF needsonly a simple distillation at atmos-pheric pressure. The recycling and dry-ing process is much more cost efficientfor 2-MeTHF because the energy cost ofdistillation is reduced by an estimated70%3. The need for an upfront capitalinvestment for a specialised distillationunit for THF recycling is also elimi-nated.

chemical advantages2-MeTHF is a versatile reaction solventcovering a range of applications includ-ing Grignard, organopalladium,organozinc, lithium hydride reductionsand biphasic reactions4. It showsincreased stability to strong bases com-pared with THF, a fact that is well doc-umented and explains its use inorganolithium chemistry applications5.

MeTHF is also more stable than THFin acidic conditions. Figure 1 showsthe intrinsic difference of stabilitybetween THF and MeTHF under acidicconditions in a homogenous solution6.In a real life situation, the hydrolysis of2-MeTHF will be much slower due toits immiscibility with water. This hasimportant implications relative to theimpurity profile and cost of qualityassociated to a given process.

THF is currently the most commonsolvent used in Grignard reactions. 2-MeTHF is challenging this positionbased on its very limited water solubil-ity and better pH stability allowing forphase separation and improved yields.Additional washing steps are eliminatedand a dry solution can be obtained bysimple azeotropic distillation.

While the generaladvantages enumer-ated above hold truefor Grignard reagentsthere are also a num-ber of advantages thatare specific to thisclass of organometal-lic reagents. It hasbeen shown, for

example, that benzyl and allylorganogrignards are generated in con-siderably better yields in 2-MeTHF ver-sus THF. In particular, benzyl deriva-tives with electron withdrawing sub-stituents systematically display a muchimproved behaviour7.

higher solubilityGrignard compounds, especially bro-mogrignard reagents, tend to be muchmore soluble in 2-MeTHF than THF.For example 3.4 M ethylmagnesiumbromide, 2.9 M phenylmagnesium bro-mide and 3.2 M methylmagnesiumbromide solutions are available onindustrial scale from Chemetall. Theconcentrations of the alkylmagnesiumbromides in 2-MeTHF are up to fourtimes higher than in THF and the sta-bility to crystallisation is improved atlower temperatures (see table 2)7.

Higher reagent concentration andlower crystallization temperature in 2-

MeTHF have animportant impactin improvingthroughput, ship-ping and storageconditions as wellas reduced solventconsumption.

From a process safety perspective,the 2-MeTHF Grignard solutions showthe same thermal stability as their THF-analogues even at much higher satura-tion concentration. In a typical RADEXexperiment the solutions were heatedup in a closed cup with a rate of45°C/h. The phenyl magnesium bro-mide solution was 50% in 2-MeTHFand 17% in THF (see figure 2). Thestart of exothermic thermal decomposi-

tion (Tonset) is observed around180°-200°C for both solutions,demonstrating that 2-MeTHFsolutions are safe even at muchhigher concentration than THFsaturated solutions.

Li organometallic usesLithium aluminum hydride (LiAlH4)has good solubility in 2-MeTHF andconcentrations of 10% (2.2M) can beeasily obtained on an industrial scale.Reduction of aldehydes, esters andacids with LiAlH4 in 2-MeTHF showedsimilar product yields as in THF withthe added benefit of simplified work-upas described above6.

2-MeTHF is a good solvent for lowtemperature lithiation reactions becauseof its low melting point, low viscosity atlow temperature and similar Lewis basestrength as THF. Figure 3 shows anillustrative example of lithiumexchange of n-butyllithium with 3-bro-mofuran at -70°C in 2-MeTHF, followedby reaction with dimethylformamide togive 3-furaldehyde6.

Methyl lithium is one of the mostversatile lithiation reagents commonlysold commercially in diethylether 5%(1.6 M) or diethoxyethane 8% (3 M)solutions. Both solutions show excel-lent stability, however have significantlimitations due to high volatility/lowflash point and, in the case ofdiethoxymethane, lack of chemical sta-bility to strongly acidic conditions.

We have found that 2-MeTHF incombination with cumene is an excel-lent substitute for the MeLi solution indiethyl ether and diethoxymethane.MeLi in 2-MeTHF/cumene 3% (1.2M)solution displays similar reactivitywhile providing an improved safetyprofile during transportation, storageand handling along with reduced costsand ease of work-up.

conclusionsThe introduction of 2-MeTHF andrelated reagents can provide an excel-lent opportunity for cost cutting solu-tions through innovation. Migration oftechnologies from THF to 2-MeTHFwill automatically render technologiesgreener as the 3R dedesiderates –reduce, recycle and reuse – are all metby the introduction of 2-MeTHF.

Achieving cost-savings throughinnovation and sustainable technolo-gies are quintessential drivers for con-tinued growth in the globalisation era.This is why we believe that companiesseeking new competitive advantageswill continue to scrutinise carefully theadvantages of 2-MeTHF. ■

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references1 Penn Specialty Chemicals and Chemetall are industrial scale producers of MeTHF and MeTHF

based organolmetallic reagents and are developing this market through a joint global marketing

agreement

2 B. Comanita, Industrie Pharma Magazine, 22, October 2006

3 B. Comanita, Specialty Chemicals Magazine, October 2006

4 B. Comanita; D. Aycock, Industrie Pharma Magazine, No.17, 2005, 54-56

5 R. Bates, J. Org. Chem. (1972) 37(4), p560.

6 David. F. Aycock, Org. Process Research & Development 2007, 11, 156-159

7 P. Rittmeyer et al., Chemetall DE 19808570

contact Dr Rainer Aul Chemetall GmbHTrakehner Strasse 3 D-60487 Frankfurt am MainGermanyT+49 69 71 65 23 44F+49 69 71 65 20 3www.chemetall.com

Dr Bogdan ComanitaPenn Specialty Chemicals, Inc.14-145 North Centre Road N5X 4C7 London, OntarioCanadaT +519 850-3232F +519 663-4446www.pschem.com

Table 2: Grignard bromides solubility in 2-MeTHFRMgBr Solution in MeTHF Solution in THF

w/w % Mol/l Cryst. Temp. w/w% Mol/l Cryst. Temp.MethylMgBr 35 3.2 <-10°C 15 1.2 <15°CEthylMgBr 40 3.4 <-10°C 8 0.6 <5°CPhenylMgBr 45 2.9 <-10°C 17 0.9 <20°C

Figure 2: RADEXdiagram forphemylmagnesiumbromide in THF and2-MeTHF

Figure 3: 2-MeTHF isan excellent solventfor lithiation