METHYLTETRAHYDROFURAN System Advantages In

2y ago
12 Views
2 Downloads
238.71 KB
38 Pages
Last View : 2m ago
Last Download : 2m ago
Upload by : Amalia Wilborn
Transcription

METHYLTETRAHYDROFURANSystem Advantages in OrganometallicChemistry and Biphasic Reactions

Agenda1.2.3.4.5.6.7.8.9.MeTHF Production and QualitySolvent PropertiesMeTHF StabilityMeTHF RecoveryGrignard ReactionsMeTHF as Solvent for Other ReactionsMeTHF in Biphasic ReactionsSummary of MeTHF versus THFRegulatory Status

MeTHF ProcessOCHOCatalystOCH3distillationPure ationPure MeTHF

MeTHF ImpuritiesMeTHF Manufacturing Specification Minimum 99% assay 150-400 ppm BHT Less than 300 ppm water

MeTHF StabilityPeroxide formation rate in unstabilized MeTHF is similar toTHFMeTHF is more stable to acid degradation than THFMeTHF is more stable to strong base than THF

MeTHF Peroxide FormationPeroxide Formation in THF and MeTHF(aged in air at room temperature)10090hydrogen peroxide 0350400450

Acid DegradationTHF and MeTHF will ring open with strong HO20%CH3

Acid DegradationTHF and MeTHF both degrade in concentrated HClTHF degrades about 3 times faster than MeTHF in 18% (5N) HClTime (hours)% MeTHF Degraded% THF Degraded40.541.527.50.832.244% in 5N HCl at 60 C

Acid DegradationWith typical process conditions, MeTHF degrades about 6 times slowerthan THF% Degradation of THF and MeTHF0.60.5THF% ons: 50:50 THF/MeTHF: 2 N HCl at 60 C120140160

Strong Base StabilityTHF reacts with n-butyllithiumOOn-BuLiHLiOH2CCH2 H2CThe reaction of n-butyllithium with MeTHF is slowerCompoundHalf life at 35 CminutesTHF10MeTHF70R. Bates, J. Org. Chem. (1972) 37(4), p560.LiH

General Comparison of MeTHF vs THFMeTHF behaves like THF in most reactions Partial water miscibility and easy drying make it a useful solvent forproduct recovery Polar properties make it a useful solvent in biphasic reactions and forextraction of polar compounds from water

Lewis Base Strength of MeTHFMeTHF is between THF and Ethylether in Lewis Basestrength and polarityPropertyMeTHFTHFEt2Odielectric const6.977.54.42dipole moment, Debye1.381.691.11water solubility, g/100g4mis1.2Hildebrand, MPa½16.918.715.5solvation energy, kcal/mol0.602.3Donor Number1820.519.2

Properties of MeTHFmolecular weight86.1bp (ºC)80.2mp (ºC)-136vapor press at 20 ºC (mm)102density at 20 ºC (g/ml)0.854viscosity at 25 ºC (cp)0.46viscosity at -70 ºC (cp)1.85refractive index at 20 ºC1.408flash point ºC-11heat of vaporization (cal/g) at bp87.1solubility in water 20 ºC g/100g14solubility water in MeTHF 20 ºC g/100g4azeotrope bp ºC71azeotrope % water10.6

Solubility of Magnesium SaltsMgCl2MgBr2MgI2MeTHF25 C 0.1 4010MeTHF80 C 0.13 50THF25 C 0.15 0.1THF60 C214.5Solubility in g/100gDiethylether forms two phases at high MgBr2 concentrations

Grignard Reagent SolubilityGrignard-Reagents in 2-MeTHF available 2Ethyl-MgBr403.480.6Phenyl-MgBr452.9170.9R-MgBr

MeTHF AzeotropesCompoundAzeo bp ºC%Compoundin Azeomethanol (64.7 ºC bp)62.857ethanol (78.5 ºC bp)74.434n-propanol (97.2 º bp)79.5177182-propanol (82.3 ºC bp)toluene (110.6 ºC bp)Water (100 ºC bp)no azeo7110.6

Grignard Reagents in MeTHF For most Grignard reagents, formation andreaction in MeTHF are similar to THF MeTHF behaves more like ethylether in theformation and reaction of some Grignard reagents(weaker Lewis Base)MeTHF R---Mg---X MeTHF

MeTHF: Higher Yield in Grignard FormationBenzyl and allyl Grignard Reagents Benzyl and allylmagnesium halide reagents are used in many agricultural andpharmaceutical synthesisMgBr BrMg In THF, formation of by-product dimer dramatically reduces yields of the Grignard reagentMgBr Br MgBr 2

MeTHF: Higher Yield in Grignard Formation#ReagentSolvent1benzyl chloride2345benzyl bromideo-methylbenzyl chlorideo-chlorobenzyl chlorideallyl 6%THF73%MeTHF89%15%19%66%16%

MeTHF: Improved Yield of Grignard Reactions Like ethyl ether, MeTHF gives less reducedproduct for Grignard reagents that contain betahydrogensRRMore additionproduct withMeTHFR2O CHCH2R2XMgR1HR1RRMore reductionproduct withTHFR2OR1OH CHHCH2XMgR1OHHR2 CH CH2

Better Extraction in the Grignard Work-up MeTHF gives clean phase separations in the acidquench step whereas THF needs addition of nonpolar solvents (toluene) in large excess Toluene addition gives milky emulsions and raglayers often difficult to separate MeTHF is a far better extracting solvent for awide range of extract polarities

MeTHF: Easy Solvent Recycling Several properties make MeTHF easy to recycleversus THFPropertyMeTHFTHFBoiling point (C)8066Water solubility in solvent (% at 20 C)4.1infiniteWater azeotrope composition (% water)10.66.7

MeTHF: Easy Solvent Recycling The solubility of water in MeTHF increases onlyslightly as temperature increasesSolubility of Water in MeTHF% Composition6543Only 4.6% waterat 60 C210010203040Temperature deg C50607080

MeTHF: Easy Solvent Recycling The solubility of MeTHF in water decreasesquickly as temperature increasesSolubility of MeTHF in Water% Composition25Only 6.6% MeTHFat 60 C20151050010203040Temperature (deg C)50607080

Process to Dry THF12% waterWet THF100 psipressure6.7% waterazeotropeDry THFwater

MeTHF: Easy Solvent Recycling Dry MeTHF can be recovered in a simple batchdistillation10.6% water inazeotrope60 C decanter0.4 parts MeTHF5.2 parts water(recycled to next batch)100 parts MeTHF5.2 parts water(at start of batch distillation)99.6 parts dry MeTHF

Conclusions on the Use of MeTHF vs. THF MeTHF is the choice over THF for allyl and benzylGrignard reagents MeTHF allows formation of bromo Grignard reagents athigh concentration MeTHF minimizes side reactions in Grignard chemistry MeTHF provides for easy work-up of the Grignard MeTHF improves the extraction yield in Grignard work-up MeTHF can be used to azeotropically dry the productbefore isolation MeTHF can be easily recovered and recycled MeTHF saves money

LiAlH4 Reductions with MeTHF LiAlH4 solubility in MeTHF is at least 1.8 M (7.7 g/100 g) A survey of aldehydes, esters and acids gave similar productyields for reductions run in MeTHF versus THF Product recovery is improved with MeTHF versus THF No additional solvent needed for product recovery High efficiency for recovery of water soluble orpartially water soluble compounds Fieser procedure can be used to remove salts Clean water-organic phase splits Can be used to dry product for next reaction step

LiAlH4 SolubilitySolventgrams/100 gramsMeTHF 7.7THFEthyl etherDibutyl etherDioxane132520.1

Lithiation SolventMeTHF can be used to replace THF in low temperature reactions withn-BuLiMeTHF has a low mp (forms an organic glass at –136 C) and has lowviscosity at –70 COMeTHF -70 CO n-BuLiBrDMFCHO

Zinc ChemistryMeTHF can be used in place of THF in the Reformatsky reactionOHOOBrOHNHTritylMeTHFEtOCOOEtNBr ZnZnN1EtONTritylAnhydrous ZnBr2 can be made in MeTHF with a solubility of 50 g/100gBrZn BrMeTHFZnBr2 H2CCH2MeTHF was used in the Ni catalyzed coupling of alkynlzinc bromide with nitriles2Ni(phosphine)Zn Br NC1.Nuwa, S.; Handa, S.; Miki, S., US 20050043544. MeTHF was found to provide a stablesolution and good yields in the Reformatsky reaction with ethylbromoacetate.2.Miller, J., US 20050137402

MeTHF in Biphasic Reactions Limited miscibility with water facilitates easy productrecovery Strong solvent for polar compounds typically soluble inDCM Very stable to basic conditions and stable to most acidicconditions In water systems, very clean phase separations aretypically found Water washes decant from the reactor bottom versusDCM where water is the top layer Products in MeTHF can be dried in the reactor due to thefavorable MeTHF azeotrope The 80 ºC b.p. allows condensing with cooling waterwith little vapor loss

MeTHF in Biphasic Reactions The higher apparent polarity of MeTHF in biphasicreactions is attributed to the dissolved water1NaOHBnNH2 BzClBnNHBz88% yieldPhNHAc94% yieldo-NO2OPh95% yieldNaOHPhNH2 AcClPhOH o-FPhNO2NaOHTBABr(1) David H. Brown Ripin, Synlett 2003, No. 15, p2353

MeTHF in Biphasic ReactionsThe use of MeTHF in biphasic reactions is becoming more common in patentsBayer Healthcare used MeTHF with toluene in a biphasic reaction of an acid chloride with an amine usingNaHCO3 in synthesis of RivaroxabanChristian, T., WO2004060887.MeTHF used in reductive amination of sulfite-aldehyde with triacetoxyborohydride, gives higher yieldthan NMP/cyclohexaneRagan, J., Organic Process Research Development (2003), 7(2), 155 160Reaction of dimethylcarbonate with an amine in MeTHF since high losses of product to the water phasewere found with other solventsRipin, D., Organic Process Research Development (2005), 9(1), 51-56Methf as solvent to remove BOC amine blocker with sodium butoxide in two phase water systemRipin, D., US 20050020625MeTHF used in two phase displacement reactions with acid chloride and allylbromideRipin, D., US 20050026940

MeTHF-A Good Replacement for Dichloromethane Dichloromethane and dichloroethane are polar solventsthat are used extensively in pharma and agri synthesis butare highly regulated chemicals MeTHF can often be used as a direct replacement forthese chlorinated solvents High reactivities are found when MeTHF is used inbiphasic reactions1 MeTHF provides added value because it is derived fromrenewable resources and is readily biodegradable(1) David H. Brown Ripin, Synlett 2003, No. 15, p2353

MeTHF and Dichloromethane Properties The low boiling point of dichloromethane (DCM) results in high losses to theatmosphere The high density of DCM means the water phase can not be directly decanted DCM can react with strong nucleophiles such as amines MeTHF gives clean organic-water phase separations The low water content in the DCM azeotrope means it is ineffective as adrying solventPropertyMeTHFDCMBoiling point ºC8039.8Density at 20 ºC0.861.32713810.61.5B.P. of azeotrope ºCWt % water in azeotrope

Extractions with MeTHF MeTHF removes water soluble compounds moreefficiently than DCM% isopropanol recovered10090801.5 parts702.5 parts605040MeTHFDCM

MeTHF Toxicity Tests NTP Genetic Toxicology study came back negativeNTP Chemical Disposition tests showed MeTHF was quickly excretedNTP carcinogenicity study is on holdListed as Class IV solvent by ICHRecent Merck study lists human daily exposure levels–Antonucci V; Coleman J; Ferry JB; Johnson N; Mathe M; Scott JP (2011). Toxicological Assessment of Tetrahydro-2-methylfuranand Cyclopentyl Methyl Ether in Support of Their Use in Pharmaceutical Chemical Process Development. American ChemicalSociety Publications. Org. Proc. Res. Dev., 15 (4), pp 939–941.

1 benzyl chloride THF 85% 14% MeTHF 99% 2 benzyl bromide THF 83% 15% MeTHF 98% 3 o-methylbenzyl chloride THF 78% 19% MeTHF 97% 4 o-chlorobenzyl chloride THF 20% 66% MeTHF 86% 5 allyl chloride THF 73% 16% MeTHF 89%

Related Documents:

even though BIM have only been in use there for five (5) years. (Khodeir and Nessim 2017) 2.1 Advantages and Disadvantages of BIM to Architects Mineer (2015) stated the advantages of BIM as follows: 2.1.1 Advantages Better planning and design: completed buildings with all its components are visualized before mobilizing to site.

There are some advantages to designing phase I of the city hospital without using BIM, and I believe these advantages are the reasons BIM wasn’t implemented in this phase of the project. Weighing and comparing the advantages and disadvantages between using BIM and not using BIM will form the foundation of this research.

1. Introduction 3 2. Advantages of planar technology 4 2.a. Design advantages 4 2.b. Manufacturing advantages 4 2.c. Limitations 5 2.d. Integrated versus stand-alone 5 2.e. Gluing versus clamping 6 3. Applications 6 3.a. Power conversion 6 3.b. Pulse transmission 6 4. Product range 7 4.a. Material grades 7 4.b. Cores for gluing 8 4.c. Cores for .

Advantages of Multiple Repositories There are significant advantages to splitting your source into different repositories, especially with distributed SCMs, as this is the only way that they can scale beyond 4GB or so of source code. Improved Performance Most modern distributed version co

Invoice discounting: . 4. Consider the advantages and disadvantages of each source of finance in the table below. Source of Finance Advantages Disadvantages Retained profit Net current assets Sale of assets . Outline two advantages of net c

Starbucks now dominates the coffee industry in China. In this paper, we will analyze the different market strategies Starbucks implemented and the competitive advantages gained as a result. We will also analyze how Starbucks responded to the Covid-19 outbreak in China and how their advantages were able to generate a smooth recovery.

E. ADVANTAGES AND DISADVANTAGES OF GLOBAL SOURCING There are clear advantages to global sourcing. One of the main advantages is a lower cost that comes from economies of scale or lower labor costs of foreign suppliers. Common performance metrics used to measure a successful partnership .

A maximum rotation of the pile head of 0.5 is usually demanded. Regarding axially loaded piles an important question is how the axial ultimate pile capacity can be predicted with sufficient accuracy. The ß-method commonly used in offshore design (e.g. API, 2000) is known to either over-or underestimate pile capacities, dependent on the boundary