GB2490964A - The preparation of lithium hexa alkyl disilazides - Google Patents
The preparation of lithium hexa alkyl disilazides Download PDFInfo
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- GB2490964A GB2490964A GB1108511.5A GB201108511A GB2490964A GB 2490964 A GB2490964 A GB 2490964A GB 201108511 A GB201108511 A GB 201108511A GB 2490964 A GB2490964 A GB 2490964A
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- general formula
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- lithium
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- ether
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- 238000002360 preparation method Methods 0.000 title claims description 7
- 229910052744 lithium Inorganic materials 0.000 title abstract description 23
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 title abstract description 11
- 125000000217 alkyl group Chemical group 0.000 title description 2
- 239000002904 solvent Substances 0.000 claims abstract description 55
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 31
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims abstract description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 22
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims abstract description 17
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000004292 cyclic ethers Chemical class 0.000 claims abstract description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229920000570 polyether Polymers 0.000 claims abstract description 9
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims abstract description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 3
- 150000001336 alkenes Chemical class 0.000 claims abstract description 3
- 239000001273 butane Substances 0.000 claims abstract description 3
- 239000012535 impurity Substances 0.000 claims abstract description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims abstract description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 35
- 239000000203 mixture Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 7
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 4
- 150000001450 anions Chemical group 0.000 claims description 4
- 229910003002 lithium salt Inorganic materials 0.000 claims description 4
- 159000000002 lithium salts Chemical class 0.000 claims description 4
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 3
- 150000001805 chlorine compounds Chemical group 0.000 claims description 3
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 2
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims description 2
- CRWNQZTZTZWPOF-UHFFFAOYSA-N 2-methyl-4-phenylpyridine Chemical compound C1=NC(C)=CC(C=2C=CC=CC=2)=C1 CRWNQZTZTZWPOF-UHFFFAOYSA-N 0.000 claims description 2
- VATRWWPJWVCZTA-UHFFFAOYSA-N 3-oxo-n-[2-(trifluoromethyl)phenyl]butanamide Chemical compound CC(=O)CC(=O)NC1=CC=CC=C1C(F)(F)F VATRWWPJWVCZTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 2
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 claims description 2
- KLKFAASOGCDTDT-UHFFFAOYSA-N ethoxymethoxyethane Chemical compound CCOCOCC KLKFAASOGCDTDT-UHFFFAOYSA-N 0.000 claims 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract description 10
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 abstract description 8
- 239000011780 sodium chloride Substances 0.000 abstract description 6
- 239000004721 Polyphenylene oxide Substances 0.000 abstract description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 abstract description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 abstract description 4
- 229910021529 ammonia Inorganic materials 0.000 abstract description 3
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 abstract description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 2
- 239000011734 sodium Substances 0.000 abstract description 2
- 229910052708 sodium Inorganic materials 0.000 abstract description 2
- MHNNAWXXUZQSNM-UHFFFAOYSA-N 2-methylbut-1-ene Chemical compound CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 abstract 2
- IIPYXGDZVMZOAP-UHFFFAOYSA-N lithium nitrate Chemical compound [Li+].[O-][N+]([O-])=O IIPYXGDZVMZOAP-UHFFFAOYSA-N 0.000 abstract 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 150000002170 ethers Chemical class 0.000 description 9
- 238000010537 deprotonation reaction Methods 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 159000000000 sodium salts Chemical class 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000005649 metathesis reaction Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229910018954 NaNH2 Inorganic materials 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 230000005595 deprotonation Effects 0.000 description 3
- 238000005868 electrolysis reaction Methods 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 231100001261 hazardous Toxicity 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- NAMDIHYPBYVYAP-UHFFFAOYSA-N 1-methoxy-2-(2-methoxyethoxy)ethane Chemical compound COCCOCCOC.COCCOCCOC NAMDIHYPBYVYAP-UHFFFAOYSA-N 0.000 description 1
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- 238000012769 bulk production Methods 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- 239000012992 electron transfer agent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
A lithium hexaalkyldisilazide of formula (1) (wherein R is C1-C6 alkyl) is prepared from the reaction of a sodium hexa-alkyl disilazide with lithium chloride, lithium bromide, lithium carbonate or lithium nitrate in a polyether or cyclic ether solvent. Compound (1) may be lithium hexamethyldisilazide (lithium bis(trimethylsilyl)amide or LiHMDS). The solvent may be THF, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or 1,4-dioxane. The solvent may comprise a non-ethereal solvent in admixture with the ether. The lithium hexa-alkyldisilazide thus formed may be substantially free of alkane or alkene impurities (such as butane or 2-methyl-butene). For example, lithium chloride and tetrahydrofuran is added to sodium amide and heated; hexamethyldisilamine (HMDS) is added; ammonia is evolved; sodium chloride is precipitated; lithium hexaalkyldisilazide is produced.
Description
PROCESS
The present invention concerns a cost effective process for the production of lithium hexa alkyl disilazide derivatives, in particular hexamethyldisilazide (LiHMDS).
Lithium hexamethyldisilazide is a useful reagent and catalyst. It is widely applied in production of pharmaceutical intermediates and in the production of polymers. It is most often used as a strong non-nucleophilic base for deprotonation and metallation reactions. It is often used for the generation of reactive enolates.
Another reagent often used for these purposes is lithium diisopropylamide (LDA) but lithium hexamethyldisilazide has the advantage that it is a more stable base than lithium diisopropylamide.
Both these reagents are available in commercial multi-ton quantities from a number of suppliers, generally as solutions in various solvents.
Another similar base that is also available in commercial multi-ton quantities is sodium hexamethyldisilazide (NaHMDS). Sodium hexamethyldisilazide is in many respects similar to lithium hexamethyldisilazide. They are both organic strong non-nucleophilic bases useful for deprotonation reactions, they have similar pKa values, both NaHMDS and LiHMDS are made from the same parent amine hexamethyldisilamine (HMDS) and in deprotonation reactions this amine is produced as a by-product with both NaHMDS and LiHMDS reagents. They are used most often as strong organic bases. In general when used in this way they deprotonate weakly acidic substrates and replace the acidic proton with a metal as shown in Scheme I below. The product organometallic species is then reacted in some fashion to form a desirable product.
Scheme I S1Me3 Si Me3,e-_..
R-H + LIN\ w-HN + R-U S1Me3 S1Me3 weak organic acid \jrganolithium reagent LiHMDS HMDS SiMe3 SiMe3 R-H + NaN\ r HN\ + S1Me3 S1Me3 weak organic acid \_rganosodium reagent NaHMDS HMDS Scheme I starts to indicate some of the differences between the two bases LiHMDS and NaHMDS. The crucial difference being that the product of the deprotonation reaction with LiHMDS on a weak organic acid is an organolit h/urn reagent while that of deprotonation with NaHMDS is an organosodiurn reagent. It is the difference in reactivity between these organolithium and organosodium reagents in their subsequent chemistries that determines which reagent is used to carry out a deprotonation reaction.
For many situations sodium hexamethyldisilazide cannot be used for deprotonation as the organosodium product formed does not allow the subsequent chemistry to be carried out successfully. This is why large manufacturers of these reagents such as BASF offer a range of LiHMDS, NaHMDS and even potassium hexamethyldisilazide (KHMDS).
Another difference between LiHMDS and NaHMDS is there respective prices.
Sodium is far more abundant than lithium on earth. Lithium metal is 5-6 times more expensive than sodium metal on a molar basis whilst sodium amide, a key compound in this chemistry, is 6-7 times less expensive than lithium amide. It is clear that for bulk production of organic intermediates in terms of cost the use of sodium hexamethyldisilazide is preferable However, it cannot be used in all situations as the organosodium reagent produced may not be suitable for subsequent chemistry.
There are a number of methods available for the production of LiHMDS and these are summarised in Scheme 2.
-
Scheme 2 2 Li + ________ + LiCI [Synthesis of BuLi] Si(Meh _________,Si(Me)3 + HN LiN\ + [SynthesisofLiHMDS] Si(Me)3 Si(Me)3 L from BuLi J Si(Me)3 \ /7 ________,Si(Me)3 \ / Li + HN\ + ff' r LiN + .==/ IDirect synthesis of LiHMDS1 Si(Me)3 "Si(Me)3 / from Li metal J The methods shown in Scheme 2 all begin either directly or indirectly with the use of lithium metal. As shown in Scheme 2, one method for the production of LiHMDS is from the reaction of butyl lithium with hexamethyldisilamine, butyl lithium in turn is made from the reaction of lithium metal with chlorobutane. It should be noted here that two moles of lithium metal are used for every 1 mole of LiHMDS produced.
An alternative method, also shown in Scheme 2, is the direct reaction of lithium metal with hexamethyldisilamine mediated by an electron transfer agent such as isoprene or styrene. Using this method the by-product 2 methyl-2-butene is produced from isoprene and indeed this compound is present in commercial formulations of LiHMDS.
The natural occurrence of lithium on earth is in the form of salts either lithium carbonate (LiCO3) or lithium chloride (Lid). Lithium metal is most often produced from lithium chloride by electrolysis. This electrolysis process represents an expensive step in the synthesis of lithium metal for example lithium metal costs approximately twice the cost of a suitable electrolysis grade of Lid. In addition lithium metal is not easy to handle at large scale as it requires special facilities, for instance it reacts with molecular nitrogen N2 and oxygen 02 and must be handled under an expensive argon atmosphere.
It is also highly reactive, it ignites in air near its melting point, it is a dangerous fire and explosion risk when exposed to water, nitrogen, acids or oxidizing agents.
To overcome these problems the present invention proposes to prepare lithium hexamethyldisilazide (LiHMDS) and other similar lithium alkyldisilazides from cheaper and safer ionic lithium sources rather than the more expensive and dangerous lithium metal. Lithium chloride and carbonate are mild low hazard reagents similar to sodium chloride that do not react with water or other solvents and are inert to gases such as air and nitrogen. It would therefore be a great deal less hazardous to produce LiHMDS from these reagents than from lithium metal.
The invention makes use of the fact that some lithium salts such as lithium chloride and lithium bromide are quite soluble in certain ethereal solvents such as tetrahydrofu ran, 1,4 dioxane, dimethoxyethane (monoglyme) and other higher ethers such as diethyleneglycol dimethyl ether (diglyme) whereas sodium salts such as sodium chloride and sodium bromide are much less soluble in these solvents.
Therefore, in the present invention there is provided a process for the preparation of compounds having the general formula (1): 1S1(R)3 LiN Si(R)3 (1) wherein each R is independently a straight or branched chain C1-C6 alkyl group; the process comprising reacting a lithium salt having the general formula (2): Lix (2) wherein X is an anion selected from chloride, bromide, carbonate or nitrate; with a compound of formula (3) /Si(R)3 Na N Si(R)3 (3) wherein R is as defined for general formula (1); characterised in that the reaction is carried out in an ethereal solvent selected from polyethers and cyclic ethers.
When this reaction is done in a suitable ethereal solvent in the presence of lithium chloride it has been surprisingly found that the compound of general formula (3) sodium hexamethyldisilazide produced reacts with the compound of general formula (2) that is in solution to give the compound of general formula (1) and a sodium salt of general formula (4): NaX (4) where X is as defined for general formula (2).
The sodium salt of general formula (4) is insoluble in the ethereal solvent and which therefore precipitates. It may be the case that precipitation of the insoluble by-product sodium salt of general formula (4) is what drives the completion of the reaction between the compound of general formula (3) and the compound of general formula (2).
Overall this can be viewed as a type of metal exchange reaction, which the present inventors believe, is driven forward by the precipitation of the insoluble by-product sodium salt. However, the effectiveness of the process is not affected by the correctness of this theory. This type of reaction is known in the art as a salt metathesis reaction. A salt metathesis reaction has never been used for the preparation of lithium hexa-alkyl disilazide derivatives such as LiHMDS.
The choice of the solvent is an important factor in determining whether the reaction is to proceed successfully or not. If the reaction is attempted in the wrong solvent the reaction will not proceed. Solvent choice is not straightforward as, in order for the reaction to proceed successfully, it is necessary to choose a solvent such that the compounds of general formulae (1), (2) and (3) are soluble and the compound of general formula (4) is insoluble in the reaction mixture under the conditions of the reaction. It appears that many of the solvents used in prior art metathesis reactions are not suitable for the production of compounds of formula (1); thus, the method will not produce the required product when carried out in ted butyl methyl ether, diethyl ether or diisopropyl ether. Yet surprisingly the reaction proceeds successfully in another ether, tetrahydrofuran. The nature of the hexa- alkyldisilamine (see general formula (5) below), which is an extremely non-polar and hydrophobic is a large factor in the determination of which solvents will be successful. This hydrophobic amine accounts approximately 25 w/w % of the soluble species present in the reaction mixture and has a large detrimental effect on the solubility of LiCI in the reaction mixture. This is in stark contrast to the other types of metathesis reaction systems mentioned above which do not contain any such non-polar hydrophobic components.
In the context of the present invention, the term "ethereal solvent" includes both solvents which consist of an ether or mixture of ethers and solvents which comprise an ether or mixture of ethers. Solvents which comprise an ether or mixture of ethers will usually contain at least 50% by volume of an ether or mixture of ethers but will more usually contain at least 60% or at least 70% by volume of an ether or mixture of ethers. In some cases, it is useful to use a solvent system which comprises about 80% by volume of an ether or mixture of ethers with the remainder being one or more additional solvents, preferably a solvent which is miscible with the ether, for example toluene. In other cases, the solvent may comprise at least 80% by volume of the ether or mixture of ethers, for example 80-100%, typically 80-90%. In a further example, the solvent may comprise at least 90%, for example 90-100% of the ether or mixture of ethers.
The term "polyether" refers to a straight or branched chain molecule, based on an alkane but wherein at least two -CH2-groups are replaced by -0-and having at least 5 atoms in the chain (including both C and 0 atoms).
Typically, the polyether will be a straight, rather than a branched molecule.
Suitably, the polyether will have 5 to 15 chain atoms and typically 5 to 9 chain atoms.
The term "cyclic ether" refers to a heterocyclic molecule having from 5 to 18 ring atoms, at least one of which is an oxygen atom, with the remainder being carbon atoms.
Typically, the cyclic ether has 5 or 6 ring atoms. Although crown ethers with, for example 12, 15, 16 or 18 ring atoms may also be used, they are less suitable than the smaller cyclic ethers because of their high cost.
Suitable ethereal solvents include, in particular, cyclic ethers such as tetrahydrofuran, tetrahydropyran and 1,4-dioxane and glymes such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, tetraethylene glycol dimethyl ether, dipropylene glycol dimethyl ether and polyethyleneglycol dimethylether.
Particularly suitable solvents for the reaction include tetrahydrofuran, mono glyme (ethylene glycol dimethyl ether), diglyme (diethylene glycol dimethyl ether), and 1,4 dioxane.
As discussed above, mixtures of these solvents with other non-ether based solvents, for example toluene, can also be utilised.
Suitably, in the compound of general formula (1), each R group is independently methyl or ethyl. In particularly suitable compounds of general formula (I), all of the R groups are methyl so the compound of general formula (1) is lithium hexamethyldisilazide and the starting material of general formula (3) is sodium hexamethyldisilazide.
Although the anion X may be chloride, bromide, carbonate or nitrate, more suitable X groups are chloride and bromide. Typically, the anion X will be chloride as lithium chloride is a readily available salt for use as a starting material.
Scheme 3 illustrates the reaction when R is methyl and X is chloride.
Scheme 3 SiMe3 ______________,SiMe3 N2N\ + Lid -LiN + NaC4 SiMe3 "S1Me3 There are many suitable ethereal solvents which can be used as the reaction solvent for the process of the present invention. The important criterion for the choice of solvent is that the compounds of general formulae (1), (2) and (3) should all be soluble in the reaction medium whereas the sodium salt of general formula (4) should be insoluble in the reaction medium so that it precipitates out of the reaction mixture, driving the reaction equilibrium towards the formation of the required product of general formula (1).
The reaction may be conducted at or near to the reflux temperature of the chosen solvent, typically at 2000 or less below the boiling point of the chosen solvent, more usually 10°C, 5°C, 2°C or 1°C below the reflux temperature of the solvent or at the reflux temperature of the solvent. In the case of tetrahydrofuran, the boiling point of the solvent is 66°C and the reaction may be conducted at that temperature.
The reaction will usually be carried out under an inert atmosphere such as nitrogen or argon, particularly nitrogen.
The compounds of general formula (3) used in the process of the invention can either be purchased or prepared. Methods for preparing compounds of general formula (3) are known and, for example, compounds of general formula (3) can be prepared by the reaction of sodium amide with a compound of general formula (5): /Si(R)3
HN
Si(R)3 (5) wherein R is as defined above for general formula (1).
Thus, a useful method for the preparation of sodium hexamethyldisilazide is the reaction between sodium amide and hexamethyldisilamine. This type of reaction is known and is disclosed in Organic Syntheses, Vol. 82, p. 140 (2005); CoIl. Vol. 11, p.986 (2009). Other methods for the synthesis of sodium hexamethyldisilazide may also be used.
Therefore, the process of the invention may optionally include the step of forming a compound of general formula (3) by the reaction of a compound of general formula (5) with sodium amide.
The reaction may be carried out in an appropriate solvent, typically an ethereal solvent as defined above and, in general the reaction temperature is at or close to the boiling temperature of the mixture. This reaction is illustrated in Scheme 4 for the case where R is methyl.
Scheme 4 SiMe3 SiMe3 NaNH2 + HN' ethereal solvent NH3 f + NaN' "SiMe3 reflux "SiMe3 Typically, as shown in Scheme 4, the chosen solvent will be an ethereal solvent, which may be the same as the solvent for the reaction between the compound of general formula (2) and general formula (3).
Conveniently, the formation of the compound of general formula (3) will be formed in situ so that the whole reaction is carried out in one pot. In this case, the reaction will consist of adding to a reaction vessel sodium amide and a compound of formula (2) such as lithium chloride in a suitable solvent such as tetrahydrofuran, preferably under a nitrogen atmosphere. The reaction mixture may be heated and a compound of formula (5), for example hexamethyldisilamine may then be added slowly and will react with the sodium amide to form a compound of formula (3) such as sodium hexamethyldisilazide (NaHMDS) which, in turn will react with the compound of general formula (2) (lithium chloride) to form the required product and an insoluble salt of general formula (4), in this case, sodium chloride. The reaction is illustrated in Scheme 5.
Scheme 5 SiMe3 S1Me NaNH2 + HN( + LID ethereal solvent NH3 + + NaCI4 SiMe3 reflux SIMe3 As shown in Scheme 5, the product which remains will be a mixture of LiHMDS and sodium chloride. The process may include one or more the additional steps selected from removing the compound of formula (4), for example by filtration, and further purifying the compound of general formula (1). Alternatively, the product mixture can be used without further purification.
Thus, the process may comprise the steps of: adding to a reaction vessel sodium amide and a compound of formula (2) in an ethereal solvent solvent selected from polyethers and cyclic ethers; ii. adding a compound of general formula (5); iii allowing the compound of general formula (5) to react with the sodium amide to form a compound of formula (3); and iv. allowing the compound of general formula (3) to react with the compound of general formula (2) (lithium chloride) to form a compound of general formula (1) and an insoluble salt of general formula (4).
This process of the present invention has the advantage that it can be used to produce products such as LiHMDS from low cost and readily available raw materials; i.e. a cheap inorganic sodium salt NaNH2 and a cheap inorganic lithium salt LiCI. The use of expensive and hazardous lithium metal is therefore avoided.
Furthermore, an additional advantage of the process of the present invention is that, unlike commercially available LiHMDS preparations, the product of the present invention is substantially pure. In particular, the product is substantially free of alkane or alkene impurities such as butane or 2-methyl-2-butene. The substantially pure product forms a further aspect of the invention.
The invention will now be described in greater detail with reference to the following non-limiting example.
Example I -Proposed mode of preparation of LiHMDS from ionic lithium source To a glass reactor is added sodium amide (19.5 g). Lithium chloride is then added (21.3 g) followed by tetrahydrofuran (248.0 g) all these operations are carried out under a nitrogen atmosphere. The heterogeneous mixture is stirred and heated to 66-67 °C -the reflux temperature.
Hexamethyldisilamine (HMDS) (84.7 g) is added to this mixture over 1 hour.
When addition of the first 5-10 % of the total HMDS charge occurs ammonia evolution will be observed, this will continue throughout the HMDS addition.
Upon complete addition of HMDS the mixture is stirred at reflux temperature (70-71 °C) for a further 1 hour whereupon ammonia evolution will have substantially subsided. The mixture is then cooled to 19 °C and stored to await further use.
Approximately 5 minutes after starting the HMDS addition the mixture will become slightly cloudy as a white precipitate is observed. This cloudiness and precipitation will become greater as more HMDS is added. Eventually after complete addition the reaction mixture will be a white slurry -a clear colourless solution with a fine precipitate of sodium chloride. This mixture can be used for subsequent chemistry.
This example is intended only to illustrate the invention, which is more particularly defined in the claims which follow.
-11 -
Claims (13)
- CLAIMS1. A process for the preparation of a compound of general formula (1): 18i(R)3 LiN 81(R)3 (1) wherein each R is independently a straight or branched chain C1-C6 alkyl group; the process comprising reacting a lithium salt having the general formula (2): Lix (2) wherein X is an anion selected from chloride, bromide, carbonate or nitrate; with a compound of general formula (3) /Si(R)3 Na N Si(R)3 (3) wherein R is as defined for general formula (1); characterised in that the reaction is carried out in an ethereal solvent selected from polyethers and cyclic ethers.
- 2. A process according to claim 1 wherein R is independently methyl or ethyl.
- 3. A process according to claim 1 or claim 2 wherein every R is methyl.
- 4. A process according to any one of claims I to 3 wherein X is chloride or bromide.
- 5. A process according to claim 4, wherein X is chloride. -12-
- 6. A process according to claim 5, wherein the solvent comprises an ether selected from tetrahydrofuran, tetrahydropyran, 1,4-dioxane, diethoxymethane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, diethylene glycol dibutyl ether, tetraethylene glycol dimethyl ether, dipropylene glycol dimethyl ether, polyethyleneglycol dimethylether and mixtures thereof.
- 7. A process according to claim 6, wherein the solvent comprises an ether selected from tetrahydrofuran, mono glyme (ethylene glycol dimethyl ether), diglyme (diethylene glycol dimethyl ether), 1,4 dioxane and mixtures thereof.
- 8. A process according to claim 6 or claim 7 wherein the solvent further comprises a non-ethereal solvent in admixture with the ether.
- 9. A process according to any one of claims 1 to 8 further comprising the step of preparing the compound of general formula (3) by reacting sodium amide with a compound of general formula (5): /Si(R)3HNSi(R)3 (5) wherein R is as defined above for general formula (1).
- 10. A process according to claim 9 wherein the reaction of the compound of general formula (5) with sodium amide is carried out in an ethereal solvent solvent selected from polyethers and cyclic ethers.
- 11. A process according to claim 9 or claim 10 wherein the compound of general formula (3) is formed in situ.
- 12. A process according to claim 11 comprising: adding to a reaction vessel sodium amide and a compound of formula (2) in an ethereal solvent solvent selected from polyethers and cyclic ethers; ii. adding a compound of general formula (5); -13 -iii allowing the compound of general formula (5) to react with the sodium amide to form a compound of formula (3); and iv. allowing the compound of general formula (3) to react with the compound of general formula (2) (lithium chloride) to form a compound of general formula (1) and an insoluble salt of general formula (4).
- 13. A compound of formula (1) substantially free of alkane or alkene impurities such as butane or 2-methyl-2-butene. -14-
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5420322A (en) * | 1994-08-31 | 1995-05-30 | Mine Safety Appliances Company | Preparation of alkali-metal hexamethydisilazanes |
| WO1997002210A2 (en) * | 1995-06-30 | 1997-01-23 | Fmc Corporation | Contaminant free organometallic amide compositions and processes for making same |
| WO1997006173A1 (en) * | 1995-08-09 | 1997-02-20 | Fmc Corporation | High purity formulations of highly substituted lithium amide bases |
| US6169203B1 (en) * | 1998-02-24 | 2001-01-02 | Mine Safety Appliances Company | Method of preparation of alkali-metal amides |
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2011
- 2011-05-20 GB GB1108511.5A patent/GB2490964A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5420322A (en) * | 1994-08-31 | 1995-05-30 | Mine Safety Appliances Company | Preparation of alkali-metal hexamethydisilazanes |
| WO1997002210A2 (en) * | 1995-06-30 | 1997-01-23 | Fmc Corporation | Contaminant free organometallic amide compositions and processes for making same |
| WO1997006173A1 (en) * | 1995-08-09 | 1997-02-20 | Fmc Corporation | High purity formulations of highly substituted lithium amide bases |
| US6169203B1 (en) * | 1998-02-24 | 2001-01-02 | Mine Safety Appliances Company | Method of preparation of alkali-metal amides |
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