Metal–halogen exchange: Difference between revisions
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In [[organometallic chemistry]], '''metal-halogen exchange''' is a fundamental reaction that converts a organic haliide into an organometallic product. Most commonly it involves the use of electropositive metals (Li, Na, Mg) and organochlorides, bromides, and iodides. |
In [[organometallic chemistry]], '''metal-halogen exchange''' is a fundamental reaction that converts a organic haliide into an organometallic product. Most commonly it involves the use of electropositive metals (Li, Na, Mg) and organochlorides, bromides, and iodides. |
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==Lithium-halogen exchange== |
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Lithium-halogen exchange is a [[Salt metathesis reaction|metathesis reaction]] between an organohalide and organolithium species. Gilman and Wittig independently discovered this method in the late 1930s.<ref name="GilmanLangham1939">{{cite journal|last1=Gilman|first1=Henry|last2=Langham|first2=Wright|last3=Jacoby|first3=Arthur L.|title=Metalation as a Side Reaction in the Preparation of Organolithium Compounds|journal=Journal of the American Chemical Society|volume=61|issue=1|year=1939|pages=106–109|issn=0002-7863|doi=10.1021/ja01870a036}}</ref> |
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{{NumBlk|:|<chem title="Lithium-Halogen exchange">R-Li + R'-X -> R-X + R'-Li</chem>|{{EquationRef|2}}}} |
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The mechanism of lithium-halogen exchange is still debated.<ref name=baileyreview>{{cite journal| title = The mechanism of the lithium - halogen Interchange reaction : a review of the literature| author = Bailey, W. F.|author2=Patricia, J. F.| journal = J. Organomet. Chem.| year = 1988| volume = 352| issue = 1–2| pages = 1–46| doi = 10.1016/0022-328X(88)83017-1}}</ref> |
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One possible pathway involves a nucleophilic mechanism that generates a reversible “ate-complex” intermediate. Farnham and Calabrese were able to isolate “ate-complex” lithium bis(pentafluorophenyl) iodinate complexed with TMEDA and obtain an X-ray crystal structure.<ref name=atecomplex>{{cite journal| title = Novel hypervalent (10-I-2) iodine structures| author = Farnham, W. B.|author2=Calabrese, J. C.| journal = J. Am. Chem. Soc.| year = 1986| volume = 108| issue = 9| pages = 2449–2451| doi = 10.1021/ja00269a055| pmid = 22175602}}</ref> |
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The "ate-complex" further reacts with electrophiles and provides pentafluorophenyl iodide and C<sub>6</sub>H<sub>5</sub>Li.<ref name=atecomplex /> A number of kinetic studies also support a nucleophilic pathway in which the carbanion on the lithium species attacks the halogen atom on the aryl halide.<ref name=Rogers>{{cite journal| title = Preliminary studies of the mechanism of metal-halogen exchange. The kinetics of reaction of n-butyllithium with substituted bromobenzenes in hexane solution| author = Rogers, H. R.|author2=Houk, J.| journal = J. Am. Chem. Soc.| year = 1982| volume = 104| issue = 2| pages = 522–525| doi = 10.1021/ja00366a024}}</ref> |
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Another possible mechanism involves single electron transfer and the generation of radicals. In reactions of secondary and tertiary alkyllithium and alkyl halides, radical species were detected by [[EPR spectroscopy]].<ref name=Fischerradical>{{cite journal| title = Electron spin resonance of transient alkyl radicals during alkyllithium-alkyl halide reactions| author = Fischer, H.| journal = J. Phys. Chem.| year = 1969| volume = 73| issue = 11| pages = 3834–3838| doi = 10.1021/j100845a044}}</ref> |
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However, whether these radicals are reaction intermediates is not definitive.<ref name =baileyreview /> The mechanistic studies of lithium-halogen exchange is also complicated by the formation of aggregates of organolithium species. |
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The rate of lithium halogen exchange is extremely fast. It is usually faster than nucleophilic addition and can sometimes exceed the rate of proton transfer. In the example below, the exchange between lithium and primary iodide is almost instantaneous, and outcompetes proton transfer from methanol to ''tert''-butyllithium. The major alkene product is formed in over 90% yield.<ref name=Bailey>{{cite journal|last=Bailey|first=W.F.|title=Metal—halogen interchange between t-butyllithium and 1-iodo-5-hexenes provides no evidence for single-electron transfer|journal=Tetrahedron Lett.|year=1986|volume=27|issue=17|pages=1861–1864|doi=10.1016/s0040-4039(00)84395-6|display-authors=etal}}</ref> |
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[[File:Fast li-x exchange'.png|center|520px|Rapid lithium iodide exchange]] |
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Lithium-halogen exchange is very useful in preparing new organolithium reagents. Exchange rates usually follow the trend I > Br > Cl. Alkyl- and arylfluoride are generally unreactive toward organolithium reagents. Lithium halogen exchange is kinetically controlled, and the rate of exchange is primarily influenced by the stabilities of the carbanion intermediates (sp > sp2 > sp3) of the organolithium reagents.<ref name=Carey /><ref name=Leroux>''The Preparation of Organolithium Reagents and Intermediates'' Leroux.F., Schlosser. M., Zohar. E., Marek. I., Wiley, New York. 2004. {{ISBN|978-0-470-84339-0}}</ref> For example, the more basic tertiary organolithium reagents (usually ''n''-butyllithium, ''sec''-butyllithium or ''tert''-butyllithium) are the most reactive, and will react with primary alkyl halide (usually bromide or iodide) to form the more stable organolithium species. Therefore, lithium halogen exchange is most frequently used to prepare vinyl-, aryl- and primary alkyllithium reagents. Lithium halogen exchange is also facilitated when alkoxy groups or heteroatoms are present to stabilize the carbanion, and this method is especially useful for the preparation of functionalized lithium reagents which cannot tolerate the harsher conditions required for reduction with lithium metal.<ref name=Leroux /> Substrates such as vinyl halides usually undergo lithium-halogen exchange with retention of the stereochemistry of the double bond.<ref name=Seebach2>{{cite journal|last=Seebach|first=D|author2=Neumann H.|title=Stereospecific preparation of terminal vinyllithium derivatives by Br/Li-exchange with t-butyllithium|journal=Tetrahedron Lett.|year=1976|volume=17|issue=52|pages=4839–4842|doi=10.1016/s0040-4039(00)78926-x}}</ref> |
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:[[File:Retention of stereochem.png|center|500px|Retention of stereochem]] |
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Below is an example of the use of lithium-halogen exchange in the synthesis of morphine. Here, [[n-butyllithium|''n''-butyllithium]] is used to perform lithium-halogen exchange with bromide. The nucleophilic carbanion center quickly undergoes carbolithiation to the double bond, generating an anion stabilized by the adjacent sulfone group. An intramolecular S<sub>N</sub>2 reaction by the anion forms the cyclic backbone of morphine.<ref name=morphinelix>{{cite journal| title = Studies culminating in the total synthesis of (dl)-morphine| author = Toth, J. E.|author2=Hamann, P.R.|author3=Fuchs, P.L. | journal = J. Org. Chem.| year = 1988| volume = 53| issue = 20| pages = 4694–4708| doi = 10.1021/jo00255a008}}</ref> |
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[[File:Synthesis of morphine.png|center|650px|synthesis of morphine lithium halogen exchange]] |
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Lithium halogen exchange is a crucial part of Parham cyclization.<ref name=parham>{{cite journal| title = Aromatic organolithium reagents bearing electrophilic groups. Preparation by halogen-lithium exchange| author = Parham, W.P.|author2=Bradsher, C.K.| journal = Acc. Chem. Res.| year = 1982| volume = 15| issue = 10| pages = 300–305| doi = 10.1021/ar00082a001}}</ref> In this reaction, an aryl halide (usually iodide or bromide) exchanges with organolithium to form a lithiated arene species. If the arene bears a side chain with an electrophillic moiety, the carbanion attached to the lithium will perform intramolecular nucleophilic attack and cyclize. This reaction is a useful strategy for heterocycle formation.<ref name=parhamheterocycles>{{cite journal| title = Aryl and Heteroaryllithium Compounds by Metal - Halogen Exchange. Synthesis of Carbocyclic and Heterocyclic Systems| author = Sotomayor, N.|author2=Lete, E.| journal = Curr. Org. Chem.| year = 2003| volume = 7| issue = 3| pages = 275–300| doi = 10.2174/1385272033372987}}</ref> In the example below, Parham cyclization was used to in the cyclization of an isocyanate to form isoindolinone, which was then converted to a nitrone. The nitrone species further reacts with radicals, and can be used as "spin traps" to study biological radical processes.<ref name=mitospin>{{cite journal| title = Synthesis of a mitochondria-targeted spin trap using a novel Parham-type cyclization| author = Quin, C.| journal = Tetrahedron| year = 2009| volume = 65| issue = 39| pages = 8154–8160| doi = 10.1016/j.tet.2009.07.081 | pmid = 19888470| pmc = 2767131|display-authors=etal}}</ref> |
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:[[File:Parham cyclization in MitoSpin'.png|center|580px|Parham cyclization in MitoSpin]] |
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Trityl sodium is prepared by sodium-halogen exchange:<ref name=tritylsodium>{{OrgSynth |
Trityl sodium is prepared by sodium-halogen exchange:<ref name=tritylsodium>{{OrgSynth |
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Revision as of 23:54, 11 February 2021
In organometallic chemistry, metal-halogen exchange is a fundamental reaction that converts a organic haliide into an organometallic product. Most commonly it involves the use of electropositive metals (Li, Na, Mg) and organochlorides, bromides, and iodides.
Lithium-halogen exchange
Lithium-halogen exchange is a metathesis reaction between an organohalide and organolithium species. Gilman and Wittig independently discovered this method in the late 1930s.[1]
| 2 |
The mechanism of lithium-halogen exchange is still debated.[2] One possible pathway involves a nucleophilic mechanism that generates a reversible “ate-complex” intermediate. Farnham and Calabrese were able to isolate “ate-complex” lithium bis(pentafluorophenyl) iodinate complexed with TMEDA and obtain an X-ray crystal structure.[3] The "ate-complex" further reacts with electrophiles and provides pentafluorophenyl iodide and C6H5Li.[3] A number of kinetic studies also support a nucleophilic pathway in which the carbanion on the lithium species attacks the halogen atom on the aryl halide.[4] Another possible mechanism involves single electron transfer and the generation of radicals. In reactions of secondary and tertiary alkyllithium and alkyl halides, radical species were detected by EPR spectroscopy.[5] However, whether these radicals are reaction intermediates is not definitive.[2] The mechanistic studies of lithium-halogen exchange is also complicated by the formation of aggregates of organolithium species.
The rate of lithium halogen exchange is extremely fast. It is usually faster than nucleophilic addition and can sometimes exceed the rate of proton transfer. In the example below, the exchange between lithium and primary iodide is almost instantaneous, and outcompetes proton transfer from methanol to tert-butyllithium. The major alkene product is formed in over 90% yield.[6]
Lithium-halogen exchange is very useful in preparing new organolithium reagents. Exchange rates usually follow the trend I > Br > Cl. Alkyl- and arylfluoride are generally unreactive toward organolithium reagents. Lithium halogen exchange is kinetically controlled, and the rate of exchange is primarily influenced by the stabilities of the carbanion intermediates (sp > sp2 > sp3) of the organolithium reagents.[7][8] For example, the more basic tertiary organolithium reagents (usually n-butyllithium, sec-butyllithium or tert-butyllithium) are the most reactive, and will react with primary alkyl halide (usually bromide or iodide) to form the more stable organolithium species. Therefore, lithium halogen exchange is most frequently used to prepare vinyl-, aryl- and primary alkyllithium reagents. Lithium halogen exchange is also facilitated when alkoxy groups or heteroatoms are present to stabilize the carbanion, and this method is especially useful for the preparation of functionalized lithium reagents which cannot tolerate the harsher conditions required for reduction with lithium metal.[8] Substrates such as vinyl halides usually undergo lithium-halogen exchange with retention of the stereochemistry of the double bond.[9]
Retention of stereochem
Below is an example of the use of lithium-halogen exchange in the synthesis of morphine. Here, n-butyllithium is used to perform lithium-halogen exchange with bromide. The nucleophilic carbanion center quickly undergoes carbolithiation to the double bond, generating an anion stabilized by the adjacent sulfone group. An intramolecular SN2 reaction by the anion forms the cyclic backbone of morphine.[10]
Lithium halogen exchange is a crucial part of Parham cyclization.[11] In this reaction, an aryl halide (usually iodide or bromide) exchanges with organolithium to form a lithiated arene species. If the arene bears a side chain with an electrophillic moiety, the carbanion attached to the lithium will perform intramolecular nucleophilic attack and cyclize. This reaction is a useful strategy for heterocycle formation.[12] In the example below, Parham cyclization was used to in the cyclization of an isocyanate to form isoindolinone, which was then converted to a nitrone. The nitrone species further reacts with radicals, and can be used as "spin traps" to study biological radical processes.[13]
Parham cyclization in MitoSpin
Trityl sodium is prepared by sodium-halogen exchange:[14]
- Ph3CCl + 2 Na → Ph3C- Na+ + NaCl
References
- ^ Gilman, Henry; Langham, Wright; Jacoby, Arthur L. (1939). "Metalation as a Side Reaction in the Preparation of Organolithium Compounds". Journal of the American Chemical Society. 61 (1): 106–109. doi:10.1021/ja01870a036. ISSN 0002-7863.
- ^ a b Bailey, W. F.; Patricia, J. F. (1988). "The mechanism of the lithium - halogen Interchange reaction : a review of the literature". J. Organomet. Chem. 352 (1–2): 1–46. doi:10.1016/0022-328X(88)83017-1.
- ^ a b Farnham, W. B.; Calabrese, J. C. (1986). "Novel hypervalent (10-I-2) iodine structures". J. Am. Chem. Soc. 108 (9): 2449–2451. doi:10.1021/ja00269a055. PMID 22175602.
- ^ Rogers, H. R.; Houk, J. (1982). "Preliminary studies of the mechanism of metal-halogen exchange. The kinetics of reaction of n-butyllithium with substituted bromobenzenes in hexane solution". J. Am. Chem. Soc. 104 (2): 522–525. doi:10.1021/ja00366a024.
- ^ Fischer, H. (1969). "Electron spin resonance of transient alkyl radicals during alkyllithium-alkyl halide reactions". J. Phys. Chem. 73 (11): 3834–3838. doi:10.1021/j100845a044.
- ^ Bailey, W.F.; et al. (1986). "Metal—halogen interchange between t-butyllithium and 1-iodo-5-hexenes provides no evidence for single-electron transfer". Tetrahedron Lett. 27 (17): 1861–1864. doi:10.1016/s0040-4039(00)84395-6.
- ^ Cite error: The named reference
Careywas invoked but never defined (see the help page). - ^ a b The Preparation of Organolithium Reagents and Intermediates Leroux.F., Schlosser. M., Zohar. E., Marek. I., Wiley, New York. 2004. ISBN 978-0-470-84339-0
- ^ Seebach, D; Neumann H. (1976). "Stereospecific preparation of terminal vinyllithium derivatives by Br/Li-exchange with t-butyllithium". Tetrahedron Lett. 17 (52): 4839–4842. doi:10.1016/s0040-4039(00)78926-x.
- ^ Toth, J. E.; Hamann, P.R.; Fuchs, P.L. (1988). "Studies culminating in the total synthesis of (dl)-morphine". J. Org. Chem. 53 (20): 4694–4708. doi:10.1021/jo00255a008.
- ^ Parham, W.P.; Bradsher, C.K. (1982). "Aromatic organolithium reagents bearing electrophilic groups. Preparation by halogen-lithium exchange". Acc. Chem. Res. 15 (10): 300–305. doi:10.1021/ar00082a001.
- ^ Sotomayor, N.; Lete, E. (2003). "Aryl and Heteroaryllithium Compounds by Metal - Halogen Exchange. Synthesis of Carbocyclic and Heterocyclic Systems". Curr. Org. Chem. 7 (3): 275–300. doi:10.2174/1385272033372987.
- ^ Quin, C.; et al. (2009). "Synthesis of a mitochondria-targeted spin trap using a novel Parham-type cyclization". Tetrahedron. 65 (39): 8154–8160. doi:10.1016/j.tet.2009.07.081. PMC 2767131. PMID 19888470.
- ^ W. B. Renfrow Jr & C. R. Hauser (1939). "Triphenylmethylsodium". Organic Syntheses. 19: 83. doi:10.15227/orgsyn.019.0083.