Metal–halogen exchange: Difference between revisions
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In [[organometallic chemistry]], ''' |
In [[organometallic chemistry]], '''metal–halogen exchange''' is a fundamental reaction that converts an organic halide into an organometallic product. The reaction commonly involves the use of electropositive metals (Li, Na, Mg) and organochlorides, bromides, and iodides. Particularly well-developed is the use of metal–halogen exchange for the preparation of [[organolithium compound]]s. |
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Two kinds of lithium–halogen exchange can be considered: reactions involving organolithium compounds and reactions involving lithium metal. Commercial organolithium compounds are produced by the heterogeneous (slurry) reaction of lithium with organic bromides and chlorides: |
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: 2 Li + R−X → LiX + R−Li |
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Often the lithium halide remains in the soluble product. |
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Most of this article is about the homogeneous (one-phase) reaction of preformed organolithium compounds: |
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: R−Li + R′−X → R−X + R′−Li |
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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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| ⚫ | [[Butyllithium]] is commonly used. 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> It is not a [[salt metathesis reaction]], as no salt is produced. |
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| ⚫ | One proposed pathway involves a nucleophilic mechanism that generates a reversible |
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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 |
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Another proposed mechanism involves single electron transfer with 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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<ref name =baileyreview /> The mechanistic studies of lithium-halogen exchange are also complicated by the formation of aggregates of organolithium species. |
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Lithium halogen exchange is typically a fast reaction. It is usually faster than nucleophilic addition and can sometimes exceed the rate of proton transfer.<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> |
Lithium–halogen exchange is frequently used to prepare vinyl-, aryl- and primary alkyllithium reagents. 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> The presence of alkoxyl or related chelating groups accelerates lithium–halogen exchange.<ref name=Leroux /> Lithium halogen exchange is typically a fast reaction. It is usually faster than nucleophilic addition and can sometimes exceed the rate of proton transfer.<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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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 > sp<sup>2</sup> > sp<sup>3</sup>) of the organolithium reagents.<ref name=Carey>{{cite book |last = Carey | first = Francis A. | chapter = Organometallic compounds of Group I and II metals| title = Advanced Organic Chemistry: Reaction and Synthesis Pt. B | publisher = Springer | edition = Kindle | year = 2007 | isbn = 978-0-387-44899-2}}</ref><ref name=Leroux>{{cite book |title=The Preparation of Organolithium Reagents and Intermediates |author=Leroux F., Schlosser M., Zohar E., Marek I. |publisher=Wiley |location=New York |year=2004 |isbn=978-0-470-84339-0}}</ref> |
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[[File:Fast li-x exchange'.png|center|520px|Rapid lithium iodide exchange]] |
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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. 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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| ⚫ | Two mechanisms have been proposed for lithium–halogen exchange.<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 proposed pathway involves a nucleophilic mechanism that generates a reversible "ate-complex" intermediate. Farnham and Calabrese crystallized an "ate-complex" lithium bis(pentafluorophenyl) iodinate complexed with [[Tetramethylethylenediamine|TMEDA]].<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> Another proposed mechanism involves single electron transfer with 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><ref name =baileyreview /> The mechanistic studies of lithium–halogen exchange are complicated by the formation of aggregates of organolithium species. |
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==Other metals== |
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:[[File:Retention of stereochem.png|center|500px|Retention of stereochem]] |
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;Magnesium–halogen exchange |
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| ⚫ | [[Grignard reagent]]s can be prepared by treating a preformed Grignard reagent with an organic halide. This method offers the advantage that the Mg transfer tolerates many functional groups. A typical reaction involves [[isopropylmagnesium chloride]] and aryl bromide or iodides:<ref>{{cite journal | last1 = Knochel | first1 = P. | last2 = Dohle | first2 = W. | last3 = Gommermann | first3 = N. | last4 = Kneisel | first4 = F. F. | last5 = Kopp | first5 = F. | last6 = Korn | first6 = T. | last7 = Sapountzis | first7 = I. | last8 = Vu | first8 = V. A. | year = 2003 | title = Highly Functionalized Organomagnesium Reagents Prepared through Halogen–Metal Exchange | journal = Angewandte Chemie International Edition | volume = 42 | issue = 36| pages = 4302–4320 | doi = 10.1002/anie.200300579 | pmid=14502700}}</ref> |
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Magnesium [[ate complex]]es metalate aryl halides:<ref>{{cite journal |doi=10.15227/orgsyn.089.0460|title=Preparation of ''t''-Butyl-3-Bromo-5-Formylbenzoate Through Selective Metal-Halogen Exchange Reactions |journal=Organic Syntheses |year=2012 |volume=89 |page=460 |first1=Juan D. |last1=Arredondo |first2=Hongmei |last2=Li |first3=Jaume |last3=Balsells |doi-access=free}}</ref> |
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: ArBr + Li[MgBu<sub>3</sub>] → ArMgBu<sub>2</sub> + BuBr |
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| ⚫ | [[Grignard reagent]]s can be prepared by treating a preformed Grignard reagent with an organic halide. |
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;Zinc–halogen exchange |
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Zinc–halogen exchange:<ref name=Knochel>{{cite journal |doi=10.1002/chem.201904794 |title=Recent Advances of the Halogen–Zinc Exchange Reaction |year=2020 |last1=Balkenhohl |first1=Moritz |last2=Knochel |first2=Paul |journal=Chemistry – A European Journal |volume=26 |issue=17 |pages=3688–3697 |pmid=31742792 |pmc=7155102}}</ref> |
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: LiBu<sub>3</sub>Zn + R−I → Li[R−ZnBu<sub>2</sub>] + BuI |
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==Applications== |
==Applications== |
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Several examples can be found in organic syntheses.<ref>{{cite journal |title=Synthesis of 4-, 5-, and 6-methyl-2,2'-bipyridine by a Negishi Cross-coupling Strategy: 5-methyl-2,2'-bipyridine |author=Adam P. Smith |author2=Scott A. Savage |author3=J. Christopher Love |author4=Cassandra L. Fraser |journal=Org. Synth. |year=2002 |volume=78 |page=51 |doi=10.15227/orgsyn.078.0051}}</ref> |
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| ⚫ | Below |
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| ⚫ | Below lithium–halogen exchange is a step 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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| ⚫ | 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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==References== |
==References== |
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[[Category:Organometallic chemistry]] |
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Latest revision as of 17:34, 25 September 2023
In organometallic chemistry, metal–halogen exchange is a fundamental reaction that converts an organic halide into an organometallic product. The reaction commonly involves the use of electropositive metals (Li, Na, Mg) and organochlorides, bromides, and iodides. Particularly well-developed is the use of metal–halogen exchange for the preparation of organolithium compounds.
Lithium–halogen exchange
[edit]Two kinds of lithium–halogen exchange can be considered: reactions involving organolithium compounds and reactions involving lithium metal. Commercial organolithium compounds are produced by the heterogeneous (slurry) reaction of lithium with organic bromides and chlorides:
- 2 Li + R−X → LiX + R−Li
Often the lithium halide remains in the soluble product.
Most of this article is about the homogeneous (one-phase) reaction of preformed organolithium compounds:
- R−Li + R′−X → R−X + R′−Li
Butyllithium is commonly used. Gilman and Wittig independently discovered this method in the late 1930s.[1] It is not a salt metathesis reaction, as no salt is produced.
Lithium–halogen exchange is frequently used to prepare vinyl-, aryl- and primary alkyllithium reagents. Vinyl halides usually undergo lithium–halogen exchange with retention of the stereochemistry of the double bond.[2] The presence of alkoxyl or related chelating groups accelerates lithium–halogen exchange.[3] Lithium halogen exchange is typically a fast reaction. It is usually faster than nucleophilic addition and can sometimes exceed the rate of proton transfer.[4]
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.[5][3]
Mechanism and scope
[edit]Two mechanisms have been proposed for lithium–halogen exchange.[6] One proposed pathway involves a nucleophilic mechanism that generates a reversible "ate-complex" intermediate. Farnham and Calabrese crystallized an "ate-complex" lithium bis(pentafluorophenyl) iodinate complexed with TMEDA.[7] The "ate-complex" further reacts with electrophiles and provides pentafluorophenyl iodide and C6H5Li.[7] 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.[8] Another proposed mechanism involves single electron transfer with the generation of radicals. In reactions of secondary and tertiary alkyllithium and alkyl halides, radical species were detected by EPR spectroscopy.[9][6] The mechanistic studies of lithium–halogen exchange are complicated by the formation of aggregates of organolithium species.
Other metals
[edit]- Magnesium–halogen exchange
Grignard reagents can be prepared by treating a preformed Grignard reagent with an organic halide. This method offers the advantage that the Mg transfer tolerates many functional groups. A typical reaction involves isopropylmagnesium chloride and aryl bromide or iodides:[10]
- i-PrMgCl + ArCl → i-PrCl + ArMgCl
Magnesium ate complexes metalate aryl halides:[11]
- ArBr + Li[MgBu3] → ArMgBu2 + BuBr
- Zinc–halogen exchange
Zinc–halogen exchange:[12]
- LiBu3Zn + R−I → Li[R−ZnBu2] + BuI
Applications
[edit]Several examples can be found in organic syntheses.[13]
Below lithium–halogen exchange is a step 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.[14]
Lithium–halogen exchange is a crucial part of Parham cyclization.[15] 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.[16] 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.[17]
Parham cyclization in MitoSpin
References
[edit]- ^ 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.
- ^ 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.
- ^ a b Leroux F., Schlosser M., Zohar E., Marek I. (2004). The Preparation of Organolithium Reagents and Intermediates. New York: Wiley. ISBN 978-0-470-84339-0.
{{cite book}}: CS1 maint: multiple names: authors list (link) - ^ 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.
- ^ Carey, Francis A. (2007). "Organometallic compounds of Group I and II metals". Advanced Organic Chemistry: Reaction and Synthesis Pt. B (Kindle ed.). Springer. ISBN 978-0-387-44899-2.
- ^ 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.
- ^ Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. (2003). "Highly Functionalized Organomagnesium Reagents Prepared through Halogen–Metal Exchange". Angewandte Chemie International Edition. 42 (36): 4302–4320. doi:10.1002/anie.200300579. PMID 14502700.
- ^ Arredondo, Juan D.; Li, Hongmei; Balsells, Jaume (2012). "Preparation of t-Butyl-3-Bromo-5-Formylbenzoate Through Selective Metal-Halogen Exchange Reactions". Organic Syntheses. 89: 460. doi:10.15227/orgsyn.089.0460.
- ^ Balkenhohl, Moritz; Knochel, Paul (2020). "Recent Advances of the Halogen–Zinc Exchange Reaction". Chemistry – A European Journal. 26 (17): 3688–3697. doi:10.1002/chem.201904794. PMC 7155102. PMID 31742792.
- ^ Adam P. Smith; Scott A. Savage; J. Christopher Love; Cassandra L. Fraser (2002). "Synthesis of 4-, 5-, and 6-methyl-2,2'-bipyridine by a Negishi Cross-coupling Strategy: 5-methyl-2,2'-bipyridine". Org. Synth. 78: 51. doi:10.15227/orgsyn.078.0051.
- ^ 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.