Electrophilic fluorination

Electrophilic fluorination is the combination of a carbon-centered nucleophile with an electrophilic source of fluorine to afford organofluorine compounds. Although elemental fluorine and reagents incorporating an oxygen-fluorine bond can be used for this purpose, they have largely been replaced by reagents containing a nitrogen-fluorine bond.[1]

Electrophilic fluorination offers an alternative to nucleophilic fluorination methods employing alkali or ammonium fluorides and methods employing sulfur fluorides for the preparation of organofluorine compounds. Development of electrophilic fluorination reagents has always focused on removing electron density from the atom attached to fluorine; however, compounds containing nitrogen-fluorine bonds have proven to be the most economical, stable, and safe electrophilic fluorinating agents. Electrophilic N-F reagents are either neutral or cationic and may possess either sp2\- or sp3-hybridized nitrogen. Although the precise mechanism of electrophilic fluorination is currently unclear, highly efficient and stereoselective methods have been developed.

Some common fluorinating agents used for organic synthesis are N-fluoro-o-benzenedisulfonimide (NFOBS), N-fluorobenzenesulfonimide (NFSI), and Selectfluor.[1]

## Mechanism and stereochemistry

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### Prevailing mechanism

[edit]

The mechanism of electrophilic fluorination remains controversial. At issue is whether the reaction proceeds via an SN2 or single-electron transfer (SET) process. In support of the SN2 mechanism, aryl Grignard reagents and aryllithiums give similar yields of fluorobenzene in combination with N-fluoro-o-benzenedisulfonimide (NFOBS), even though the tendencies of these reagents to participate in SET processes differ substantially.[2] Additionally, radical probe experiments with 5-hexenyl and cyclopropyl enol ethers did not give any rearranged products.[3] More recently, kinetic studies on electrophilic fluorination of a series of 1,3-dicarbonyl derivatives by a range of N-F reagents have suggested the SN2 mechanism is more likely through Eyring and Hammett studies.[4]

On the other hand, the lifetime of radicals in the SET process is predicted to be four orders of magnitude shorter than the detection limit of even the most sensitive of radical probes. It has been postulated that after electron transfer, immediate recombination of the fluorine radical with the alkyl radical takes place.[5]

### Stereoselective variants

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Stereoselective fluorinations may be either diastereoselective or enantioselective. Diastereoselective methods have focused on the use of chiral auxiliaries on the nucleophilic substrate. For fluorinations of carbonyl compounds, chiral oxazolidinones have been used with success.[6]

Tandem conjugate addition incorporating a chiral nucleophile has been used to synthesize β-amino α-fluoro esters in chiral, non-racemic form.

Enantioselective methods employ stoichiometric amounts of chiral fluorinating agents. N-fluoroammonium salts of cinchona alkaloids represent the state of the art for reactions of this type. In addition, these reagents are easily synthesized from Selectfluor and the parent alkaloids.[7]

## Scope and limitations

[edit]

### Fluorinating reagents

[edit]

Electrophilic N-F fluorinating reagents incorporate electron-withdrawing groups attached to nitrogen to decrease the electron density on fluorine. Although N-fluorosulfonamides are fairly weak fluorinating reagents, N-fluorosulfonimides, such as N-fluorobenzenesulfonimide (NFSI), are very effective and in common use. N-fluoro-o-benzenedisulfonimide (NFOBS) is synthesized from the disulfonic acid.[2]

The use of salts of cationic nitrogen increases the rates and yields of electrophilic fluorination, because the cationic nitrogen removes electron density from fluorine. N-fluoropyridinium ions and iminium ions can also be used as electrophilic fluorinating reagents. The counteranions of these salts, although they are not directly involved in the transfer of fluorine to the substrate, influence reactivity in subtle ways and may be adjusted using a variety of methods.[8]

The most synthetically useful ammonium salts are the substituted DABCO bis(ammonium) ions, including Selectfluor.[9] These can be easily synthesized by alkylation followed by fluorination. The difluoro version, which might at first seem more useful, delivers only a single fluorine atom.

More specialized electrophilic fluorinating reagents, such as neutral heterocycles containing N–F bonds,[10] are useful for the fluorination of a limited range of substrates.

### Nucleophilic substrates

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Simple fluorinations of alkenes often produce complex mixtures of products. However, cofluorination in the presence of a nucleophile proceeds cleanly to give vicinal alkoxyfluorides.[11] Alkynes are not fluorinated with N-F reagents. An anionic surfactant was used to facilitate contact between aqueous Selectfluor and the alkene.

Fluorination of electron-rich aromatic compounds gives aryl fluorides. The two most common problems in this class of reactions are low ortho/para selectivities and dearomatization (the latter is a particularly significant problem for phenols).[12]

Enol ethers and glycals are nucleophilic enough to be fluorinated by Selectfluor.[13] Similar to other alkenes, cohalogenation can be accomplished either by isolation of the intermediate adduct and reaction with a nucleophile or direct displacement of DABCO in situ. Enols can be fluorinated enantioselectively (see above) in the presence of a chiral fluorinating agent.

Metal enolates are compatible with many fluorinating reagents, including NFSI, NFOBS, and sulfonamides. However, the specialized reagent 2-fluoro-3,3-dimethyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide consistently affords better yields of monofluorinated carbonyl compounds in reactions with lithium enolates. Other metal enolates afforded large amounts of difluorinated products.[14]

## Comparison with other methods

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Although the use of molecular fluorine as an electrophilic fluorine source is often the cheapest and most direct method, F2 often forms radicals and reacts with C-H bonds without selectivity. Proton sources or Lewis acids are required to suppress radical formation, and even when these reagents are present, only certain substrates react with high selectivity.[15] Handling gaseous F2 requires extremely specialized and costly equipment.

Reagents containing O-F bonds, such as CF3OF, tend to be more selective for monofluorination than the N-F reagents.[16] However, difficulties associated with handling and their extreme oxidizing power have led to their replacement with N-F reagents.

Xenon di-, tetra-, and hexafluoride are selective monofluorinating reagents. However, their instability and high cost have made them less popular than the nitrogenous fluorinating agents.[17]

## Typical conditions

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Although fluorinations employing N-F reagents do not use molecular fluorine directly, they are almost universally prepared from F2. Proper handling of F2 requires great care and special apparatus.[18] Poly(tetrafluoroethylene) (PTFE, also known as Teflon) reaction vessels are used in preference to stainless steel or glass for reactions involving molecular fluorine. F2 blends with N2 or He are commercially available and help control the speed of delivery of fluorine. Temperatures should be kept low, and introduction of fluorine slow, to prevent free radical reactions.

## See also

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* Electrophilic halogenation
* Nucleophilic fluorination

## References

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1. ^ a b Baudoux, Jérôme; Cahard, Dominique (2008). "Electrophilic Fluorination with <SCP>N</SCP> – <SCP>F</SCP> Reagents". Organic Reactions. pp. 1–326\. doi:10.1002/0471264180.or069.02. ISBN 978-0-471-26418-7.
2. ^ a b Davis, F. A.; Han, W.; Murphy, C. K. J. Org. Chem. 1995, 60, 4730.
3. ^ Differding, E.; Rüegg, G. M. Tetrahedron Lett. 1991, 32, 3815.
4. ^ Rozatian, Neshat; Ashworth, Ian W.; Sandford, Graham; Hodgson, David R.W. (2018). "A quantitative reactivity scale for electrophilic fluorinating reagents". Chemical Science. 9 (46): 8692–8702\. doi:10.1039/C8SC03596B. PMC 6263395. PMID 30595834.
5. ^ Piana, S.; Devillers, I.; Togni, A.; Rothlisberger, U. Angew. Chem. Int. Ed. Engl. 2002, 41, 979.
6. ^ Davis, F. A.; Kasu, P. V. N. Tetrahedron Lett. 1998, 39, 6135.
7. ^ Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc. 2001, 123, 7001.
8. ^ Umemoto, T.; Harasawa, K.; Tomizawa, G.; Kawada, K.; Tomita, K. Bull. Chem. Soc. Jpn. 1991, 64, 1081.
9. ^ Stavber, S.; Zupan, M.; Poss, A. J.; Shia, G. A. Tetrahedron Lett. 1995, 36, 6769.
10. ^ Laali, K. K.; Tanaka, M.; Forohar, F.; Cheng, M.; Fetzer, J. C. J. Fluorine Chem. 1998, 91, 185.
11. ^ Lal, G. S. (1993). "Site-Selective Fluorination of Organic Compounds Using l-Alkyl-4-fluoro-l,4-diazabicyclo[2.2.2]octane Salts (Selectfluor Reagents)". J. Org. Chem. 58 (10): 2791. doi:10.1021/jo00062a023.
12. ^ Zupan, M.; Iskra, J.; Stavber, S. (1995). "Chemistry of Organo Halogenic Molecules. 140. Role of the Reagent Structure on the Transformations of Hydroxy Substituted Organic Molecules with the N-Fluoro Class of Fluorinating Reagents". Bull. Chem. Soc. Jpn. 68 (6): 1655. doi:10.1246/bcsj.68.1655.
13. ^ Albert, M.; Dax, K.; Ortner, J. Tetrahedron 1998, 54, 4839.
14. ^ Differding, E.; Lang, R. W. Helv. Chim. Acta. 1989, 72, 1248.
15. ^ Chambers, R. D.; Hutchinson, J.; Sandford, G. J. Fluorine Chem. 1999, 100, 63.
16. ^ Rozen, S. Chem. Rev. 1996, 96, 1717.
17. ^ Ramsden, C. A.; Smith, R. G. J. Am. Chem. Soc. 1998, 120, 6842.
18. ^ Umemoto, T.; Nagayoshi, M. Bull. Chem. Soc. Jpn. 1996, 69, 2287.

* v
* t
* e

Fluorine compounds

* v
* t
* e

Salts and covalent derivatives of the fluoride ion

| HF |  |  |  | ?HeF2

|
|
|
|

LiF | BeF2 | BF
BF3
B2F4
+BO3 | CF4
CxFy
+CO3 | NF3
FN3
N2F2

N2F4
NF2
?NF5

+NO3 | OF2
O2F2

O3F2
O4F2
?OF4 | F2 | Ne
NaF | MgF2 | AlF
AlF3 | SiF4 | P2F4
PF3
PF5
+PO4 | S2F2
SF2
S2F4
SF3
SF4
S2F10
SF6
+SO4 | ClF
ClF3
ClF5 | ?ArF2
?ArF4
KF | CaF
CaF2 |  | ScF3 | TiF2
TiF3
TiF4 | VF2
VF3
VF4
VF5 | CrF2
CrF3
CrF4
CrF5
?CrF6 | MnF2
MnF3
MnF4
?MnF5 | FeF2
FeF3
FeF4 | CoF2
CoF3
CoF4 | NiF2
NiF3
NiF4 | CuF
CuF2
?CuF3 | ZnF2 | GaF2
GaF3 | GeF2
GeF4 | AsF3
AsF5 | Se2F2
SeF4
SeF6
+SeO3 | BrF
BrF3
BrF5 | KrF2
?KrF4
?KrF6
RbF | SrF
SrF2 |  | YF3 | ZrF2
ZrF3
ZrF4 | NbF4
NbF5 | MoF4
MoF5
MoF6 | TcF4
TcF

TcF6 | RuF3
RuF

RuF5
RuF6 | RhF3
RhF4
RhF5
RhF6 | PdF2
Pd[PdF6]
PdF4
?PdF6 | Ag2F
AgF
AgF2
AgF3 | CdF2 | InF
InF3 | SnF2
SnF4 | SbF3
SbF5 | TeF4
?Te2F10
TeF6
+TeO3 | IF
IF3
IF5
IF7
+IO3 | XeF2
XeF4
XeF6
?XeF8
CsF | BaF2 |   | LuF3 | HfF4 | TaF5 | WF4
WF5
WF6 | ReF4
ReF5
ReF6
ReF7 | OsF4
OsF5
OsF6
?OsF

?OsF
8 | IrF2
IrF3
IrF4
IrF5
IrF6 | PtF2
Pt[PtF6]
PtF4
PtF5
PtF6 | AuF
AuF3
Au2F10
?AuF6
AuF5•F2 | Hg2F2
HgF2
?HgF4 | TlF
TlF3 | PbF2
PbF4 | BiF3
BiF5 | ?PoF2
PoF4
PoF6 | AtF
?AtF3
?AtF5 | RnF2
?RnF

?RnF

FrF  | RaF2 |   | LrF3 | Rf  | Db  | Sg  | Bh  | Hs  | Mt  | Ds  | Rg  | Cn  | Nh  | Fl  | Mc  | Lv  | Ts  | Og
| ↓  |  |
| LaF3 | CeF3
CeF4 | PrF3
PrF4 | NdF2
NdF3
NdF4 | PmF3 | SmF
SmF2
SmF3 | EuF2
EuF3 | GdF3 | TbF3
TbF4 | DyF2
DyF3
DyF4 | HoF3 | ErF3 | TmF2
TmF3 | YbF2
YbF3
AcF3 | ThF2
ThF3
ThF4 | PaF4
PaF5 | UF3
UF4
UF5
UF6 | NpF3
NpF4
NpF5
NpF6 | PuF3
PuF4
PuF5
PuF6 | AmF2
AmF3
AmF4
?AmF6 | CmF3
CmF4
?CmF6 | BkF3
BkF
4 | CfF3
CfF4 | EsF3
EsF4
?EsF6 | Fm  | Md  | No

PF−6, AsF−6, SbF−6 compounds|

* AgPF6
* KAsF6
* LiAsF6
* NaAsF6
* HPF6
* HSbF6
* NH4PF6
* LiSbF6
* KPF6
* KSbF6
* LiPF6
* NaPF6
* NaSbF6
* TlPF6

AlF2−5, AlF3−6 compounds|

* (NH4)3[AlF6]
* Cs2AlF5
* Li3AlF6
* K3AlF6
* Na3AlF6

chlorides, bromides, iodides
and pseudohalogenides|

* BaClF
* SiIBrClF
* CFN
* ClFO2
* PbFBr
* PbFCl
* SrFCl

SiF2−6, GeF2−6 compounds|

* BaSiF6
* BaGeF6
* (NH4)2SiF6
* Na2[SiF6]
* K2[SiF6]
* Li2GeF6
* Li2SiF6

Oxyfluorides|

* AcOF
* BrOF3
* BrO2F
* ErOF
* HoOF
* BrO3F
* NdOF
* LaOF
* SmOF
* TbOF
* ThOF2
* VOF

* TcO

* PrOF
* PuOF
* WOF

* YOF
* ClOF3
* ClO2F3

Organofluorides|

* CBrF3
* CBr2F2
* CBr3F
* CClF3
* CCl2F2
* CCl3F
* CF2O
* CF3I
* CHF3
* CH2F2
* CH3F
* C2Cl3F3
* C2H3F
* C6H5F
* C7H5F3
* C15F33N
* C3H5F
* C6H11F

with transition metal,
lanthanide, actinide, ammonium|

* VOF3
* CrOF4
* CrF2O2
* NH4F
* (NH4)3CrF6
* (NH4)3GaF6
* (NH4)2GeF6
* (NH4)3FeF6
* (NH4)3InF6
* NH4NbF6
* (NH4)2SnF6
* NH4TaF6
* (NH4)3VF6
* (NH4)2ZrF6
* CsXeF7
* Li2SnF6
* Li2TiF6
* LiWF6
* Li2ZrF6
* K2TiF6
* Rb2TiF6
* Na2TiF6
* Na2ZrF6
* K2NbF7
* K2TaF7
* K2ZrF6
* UO2F2

nitric acids|

* FNO
* FNO2
* FNO3

bifluorides|

* KHF2
* NaHF2
* NH4HF2

thionyl, phosphoryl,
and iodosyl|

* F2OS
* F3OP
* PSF3
* IOF3
* IO3F
* IOF5
* IO2F
* IO2F3

Chemical formulas
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