F2

Taming the Dragon Called φθόριο

Huaiju Wang Joint Group Meeting Mar. 30, 2018

Fragile organic molecules Mineral Sources of Fluorine

Fluorite (fluorspar) Fluorapatite Cryolite

CaF2 Ca5(PO4)3F Na3AlF6

Antozonite

CaF2 Kraus, F.; et al. ACIE 2012, 51, 7847 History of Fluorine

I think hydrofluoric acid My glass got corroded! has H and another 1771 element similar to Cl. Circa 1810 Carl Wilhelm Scheele Humphry Davy

1764 1810 Andreas Sigismund Marggraf André-Marie Ampère Mine too! It must be Let's call it "fluor-ine", an acid, say, "fluss- because, you know, spats-syran." chlor-ine. History of Fluorine

Electrolysis of KHF2•HF 1886 in cooled platinum/iridium cell Henri Moissan

Air F2 Cl2 History of Fluorine

UF6 and fluorocarbons Freon and Teflon Circa 1940 Circa 1930 Manhattan Project GM and DuPont 4614 BIGELOW,PEARSON. COOK AND MILLER,JR. Val. 55

[CONTRIBUTION FROM THE CHEMICAL LABORATORYOB DUKE UNIVERSITY] The Action of Elementary Fluorine upon Certain Aromatic Organic Compounds under Various Conditions. I

BY LUCIIJSA. BIGELOW,J. HERBERTPEARSON, LOUIS B. COOKAND WILLIAMT. MILLER,JR. Fluorine is the most reactive, as well as the most electronegative, of all the elements, and it is surprising, therefore, to find that the direct fluorination of organic compounds has received scant attention from Early Attempts with F2 earlier investigat0rs.l This is due in part to the enormous reactivity of the fluorine, which combines explosively with most organic compounds when the two are brought in contact; and in Dart also to the fact that the reactions of free fluorine, at least upon aromatic compounds, do F O O not seem to follow well-recog-F2 Me OH nized linesMe whichOH might be pre- O CCl , 0 ºC 4 F dicted by analogy and studied OH readily. The work to be de-

scribed in this paper representsF2 grey solid the initial stage of a careful yellow solid white solid study of the controlled reactionsCCl4, 0 ºC of elementary fluorine upon a variety of aromaticCl organic com- F Cl Cl F Cl Cl pounds, under a number ofF dif-2 F Cl fering types of experimental Cl F Cl Cl CCl , 0 ºC conditions. 4 F Cl Cl Cl F The Apparatus F Cl The fluorine was generatedF2 by C Cl Cl the electrolysis2 6of molten potassium Cl F bifluoride, at 2503OOo, invapor an electro- over Cu Cl lytic cell made of heavy copper, and F illustrated in detail in Fig. 1. FThis2 F F generator wasC2 Hdesigned6 several years F ago by Paul M. Gross andvapor J. S. Buckover Cu F F in this Laboratory, and was similar in principle to several which have been described previously in thv. Iircmture. It dilfcred significantly from there. however. in that thecopper pipe which held the graphite anode also 5crved a5 the wit for the fluorine, and wzs supponcd by mmnc of H fluorite ring, which was hoth insulating. and enrlre~y Bigelow, L. A.; et al. JACS 1933 – 1938 inert. even under severc upernring conditions. The gac, :dtcr heing %elfree at rheanode, was passed through a copper tuhe approximatrly 63 X 3.5 cm. filled with anhydrous

(I)'The most imporia~tlht~r~~ur~ irlercncc~ OIC as lollv~~Umsm Lum.9, rrnd , la. 1513 (1886): 10s. 102 256 BOIJ (Ip.80). llumiitoa. J. I'hjr Chcn , 23. 572 1'*1.1., Fichtrr md llllmpr* lido Chim. .t

gas phase H3C H Cl Cl H3C Cl H Cl ΔrHº = –24 kcal/mol

gas phase H3C H F F H3C F H F ΔrHº = –103 kcal/mol

gas phase H3C CH3 2 CH3• ΔrHº = 90 kcal/mol

gas phase 1 H3C H /2 O O H3C OH ΔrHº = –27 kcal/mol

gas phase H3C H 2 O O O C O 2 H OH ΔcHº = –192 kcal/mol

“The action of fluorine on a carbon compound can be likened to a combustion process where the products are carbon tetrafluorides and hydrogen fluoride” – Alan M. Lovelace

Enthalpy of reaction calculated from JANAF table A Thermodynamic Trick

gas phase H3C H F F H3C F H F ΔrGº = –103 kcal/mol

Initiation gas phase F F 2 F• ΔrGº = 30 kcal/mol

gas phase H3C H F F CH3• F• H F ΔrGº = –6 kcal/mol

Propagation

gas phase H3C H F• CH3• H F ΔrGº = –36 kcal/mol

gas phase CH3• F F H3C F F• ΔrGº = –68 kcal/mol

Termination gas phase CH3• F• H3C F ΔrGº = –98 kcal/mol

gas phase 2 CH • 3 H3C CH3 ΔrGº = –70 kcal/mol

Lagow, R. J.; et al. Prog. Inorg. Chem., 1979, 26, 161 Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 92

92 Chapter 4

Chambers: Fluorine in Organic Chemistry Final Proof 4.8.2004 6:47pm page 92 3 X ½ Š

92 Chapter 4 Kinetics to the Rescue Figure 4.1 168 RICHARD J. LAGOW and JOHN L. MARGRAVE I are more demanding than isopropyl groups. Indeed, van der Waals3 volumes, ˚ 3 repulsion˚ 3X ½ Š CH3 16:8 A compared to CF3 42:6 A , further illustrateF this point [5] (Figure 4.2). ¼ ¼electron density 5 ½ Š Figure 4.1 H F H H F F are more demanding than isopropyl groups. Indeed, van der Waals volumes, ˚ 3 ˚ 3 CH3 16:8 A compared to CF3 42:6 A , further illustrate this point [5] (Figure 4.2). ¼ I ¼ I I I 5 16.8A3 I 42.6AI 3 ½ Š Fig. 1. The stericH protection of the carbon backbone by fluorineF of a polytetrafluoro- ethylene chain.H The helicalH configuration of fluorine with a repeatF distance of 16.8 K Figure 4.2 (- - - -) results from the steric crowding of adjacent fluorine.F The nonbonding electron cloud of the attached fluorine atoms would tend to repel some of the3 incident fluorine molecules as they 3 approach the carbon Table 4.1 skeleton.Steric parametersThis16.8A reduces the [4]number of effective collisions,42.6A making it possible to increase the total number of collisions and still not accelerate the reaction rate as Figure 4.2 the reaction proceeds toward completion. This sheath of fluorine atoms is one of Substituent Taft Es Charton n the reasons for the inertness of Teflon and other fluorocarbons and also explains the greater success commonly reported in the literature when the hydrocarbon Table 4.1 Steric parameters [4] H to be fluorinated is partially fluorinated in advance1.24 by some other process or is 0 prechlorinated. þ F Substituent Taft0.78E Charton n — þ s OH C. Kinetic Control of the Reactions0.69 of Elemental Fluorine — H þ1.24 0 CH3 F þ 0.780 — 0.52 The most crucial element in the controlþ of direct fluorination, a kinetic CH2CH3 OHconsideration, is the dilution technique. In 0.69 most0.07 previous work on reactions — of 0.56 CH elemental fluorine, dilution with nitrogenþÀ or0 helium has been employed. 0.52 How- CH CH3 2 3 0.47 0.76 ð ÞCH2ever,CH3 the concentration of fluorine in theÀ 0.07 reactor has been kept at a 0.56constant C CH3 value (usually 10% or greater) by introducingÀ 1.54 a specified mixture of fluorine and 1.24 3CH CH3 0.47 0.76 ð Þ ðnitrogen,Þ2 for example, a 10: 1 nitrogen-to-fluorineÀÀ ratio, relatively rapidly into a CH2F C CH3 1.540.24 1.24 0.62 ð reactor.Þ3 Such a dilution scheme correspondsÀÀ to the horizontal straight line in CHF CH2F 0.240.67 0.62 0.68 2 Fig. 2. The rate of reaction between aÀ hydrocarbon compound and a 10% CHF2 À0.67 0.68 CF3 fluorine mixture is relatively high and Àthe 1.16very exothermic process leads to 0.91 CF3fragmentation (Table 111) and in some cases,À1.16 to combustion. The initial 0.91stages of reaction are most critical and nearly all theÀ fragmentation occurs at this time. A

III ELECTRONICIII ELECTRONIC EFFECTS EFFECTS OF OF POLYFLUOROALKYL POLYFLUOROALKYLChambers, R. D. Fluorine in Organic Chemistry, Blackwell Publishing, 2004 GROUPS [6] GROUPS [6] In this section we will deal with the effects of a polyfluoroalkyl group as a whole attached In this sectionto a saturated, we will and deal therefore with not the formally effects charged, of a polyfluoroalkyl carbon atom. The effect group of fluorine as a whole and attached to a saturated,fluorinated and therefore groups directly not bonded formally to reaction charged, centres carbon such as atom. intermediate The effect carbocation of fluorine and and carbanion sites will be treated in separate sections. fluorinated groups directly bonded to reaction centres such as intermediate carbocation and carbanionA Saturated sites will besystems treated in separate sections. 1 Strengths of acids A SaturatedAs fluorine systems is the most electronegative element, it could be expected that the introduction of a fluorine atom or polyfluoroalkyl group into the carbon chain of an organic acid, such 1 Strengths of acids As fluorine is the most electronegative element, it could be expected that the introduction of a fluorine atom or polyfluoroalkyl group into the carbon chain of an organic acid, such Elemental Fluorine as an F Source With Enough Dilution

F 10% (v/v) F2/N2

CFCl3, –78 ºC

Me OAc 10% (v/v) F2/N2 Me OAc 0.1 eq. PhNO2 Me H excess NaF Me H 50% H H F H CFCl3/CHCl3, –25 ºC AcO AcO H H

Me 10% (v/v) F /N Me Me 2 2 0.1 eq. PhNO2 reductive Me excess NaF dechlorination F Me H Me Me H Me Me H H CFCl3/CHCl3, –25 ºC H/F H H Me AcO Cl HO Cl mono 40% di 20%

Hesse, R. H.; et al. JACS 1976, 98, 3034 Hesse, R. H.; et al. JACS 1976, 98, 3036 The Cambridge Lineage

O O 4% (v/v) F2/N2 O O t-Bu/Me NO2 t-Bu/Me NO2 CFCl3/CHCl3 (1:1), –78 ºC H F

Me: 60% t-Bu: 50% 2.6–2.8 CH2: sp CH: sp2.8–3.0 C H F

F

O O

O 4% (v/v) F2/N2 O

t-Bu/Me NO2 CFCl3/CHCl3 (1:1), –78 ºC t-Bu/Me NO2

H F

Me: 65% t-Bu: 83%

Rozen, S.; et al. JACS 1980, 102, 6860 Rozen, S.; et al. JOC 1987, 52, 2769 A Delicate Case

≤ 20% (v/v) F /N Me O t-Bu 2 2 small amounts of random fluorination H via radical mechanism O CFCl3/CHCl3

sp2.1

H O

t-Bu/Me ≤ 20% (v/v) F2/N2 small amounts of random fluorination via radical mechanism CFCl /CHCl O 3 3 Me/t-Bu

H

CO2Me CO2Me 4% (v/v) F /N CO2Me 2 2 CO2Me 25% Me CFCl3/CHCl3 (1:1), –75 ºC Me H F

Rozen, S.; et al. JOC 1987, 52, 2769 Paraffin – Not Enough Affinity?

t-Bu F

t-Bu F H H NO 2 F

O F F

O

50% 70% 70% 90% 80% 50 eq. F2 as 4% mixture in N2 1.1 eq. F2 as 1.3% mixture in N2 (2.5% F2/N2) (1% F2/N2) (1% F2/N2)

Me F Me F sp2.7 10% 15%

Me H Me H t-Bu H t-Bu H

1.5% F2/N2 1.5% F2/N2

t-Bu H t-Bu H Me H Me H

sp3.0 60% 50%

t-Bu F t-Bu F

Rozen, S.; et al. JOC 1987, 52, 2769 Selectfluor – You are Too Picky

Cl N F F N F

10% F2/N2 Selectfluor MeCN, 0 ºC MeCN, reflux

F F F F

F H H F F

H H H

F H H F F H H H

X O Me O Me

3 F-substitution at Me X Me H >7 F-substitution at tertiary positions secondary positions as only products X H H H in low conversion AcO AcO X H X

Chambers, R. D.; et al. J. Chem. Soc. Perkin Trans. 1, 2002, 2190 Chambers, R. D.; et al. J. Fluorine Chem. 2008, 129, 811 Cooperation with Other Halogens

1.5% F2/N2 Br/I F > 80% CHCl3, –75 ºC

O O Me Me Me Me X2 Me H 10% F2/N2 Me H > 60% H H CHCl3, –75 ºC H H O O X

OMe O Me CN CN I 92% 81% Straight from arene 80% "moderate"

Br Br I Simply premix NO2 X2 and F2 in cold CFCl3 O O NO2 Me Equivalent-sensitive I I Br 90% 93% 85% 50%

Br Br NO2 I

Rozen, S.; et al. JOC 1981, 46, 733 Rozen, S.; et al. JOC 1988, 53, 5545 Rozen, S.; et al. JOC 1985, 50, 3342 Rozen, S.; et al. JOC 1988, 53, 1123 Hydrogen Bond Matters

1–5% F2/N2 Me F Me CFCl3/CHCl3/EtOH, –75 ºC F

F n-hexyl O O F OAc n-hexyl F F F F CO2Me F F CO2Me Yields ~ 50% O F F

F O F CO2Et Me OAc F N Boc F F F

Ionic Syn Addition

F

Me OAc R R Me OAc R F F R F OAc F Me OAc Me F

Rozen, S.; et al. JOC 1986, 51, 3607 Toyota, A.; et al. Tetrahedron 1995, 51, 8783 More Extreme Hydrogen-Bonding

CO2H CO2H

10% F2/N2

HCO2H or H2SO4, 10 ºC F F F

Solvent pKa Yield

98% H2SO4 –3.6 84% 98% HCO2H 3.8 65% CF3CO2H 3.1 56% AcOH 4.8 25% CF3CH2OH 12.4 10% CCl2FCClF2 –– 0%

O O O O 10% F2/N2 Me Me Me Me HCO H, 10 ºC 2 F

O O O O O O O O O F F O OH O Me OEt OH Me Me Me Me O F F Me Me F Cl F F

Yields: 60–80%

Chambers, R. D.; et al. J. Chem. Soc. Perkin Trans. 1, 1996, 2271 Chambers, R. D.; et al. Tetrahedron 1996, 52, 1 Chambers, R. D.; et al. J. Chem. Soc. Perkin Trans. 1, 1996, 605 Elemental Fluorine as an Oxidant (No Burning) Exciting Oxidations

H O Me H2O RCO2H O F H 2 MeCN F FOH O F2 FOH N 2 H F H R O O

Baeyer-Villiger Secondary Alcohol to Ketone C–H Activation O O Me Me

O Me OH

O O OH

O

O H

O18/16 O OAc t-Bu 16/18 O O OH

HO t-Bu O Me Me 18 OMe O OH

F F F F F F OMe H OH OMe F F F F F F

Chambers, R. D.; et al. Tetrahedron 1997, 53, 15833 Rozen, S. Acc. Chem. Res. 1996, 29, 243 Difficult Oxidations

HOF first isolated in 1970s The complex is stable for hours at r.t., by Appelman, trying to generate even longer at the common reaction OF2 by reacting F2 HOF•MeCN temperature ~ –78 ºC. Supposedly with ice at –50 ºC. stablized by the H-bonding N…H–O.

Expectedly unstable, until when + "HO " Synthesized and used in situ as Rozen came across its MeCN an electrophilic oxygen source. complex when doing reaction with Much more reactive than peroxides. F2 in wet MeCN.

Epoxidation TMS Enol Ether Hydroxylation

O O OH

Me Me 90% O O 25% w/ DMDO after 24 h Me Me

O O OH Ph Ph t-Bu Ph PhCHO O O Ph Ph Me Me Ph Ph Me O O O O CO Me CO2Me 2 OH O

O O n-Pr CO2Me 97% n-Pr 17 d w/ DMDO OH O O Rozen, S. Acc. Chem. Res. 2014, 47, 2378 COMMUNICATIONS

however, various premixed mixtures of F2 in inert gases are commercially available, which simplifies the process. Working with fluorine is relatively simple if elementary precautions are taken and we have had no bad Show-off Oxidations experiences working with it.

General procedure for producing HOF ´ CH3CN: Mixtures of 10 ± 15% F2 with nitrogen were used in this work. They were passed at a rate of about 1 400 mLminÀ through a cold ( 10 8C) mixture of CH CN (400 mL) and À 3 H2O (40 mL). The development of the oxidizing power was monitored by reacting aliquots withO anO acidic aqueous solution of KI. The liberated Impossible until now (1999) iodine was then titratedS with thiosulfate. Typical concentrations of the C(CF3)3 N “All such [reports] are wrong.” oxidizing reagent were around 0.3 ± 0.4 m. These solutions were used as “Claims of their existence [...] should be withdrawn.”obtained with no further purification or isolation of the reagent. N O F O – R. D. Gillard in 1989 1: A solution of 1,10-phenanthroline (2; 0.5 g) in chloroform (20 mL) at

08C was added to 2.2 equivalents of the HOF ´ CH3CN solution. After 5 min the mixture wasO neutraliO zed using a saturated sodium bicarbonate S solution, extracted with CHCl3 , dried over MgSO4, filtered, and evapo- n-C8F17 rated. The crude product was purified by recrystallization from EtOH/H2O (1/3) to Megive 1,10-phenanthroline-N,N-dioxide (1), m.p. 200 8C; IR: nÄ 1 13 ˆ 1221, 1211, 775, 757 cmÀ ; C NMR: d 139.5, 133.2, 127.6, 123.1, 121.2, ˆ 98.8; HR-MS (EI) m/z: 212.0585 [M‡], calcd for C12H8N2O2 212.0586;

elemental analysis calcd for C12H8N2O2 : C 67.92, H 3.80, N 13.20; found: C 67.77, H 4.26,OAcN 12.83. Crystallographic data (excluding structure factors) Figure 1. Structure of 1 in the solid state (R 0.0555, wR2 0.1267). ˆ ˆ for the structure reported in this paper have been deposited with the a) View from above; b) side view without hydrogen atoms. Selected bond Cambridge CrystallogrO O aphicO Data Centre as supplementary publication no. lengthF s [Š] and angles [ ]:[16] N1-O1 1.297(1), N10-O2 1.315(1), N1-C13 AcO N 8 NH2 CCDC-132810.AcO CopiesS of the data can be obtained free of charge on F1.391(1), N10-C11 1.383(1), C2-C3 1.388(2), C8-C9 1.388(2), C3-C4 O O application to CCDCOAc , 12 Union Road, Cambridge CB2 1EZ, UK (fax: 1.381(2), C7-C8 1.382(2), C4-C14 1.404(2N ), NC7-C12 1.403(2), C13-C11 S N ( 44)1223-336-033; e-mail: [email protected]). 1.440(2), C5-CO 6 1.354(2), C13-C14 1.413(1N ), NC11-C12 1.418(2), C5-C14 ‡ 1.441(2N ), C6-C12 1.437(2), O1-O2 2.5; O1-N1-C2 119.07(9), O1-N1-C13 O O 121.07(9)O, O2-N10-C9 119.30(9), O2-N10-C11NO 120.25(9), N1-C13-C14 Received: August 10, 1999 [Z13857IE] 2 S 118.26(9), C11-C13-C14 118.98(10), C5-C14-C13 118.9(10), C6-C5-C14 Br GermanBrversion: Angew. Chem. 1999, 111, 3680 ± 3682 121.01(10).

Keywords: fluorineMe ´ helical structures ´ nitrogen hetero- O Cl cycles ´ N oxides ´ oxidation The torsion angleN of N1-C13-C11-N10 for 2 is less then 0.58, Me N Ph À for the monoxide 3 it is 0.98, but Nfor theN dioxide 1 the value O O O O O À O t-Bu S S increases to 31.7(2)8. These parametersN N are responsible for t-Bu Me N À [1] F. Linsker,SR. L. Evans, J. Am.S Chem. Soc. 1946, 68, 403. the helical characN ter of the whole molecOule (Figure 1b). The O [2] G. Maerker,O OF. H. Case, J. Am.O OChem. Soc. 1958, 80, 2745. individual aromatic rings are also somewhat distorted. While [3] E. J. Corey, A. L. Borror, T. Foglia, J. Org. Chem. 1965, 30, 282. the outer rings are practically identical and show only a [4] D. Wenkert, R. B. Woodward, J. Org. Chem. 1983, 48, 283. modest distortion (the torsion angle N1-C2-C3-C4, for [5] R. AntkRozenowiak, S., W Acc.. Z. Chem.Antkowiak Res., 2014Heterocy, 47,cles 23781998, 47, 893. [6] R. D. Gillard, Inorg. Chim. Acta. 1981, 53, L173. example, is only 2.91(2) ), the central ring is somewhat less 8 [7] R. D. Gillard, Inorg. Chim. Acta. 1989, 156, 155. symmetrical and has been forced considerably away from [8] S. Rozen, M. Brand, Angew. Chem. 1986, 98, 565; Angew. Chem. Int. planarity (C13-C11-C12-C6 11.98(2)8 and N1-C13-C14- Ed. Engl. 1986, 25, 554. ˆ C5 163.71(1)8). [9] A detailed procedure for the preparation and handling of the reagent ˆ À The separation of the two oxygen atoms by only 2.5 Š is can be found in: S. Dayan, Y. Bareket, S. Rozen, Tetrahedron 1999, 55, 3657. reflected in the UV spectrum of 1, which shows a considerable [10] S. Rozen, Acc. Chem. Res. 1996, 29, 243. red shift as expected from such a nonbonding interaction: [11] S. Rozen, A. Bar-Haim, E. Mishani, J. Org. Chem. 1994, 59, 1208. Phenanthroline mono N-oxide (3) has three main absorptions [12] S. Rozen, Y. Bareket, J. Org. Chem. 1997, 62, 1457. 4 4 [13] M. H. Hung, B. E. Smart, A. E. Feiring, S. Rozen, J. Org. Chem. 1991, at 239 nm (emax 1.9 10 ), 268 nm (emax 2.7 10 ), and ˆ  ˆ  56, 3187. 313 nm (e 4.6 103), while the N,N-dioxide 1 absorbs at max [14] S. Dayan, J. Almog, O. Khodzhaev, S. Rozen, J. Org. Chem. 1998, 63, ˆ  4 4 232 nm (sh, emax 1.75 10 ), 278 nm (emax 1.3 10 ), 2752. ˆ 3  ˆ 3  335 nm (emax 2.8 10 ), and 366 nm (emax 2.1 10 ). [15] S. Dayan, M. Kol, S. Rozen, Synthesis 1999, 1427. ˆ  ˆ  [16] The X-ray values reported are the average of the corresponding values of the two independent molecules found in the asymmetric unit. The Experimental Section parameters may vary up to 0.68 and 0.2 Š from each other.

1 H NMR spectra (CDCl3 or D2O; TMS) were recorded on a Bruker AC-200 13 spectrometer; the proton broad-band decoupled C NMR spectra (CDCl3 ; TMS) were recorded at 90.5 MHz. High-resolution mass spectra were measured on a VG micromass 7070H instrument. IR spectra were recorded

in CHCl3 or in KBr pellets on a Bruker Vector22 FT-IR spectrophotometer. UV spectra were recorded on a Korton UVIKON 931 spectrophotometer

using water as the solvent. A Nonius Kappa CCD diffractometer with MoKa radiation (l 0.7107 Š) was used for the crystal structure elucidation. ˆ General procedure for working with fluorine: Fluorine is a strong oxidant and a very corrosive material. It should be used only with an appropriate vacuum line such as that described in ref. [15]. For the occasional user,

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Standard Package Information—Europe Material Number 414966 414308 419100 Cylinder Size 12 x 50 L Steel 50 L Steel 10 L Steel Fill Weight (kgs) 420 35 6 Valve Connection Manual DISS 716 Manual DIN 6 Manual DIN 6 Cylinder Dimensions (in) Upon Request 23X149 82X14

Commercial Grade Specifications ® Airopak is our standard F2 in N2 10% F2 ± 1% purity grade fluorine nitro- gen mixture for industrial Standard Package Information applications. Material Number 37010 Cylinder Size 49 L Steel ® Airopak is a toxic, ex- Fill Weight (lbs) 21.1 tremely reactive, corro- Fill Weight (kgs) 9.6 Figure 1. Schematicsive, representation oxidizing compressed of modular microreactor Valve Connection device. Wrench-CGA 330 gas mixture Elementalwith a sharp, Cylinder Dimensions Fluorine (in) in Lab 9X57 Furthermore, whilstpungent batch-wise smell. processes, involving passage benzoyl fluoride is readily hydrolysed, making isolation difficult,

of fluorine diluted in nitrogen into a rapidly stirred solution of 3,5-dinitrobenzyl alcohol and pyridine were added to the crude substrate, have been used successfully for fluorination processes, reaction mixture, which was then heated to room temperature continuous flow reactors have been developed at Durham that in order to transform the acid fluoride into an easily isolable, enable very effective, simple scale-up of gas/liquid“In glass reactions. vessels,20–25 myhydrolytically young friend” stable ester 3a for characterisation purposes. It Amultichanneldevice,20 where gas and liquid reagents are is, therefore, a very simple procedure in principle to separate – D. H. R. Barton, when asked how he conducted reactions using CF3OF supplied to many channels from single feedstock reservoirs, out ring fluorinated products from side chain fluorinated systems allowing the large-scale synthesis of fluorinated derivatives (e.g., due to the ready hydrolysis of acid fluorides. The yield of the 100 g of fluorinated ketoesters can be produced from a single ester 3a is calculated from the two-step reaction of 1a. 9-channel device in a 24 h period), is shown in Figure 1. Fluorinations of a range of para-substituted benzaldehyde In this paper, we continue our studies on the use of elemental derivatives 1 were performed under similar conditions, and fluorine1 as a viable reagent for organic synthesis in studies where appropriate, esters 3 formed upon addition of dinitroben- Chambers, R. D.;concerning et al. Org. theProcess direct Res. fluorination Dev. 2008 of a, variety12, 339 of benzaldehyde zyl alcohol and pyridine to the reactionRozen mixture, S. Acc. for character- Chem. Res. 1996, 29, 243 derivatives using both batch and continuous flow techniques. ization. In each case the ratios of products were measured by Fluoroaromatic systems, which may be accessed by direct 19FNMRanalysisbeforereactionwork-upsohandlinglosses fluorination rather than multistep fluorodediazoniation processes, are not reflected in the results (Table 1). Fluoroarenes 2f,g,h,k are very important building blocks for application in the life were isolated by column chromatography and identified by 1 science and materials industries.26 Direct fluorination of various comparison with authentic samples. methoxy benzaldehyde derivatives have been reported previ- Both 4-methyl- and 4-methoxy-benzaldehyde, 1b and 1c, ously to give the corresponding fluoroaromatic products.9 gave fluoroaromatic products 2e,f and 2g,h,respectively, consistent with an electrophilic substitution process, and no 2. Results and Discussion benzoyl fluoride derivatives were observed in either case. In Direct fluorination of benzaldehyde 1a in acetonitrile at 0 contrast, 4-trifluoromethyl- and 4-cyano-benzaldehyde, 1d and °Cgaveamixtureoffourproducts2a-d in 48% conversion 1e,gavethecorrespondingacidfluorides2j and 2l in significant in the ratio 0.9:5.2:1.9:1, arising from displacement of the ortho, quantities, and these were characterised as esters 3c and 3d, meta, para and aldehydic hydrogen atoms, respectively. Reac- respectively. tion conversion and ratio of products was measured by GCMS By similar processes, a short series of meta-substituted and 19FNMRanalysisofthecrudereactionmixturewithan benzaldehyde derivatives 4 in which both substituents are added internal reference and comparison with literature data. electron-withdrawing groups gave mixtures of the corresponding Benzoyl fluoride 2d was detected (δF )+20.3 ppm), and since 5-fluoroaromatic and benzoyl fluoride products 5.Thebenzoyl fluorides were isolated and characterised as the corresponding (19) Butters, M.; Ebbs, J.; Green, S. P.; MacRae, J.; Morland, M. C.; Murtiashaw, C. W.; Pettman, A. J. Org. Proc. Res. DeV. 2001, 5, 28. esters 6 by the techniques described above, and fluoroarenes (20) Chambers, R. D.; Fox, M. A.; Holling, D.; Nakano, T.; Okazoe, T.; 5a,c,e were isolated by column chromatography and identified Sandford, G. Lab. Chip 2005, 5, 191. (21) Chambers, R. D.; Fox, M. A.; Holling, D.; Nakano, T.; Okazoe, T.; by comparison with authentic samples (Table 2). Sandford, G. Chem. Eng. Technol. 2005, 28, 344. The results in Tables 1 and 2 indicate that the relative (22) Chambers, R. D.; Fox, M. A.; Sandford, G. Lab. Chip 2005, 5, 1132. proportions of products arising from fluorination of the aromatic (23) Chambers, R. D.; Holling, D.; Sandford, G. UK Pat. Appl. PCT/GB03/ 01993, 2002. ring or the aldehyde group depends on the nature of the ring (24) Chambers, R. D.; Sandford, G. Chim. Oggi 2004 , 13. substituent. In all cases, when a strong electron-withdrawing (25) Chambers, R. D.; Spink, R. C. H. Chem. Commun. 1999, 883. (26) Clark, J. H.; Wails, D.; Bastock, T. W. Aromatic Fluorination; CRC group is attached to the ring (NO2,CN),thenfluorinationoccurs Press: London, 1996. preferentially on the carbonyl group to give the corresponding

340 • Vol. 12, No. 2, 2008 / Organic Process Research & Development Toxicity of Fluorine Gas

AEGL – Acute Exposure Guideline Levels (ppm over duration of time) Level 1: Discomfort or irritations, but effects are transient, reversible, and not disabling Level 2: Irreversible or serious long-lasting adverse health effects, could impair ability to escape Level 3: Death

Data used herein: 8 h for Level 1, 1 h for Level 2, 10 min for Level 3 concentrations

Gas/Vapor Level 1 Level 2 Level 3

F2 1.7 5.0 36

Cl2 0.5 2.0 50

Br2 0.03 0.2 19

CO "not recommended" 83 1700

NH3 30 160 2700

PhSH n/a 0.5 3.0

PhH 9.0 800 ~9700

PhMe 67 560 ~10000

Acetone 200 3200 ~16000

Hexane n/a 2900 ~12000

Sarin 0.17 ppb 6.0 ppb 64 ppb

EPA AEGL Values, published as Acute Exposure Guideline Levels for Selected Airborne Chemicals