Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Fluorite crystals, Industrial preparations of fluorocarbons

CaF2 “The most • Major source of is from fluorspar (CaF2), and from colorful phosphate rock (3.8 % F) mineral in • HF produced by distillation (Bp 20 oC) from fluorspar and the world” H2SO4 • Most fluorocarbons are produced from HF by either direct Primary text : reaction, electrolyzing solutions, fluorination with F2 or Chambers, R. D. Fluorine in metal organic chemistry. Blackwell, • Reactive halides are easily displaced with (Swarts 2004. reaction) ‘Fun’ fluorine facts Cl Cl KF Cl Cl F Cl Cl F • Highy toxic, pale yellow Cl NMP F F Cl Cl Cl Cl F F diatomic gas o 200 C F th Cl Cl F • 13 most abundant Cl Cl F element in crust Henri Moisson Chambers et al. J. Chem. Soc., Perkin Trans 1, 1997, 3623. 58 % • 1529, named ‘Fluo’ for ”In recognition of the great services rendered by him in his F “flow” since ores were low F F investigation and isolation of the pyrolysis Br o melting element fluorine ... The whole Br 500 - 700 C F F • Fluorocarbons are world has admired the great Br F Pt, Ni and Ni tubes greenhouse gases with experimental skill with which F global-warming-potentials you have studied that savage 30 % beast among the elements.” 100 – 200 000 x CO2 Wall et al. US2927138, 1960. Important events in the history of fluorocarbons • The most important fluorocarbon, , has • 1890-1938 Pioneering work by Swartz / “fluorine martyrs” many methods of product involving F2C: dimerization O o • 1886 Moisson isolated F2, later wins Nobel 800 C F F 600 - 800 oC CHF Cl • 1930 Midgey/Henne discover fluorocarbon F3C OH 2 -CO2 F F -HCl • 1937 Simons isolates CF4, C2F6, C3F8, C4F10, C6F14 -HF • 1938 Plunkett accidentally discovers Teflon at Dupont 700 - 800 oC • 1940-1945 WWII drives discovery as stable materials -HF CF3H 1 235 intolerant to UF6 in U production Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Sterics Electronic effects • C-F is very only slightly larger than C-H bond Factors comparing fluorocarbons with hydrocarbons • C-F is isosteric with C-O 1. • CF3 occupies a significantly larger volume than CH3 2. Unshared electron pairs 3. Leaving groups / displacement of F- H F 4. C-F vs. C-H bond strengths H H F F 5. Size difference 16.8 Å3 42.6 Å3 H F Cl Seebach. Angew. Chem., Int. Ed., 1990, 29, 1320. Electronegativity (Pauling) 2.20 3.98 3.16 Ionization energy (kcal/mol) 314 403 299 Halogen bonding : Fact or fiction ? Electron affinity (kcal/mol) 17.7 79.5 83.3 Bond energy X-X (kcal/mol) 104 37.5 57.8 • There has been an ongoing debate on whether fluorine Bond length C-X (Angst.) 1.091 1.319 1.767 can form halogen bonding Van der Waals radius (Angst.) 1.20 1.47 1.75 • Consensus appears to suggest that no σ-hole is present, and therefore does not classify as a • F+ not observed (unlike other halogens) LP repulsion • Slightly larger radius than hydrogen sigma-hole • Electron affinity and X-X bond strength Halogen bond Halogen bond donor δ- acceptor is lower than chlorine b/c unshared F F δ+ electron repulsion R3C X δ+ LB δ- Fluorine forms very strong bonds anisotropic X = Cl, Br, I • B-F, Si-F, H-F and C-F are strongest bonds due to ionic - e distribution sigma-hole bonding character • Pauling proposed no-bond resonance, now used often C-F bond BDE length (Å) (kcal/mol) qC qF F F CH3F 1.385 109.9 0.01 -0.23 F F F F CH2F2 1.357 119.5 0.40 -0.23 CHF3 1.332 127.5 0.56 -0.21 F F CF4 1.319 130.5 0.72 -0.18 Pauling, The Nature of the Chemical Bond, Cornell Univ. Press, Ithaca, Eskandari and Lesani. Chem. Eur. J. 2015, 21, 4739. 2 NY, 1960. Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Hyperconjugation , and volatility • C-F bonds are strong hyperconjugative acceptors b/c of • Low intramolecular attractive forces b/c electroneg. of their low LUMO fluorine reduces polarizability and therefore the London- C-C C-H C-F dispersion force • Results in low , low and σ* σ* heats of vaporization, higher volatility and lipophilicity H F σ* Polarizeability H H H H F F F F E H H F F Best acceptor (for CH X, x10-24cm3) 3 H vs. F H F H H H H H F F F F F σ H 2.59 σ F 2.97 n-hexane n- Best donor Cl 4.72 o o σ Bp = 68 C Bp = 56 C Br 6.03 Density = 0.66 g/mL Density = 1.68 g/mL Gauche effect • Vicinal fluorocarbons adopt gauche conformation to • Comparably higher densities maximize hyperconjugation Saturated fluorocarbons δ+ H H F H F F C F F C F F C F H H δ- * * F H H H * σC-F and σ C-F 2 x σC-F and σ C-F 2 x σC-H and σ C-F F anti gauche H Highly polarized No-bond resonance F F F H H H F F Unsaturated fluorocarbons vs. • Opposing contributions leads to variable reactivity H H H H C-H is better donor F H F F • Useful for explaining many phenomena δ- δ+ δ+ δ-

F F F Polarized π-bond Pauli repulsion N N N N Why ? F Stability of hybridization

ν = 1720 cm-1 ν = 1780 cm-1 109o 90o 2 x 90o O O Most H vs. F Why ? F > F > F H H H F stable 3 H H 3 2 H H H F sp sp sp Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Carbocations Carbanions • Carbocations are stabilized when bearing fluorine by • Carbanions are destabilized when bearing fluorine by mesomeric stabilization and destabilized when alpha to Pauli repulsion and stabilized when alpha to fluorine

fluorine More stable More stable F F C > C F C F C F > C Pauli repulsion • George Olah discovered several long-lived • Base-catalyzed deuterium exchange experiments show carbocations stabilized by fluorine from strong LA fluorine is least stabilizing halogen when bound directly

F Haloform Rate of exchange (105k)(l.mol-1s-1) SbF5 CHF Too slow to measure R R R R R R SbF6 3 o CHCl3 820 F -60 C F F CHBr3 101 000 SO2 R = aryl, alkyl CHI3 105 000 CHCl2F 16 CHBr2F 3600 Olah et al. J. Am. Chem. Soc., 1967, 89, 1268. CHI2F 8800 Hine et al. J. Am. Chem. Soc., 1957, 79, 1406. • Electrophilic aromatic substitution also demonstrates the counterintuitive stabilization of fluorine • Carbanions bearing fluorine will often adopt a pyramidal

H Br structures to avoid repulsion Br H Me Me Me Me Me Me Br 13 kcal/mol H F H F H more stable than H Me Me Me Me Me Me X X X Burdon et al. J. Chem. Soc., Perkin 1, 1979, 1205.

X Rel. Rate Br H • Carbanions with alpha are stabilized Me Me H 1 F F F F H F CF3 F 4.62 H F3C H F3C C F C C C C H Cl 0.145 Me Me 3 F F Br 0.062 F CF3 CF3 F Rel. rate D/H exchange 1 6 105 109 Approx. pKa 31 30 Mare and Ridd, Aromatic Substitution, Butterworths, London,4 1959. 20 411 Andreades, J. Am. Chem. Soc., 1964, 86, 2003. Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Carbon radicals • Fluorocarbons produce electrophilic radicals • Unlike other heteroatoms, fluorine offers little electrophilic radical stabilization to bound radicals, likely due to repulsion C8F17 C8F17 Least Most R add R stable CF3 < CH3 < CF2H < CFH2 stable R K rel OMe 1.41 Me 1.33 H 1.0 H H Cl 0.77 C F C F pyramidal CF 0.53 H H Me 3 Avila et al. J. Am. Chem. Soc., 1994, 116, 99. Me Carbenes H H C C F • Fluorine, a σ-acceptor and π-donor, leads to a very F F F F o By EPR at -108 C stable, singlet, ambiphilic carbenes Non-planar radical repulsion • Singlet state in energetically favored due to orbital Pasto et al. J. Org. Chem., 1987, 52, 3062. mixing and Pauli repulsion E - E Kawamura et al. J. Am. Chem. Soc., 1977, 99, 8251. Triplet singlet Worthington et al. (kcal/mol) H C: -9 • Adjacent fluorines (or other EWGs) are destabilizing, J. Phys. Org. Chem. 2 FHC: 15 but steric crowding can lead to kinetically stable 1997, 10, 755. F2C: 57 radicals

Least Most • π-MO description of singlet and triplet F2C: stable CF CH stable * * 3 2 < CH3 < F2CHCH2 < FCH2CH2 < CH3CH2 π π

Pross et al. Tetrahedron, 1980, 36, 1999. pz py p py • Steric crowding allows Scherer radical to be stable at rt z with present ! Observed by EPR vs. F CF sp2 3 F CF3 F3C CF3 F (σ) 2 F3C CF3 sp3 sp3 F π π F C F 3 F3C F F CF F 3 F CF3 F F F Stable Scherer radical 5 Scherer et al. J. Am. Chem. Soc., 1985, 107, 718. singlet triplet More stable Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Reactivity Nucleophilic aromatic substitution • Two-step mechanism of addition of nucleophiles to Displacement electron-poor arenes. Recent work suggesting a • As a nucleophile, fluoride reactivity increases with concerted mechanism in not operative. decreasing lattice energy Most Kwan et al. Nature Chemistry, 2018, 10, 917. nucleophilic CsF > KF > NaF ~ LiF X Nu X Nu (in aprotic ) NO2 NO2 Nu NO2 + X 2 • Fluoride is generally a poor leaving group for SN slow fast NO2 NO2 processes b/c of its low polarizability and strong C-F NO2 Meisenheimer bonds Faster Me complex F >> Cl > Br > I rate Rel. Rate of displacement of at 18oC Me X • Generally, O/N nucleophiles react faster than C/S b/c Reagent X = F X = Cl C = Br X = I Piperidine 1 68.5 17 800 50 500 Hard-Soft-Acid/Base MeONa/MeOH 1 71 3 500 4 500 • meta-fluorine stabilizes the Meisenheimer complex best X Nu Comparison of k /k Tronov et al. J. Russ. Phys. Chem. Soc., 1926, 58, 1270. R F H δ- δ- MeO-/MeOH, 58 oC ortho-F meta-F para-F • Lewis acids/Bronsted acids activated C-F bonds, as well derivatives R Pauli repulsion 57 106 0.43 δ- Pyridine derivatives 79 30 0.33 as hydrogen bonding solvents increase rate of R displacement due to strong H-F hydrogen bonding One R = F Chambers et al. J. Chem. Soc., Perkin Trans. 1, 1988, 255. Addition / Elimination • Bond polarization allows facile additions, and the lower • Regioselectivity can be predicted

rate of fluoride elimination relates to the higher bond Regioselectivity R For R = H, Me, CF3 For R = EDG strength of subst. of F F para meta Nu R EDG R Site + F F F F δ+ C/O Nu C/O C/O X H para F F X X Nu Me para F δ- CF3 para F F F δ+ δ+ F Fastest NH2 meta most F Br > Cl > F F rate OH meta activating fluorine EDG directing 6 Swain et al. J. Am. Chem. Soc., 1953, 75, 246. interactions overrides reactivity (2 x meta + 2 x ortho) Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Cycloadditions • 6-member rings are less common, and often contaminated • Fluorocarbons have an unusual propensity to form with [2+2] adducts

4-member rings F F F o H F F F F F 475 C 200 oC + F F F F + F F F F F F H F F F F F F 2 : 1 o SM Prd ΔH (kcal/mol) Ea (kcal/mol) Keq at 315 C Drisdale et al. J. Am. Chem. Soc., 1958, 80, 245.

-8 33 9000 • Fluorine does not significantly lower the LUMO of alkenes, but fluorinated substituents and strain does CF F O F 3 F 120 oC F F F F + F F F3C O 12 47 0.0056 F F ether, 16 h F F F F F F F 35 % 2 2 2 sp C-F 6 sp C-F Albekov et al. Bull. Acad. Sci. USSR (Div. Chem. Sci.), 1988, 37, 777.

Cheswick. J. Am. Chem. Soc., 1966, 88, 4800. Me F F F F F o Me • Mechanism is stepwise ([2π+2π] are thermally + 170 C F F disallowed) and involves formation of a diradical Me F F F 48 h Me intermediate; is not stereospecific F F 77 % Burton et al. J. Fluorine Chem., 1983, 22, 397. F CF 3 F CF3 F F F F F F F CF3 • Cycloadditions involving heteroatoms are also possible F F F F F F F F C F F F F heat 3 F3C F F3C F F F C F F CF 3 + 3 400 oC F F + mechanism ? F F CF3 F CF3 F CF F F 3 F F F F N F N CF F F F 3 F F F CF F 3 40 % F F F CF3 F F F CF3 Ratio depends on temperature Anderson et al. J. Chem. Soc. (C), 1969, 2559

Hauptschein, J. Am. Chem. Soc., 1958, 80, 842. 7 Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Photochemistry • will perform photocycloadditions • Unsurprisingly, fluoroalkenes with cyclic alkenes that form fluoroladderenes undergo a number of bizarre photochemical processes F F F F F F • Lemal has been a leading F F figure in the development, F F F F based on Fluoro “Dewar” F F F F F F 254 nm 254 nm benzene F F F F 254 nm F F 54 % singlet F F David M. Lemal Sket et al. J. Chem. Perkin. Trans. 1. 1987, 981. process F F F F Prof. emeritus Dartmouth Fluoro ‘Dewar’ Ph.D with Woodward MeO F benzene MeO F MeO F F F • Perfluorobicyclo[2.2.0]hex-1(4)-ene reacts with benzene F F F F F F F F F F F F F F F F 254 nm + C6H6 F H H H H F F F F o cyclohexane 140 C F F F F F F F F F F F 65 % 20 % 10 % He at al. Org. Lett., 2003, 4, 2135. Sket et al. Croatia chimica acta. 1079, 52, 387. • Bizarre behavior of Dewar thiophene-S-oxide • Many examples exist of polyenes forming cyclobutenes CF 3 CF O F C F C 3 S and polycyclobutenes 3 3 F3C 254 nm CF3COOOH S S F3C CF3 F F C CF F F F 3 F3C 3 F F F F F CF CF3 hv > 220 nm F 3 F F + Single 19F signal at -95 oC F F F F F Moves around ring at F F F F F F -1 O F 70 million s at rt ! S etc. F3C 1 : 1.1 F3C CF3 Jing et al. J. Org. Chem. 1994, 59, 1844. CF3 8 Bushweller and Lemal. J. Am. Chem. Soc., 1977, 629. Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Applications Why has nature rarely used fluorine ? • Surprisingly rare use of fluorine despite abundance Pharmaceuticals • Only 12 natural compounds contain C-F bonds • Fluorinated analogues of biological molecules have • Likely causes : become a popular methods of modifying pharmaceutical 1. Difficulty in forming C-F bonds agents 2. Subsequent enzymatic transformations in • Fluorine effects several necessary drug properties : plant/animals are inhibited by the presence of 1. Absorption C-F bonds 2. Membrane transport 3. Target binding (active site) Proposed causes for unreactivity of fluorine 4. Metabolism • F mostly present as insoluble salts • Size (compared with H) is not a dominant factor • F- is highly hydrated / weak nucleophilicity • Generally, F enhances the lipophilicity, acidity, solubility • F+ too difficult to form and stability of drug molecules, or be displacement and covalently attached (suicide inhibitor) One fluorinase enzyme exists in Streptomyces cattleya O O O F H O OH O N NH2 Me NH3 NH2 N N N N F C N HN 3 N F F N Me S O N N O N Ciproflaxacin Prozac Fluorinase (antibacterial) (anti-depressant) HO OH HO OH OH 5’-FDA O S-adenosylmethionine Me O HO OH F Me Me HN

F O N O H Fluoroacetate O O Toxin, inhibits OH Betamethasone 5-Fluorouracil Krebs cycle F H (anti-inflammatory) (anti-cancer) F 9 Likely suicide inhibitor O’Hagan et al. Nature, 2002, 416, 279. Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

Refrigerants Polymers • have become multi billion dollar industry • (CFCs) were introduced 60 years ago because of their unique properties and longevity to replace NH3 and SO2 gases • Most fluoropolymers are known for their : • Peak 1974, 900 000 tones of CFCs produced, principally • Chemical resistant CF2Cl2 and CHFCl2 • Thermal stability • However, the Montreal protocol in 1987 severely reduced • Low constant CFC production b/c of they decompose O3 into O2 • Low flammability Anesthetics • Low • Fluothane was the most common anesthetic in 1980, • Most are prepared by radical or suspension polymerization F F F F much better than the risks of older anesthetics (diethyl F Cookware,, F Optically clear, ether, chloroform etc.) waterproof F n n F O O used in • Now, Isoflurane, Sevoflurane and Desflurane are used F n clothing, medical F corrosive devices F C CF in the general quest for less readily metabolized PTFE 3 3 environments Teflon AF systems and faster recovery times of the patients F F Weather- F F F F Cl Cl F F F n resistant F F F coatings F F F F PVDF Membranes in Br O F O F O F F n F m F F F F F O F chlor-alkali F F F F O F Coatings, F F F cells Fluothane Isoflurane Sevoflurane Desflurane n S F HO O F flexible films O F Imaging technique PVF F • 19F-MRI (NMR) can be used Nafion • Isotopic 18F half-life is 109 minutes, decays by positron emission (measure by PET) • PET is especially useful for in-vivo studies (non-invasive) • E.g. 2-fluorodeoxyglucose is used to measure glucose metabolism OH PET HO O scanning HO agent 10 18F OH Burns / Xia group meeting Fluorocarbon fundamentals Mar. 29, 2019 Ben Boswell

ROMP polymers of fluoroalkenes • Surprisingly, Ru metathesis catalysts at high temp. is successful at preparing fluoropolymers

G-II n 140 - 180 oC F chorobenzene F Monomers :

F F F F F F F F F F F F F O O F F F F O F F F F F F F F F F3C F F F CF3

F F C F F 3 The end ! F F F OMe F F O O F F F F F F F F F F C F F F F F F F 3 F CF3 Takahira et al. (ASAHI glass). US2017/0335051. 2017.

• This method was recently extended to fluoroladderenes at modest temperature F F G-II LiAl(OtBu) H n F F 3 F F F F CHCl3 F F THF, 40 C F F F F 90 oC H H H H H H

56 % DP 300 D = 1.1 11