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Slide 7/2/2011 -1
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CF3CH2COOH
C-F bond are strong and are not cleaved by most of the reagents used for transformation of other groups
Slide 7/2/2011 -2
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We do not cover the first type but would focus on the Second type only.
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Slide 7/2/2011 -5
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Slide 7/2/2011 -6
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Sources of Fluorine
CaF2 (Fluorspar)
HF (anhydrous)
F2 (gas)
Metal Fluorides
Slide 7/2/2011 -7
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Typically reaction with elemental fluorine is an exothermic, free radical chain process
CH4 F CH3 + H-F F2 CH3F + F
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. 2F .+ R
HF
. +F
(H
= 158kj mol-1
. RH + F
. + F2 R
. R
RF
. +F
+ HF
Termination :-
. + F. R
. R
. +R
RF R2
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C-H +F2
C-F
+H-F (H = -99kcal/mol
Bear in mind that a C-C bond = ~70kcal, so the heat given out is enough to break C-C bonds (i.e. destroy the molecule). So we need to control the heat evolved.
Slide 7/2/2011 -11
Dr. S.Iyengar, R & D Chennai, 14th JUly.
11 .
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How can we use fluorine gas? We can achieve this through dilution of the F2 in an inert gas.( N2, He , Ar) 1-3% F2 in N2. One may use fluorinated solvents like CCl3F or a blend of CCl3F with CHCl3. Temp of reaction -40 to -78 deg C This enables fluorinations to proceed in normal lab settings.
Slide 7/2/2011 -12
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Addition of Fluorine to C=C Also bear in mind that addition of F2 to double bonds is also highly exothermic. C=C + For Cl2 F2 p CF-CF((H = - 104kcal/mol)
(H = -31kcal/mol
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Some Industrial example CF3-CO-CF3 (Hexafluoroacetone is used for ANESTHETICS) CH3-CO- CH3
C3 H8
C3F8
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is not oxidative, just a formal nucleophilic substitution. Most commonly C-Cl p C-F This process works best for systems able to easily form carbocations
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Active species is chromium oxyfluoride. Reaction at High temperature . Reaction of per-fluorination/ higher fluorination. Example :CCl3 CCl3 CFCl2- CCl3 CFCl2- CF2Cl CF3- CF2Cl
Slide 7/2/2011 -20
Dr. S.Iyengar, R & D Chennai, 14th JUly.
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CCl3CCl=CCl2 C6H5CCl3
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CF3CCl=CCl2 C6H5CF3
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Olahs Reagent is Pyridinium Poly hydrogen fluoride (PPHF) C6H5NH+(HF2)-. It is also known as TAMED HF. It is normally encountered as C6H5N. 9HF . This is a mixture of 30 :70 %w/w of pyridine to HF. It is quite stable and does not lose HF upto 50 deg C. Reacts with 30 alcohol more readily at 0 deg c, 20 at 20-50, 10 Need to add fluoride NaF for reaction to proceed smoothly. CH3CH2CH(OH)CH3 CH3CH2CHFCH3
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Deaminative Fluorination
Nitrogen Replacement. C-NH2 C- N2+ C-F
Provides simple convenient route for flurocarboxylic acid Reagent used is AHF/ NaNO2 & Pyridine . Skeletal rearrangement ( cationic ) occurs giving beta fluoro carboxylic acid . High Pyridine : HF ratio favors alpha fluorocarboxylic acid
C2H5CH(NH2)COOH C2H5CHFCOOH
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Oxidative Fluorinations
Electrochemical Fluorination, E.C.F. (Simons Cell)
Using a solution of hydrogen fluoride, electrolysis is performed at a voltage lower (5-6V) than that required to generate Fluorine gas. At the Nickel anode (oxidation occurs at the anode): C-H p C-F
The reaction is usually performed at 0oC, and solubility in HF can be a limiting factor. Fluorine is not generated at the anode, but hydrogen is generated at the cathode.
Slide 7/2/2011 -25
Dr. S.Iyengar, R & D Chennai, 14th JUly.
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O H3C S Cl O
E.C.F.
O F3C S F O
H2O
N(CH3)3
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E.C.F.
N(CF3)3
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The Simons cell process is believed to involve high valency Nickel Fluorides (NiF3 and NiF4). Indeed workers were able to generate NiF3 and NiF4 in situ, and these were demonstrated to be powerful fluorinating agents
K 2 N iF 6 2 F3 a H -F < -2 0 o C N iF 4 2 KBF4
0 oC
N iF 3
/2 F 2
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P h-C C l 3
H -F 40 C
o
P h-C F 3
P h3C C l
H -F R .T .
P h3C F
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CCl
CCl 9%
CCl 9 %
CCl tr
Systems that dont easily form cations require a Lewis Acid Catalyst
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+ 109.
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o
Dr. S.Iyengar, R & D Chennai, 14th JUly.
120o
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C C l4
-C F
C C l3
Cl
L .A . (H F o r S b F 5 ) H
+ C C l3 -H +
e tc . L .A .- C l -
H F, SbF5
CF3
C C l3
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(concerted)
H-F
Cl R F SbF4
H-F
R-F + H+(SbF5Cl)-
H-F
H-Cl +
H+(SbF6)32
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C H
C F
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Cobalt trifluoride is generated by reaction of Cobalt Difluoride with elemental Fluorine. 2CoF2 + F2 2CoF3
For CH p C-F, (H = - 58 kcal/mol, which is much less exothermic than direct fluorination
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Dr. S.Iyengar, R & D Chennai, 14th JUly.
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Saturated Systems
C H -1e C H -H+ C
Co(III) Co(II)
etc. C F
FC+
Recall 2CoF3
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+ C-H
Dr. S.Iyengar, R & D Chennai, 14th JUly.
2011
Unsaturated Systems
- 1e
-
- 1e
F
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14th JUly.
F
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F-
+
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F
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F
C X
F C
Fluoride ion is a very poor nucleophile in aqueous solution, but a very strong nucleophile in aprotic solvents.
If the fluoride ion is solvated it is much less accessible to perform nucleophilic attack.
Dr. S.Iyengar, R & D Chennai, 14th JUly.
38 .
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These are solvents without protic hydrogens (esp. O-H, N-H, etc)
H 3C N C H CH3 . .F . H 3C N C CH3 CH3 . .A .
N.
.P .
They have a high dielectric constant. (i.e. polar) They act by solvating the metal cation.
Slide 7/2/2011 -39
Dr. S.Iyengar, R & D Chennai, 14th JUly.
39 .
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Or CsF has the free-est fluoride ion). Potassium fluoride is the most frequently used fluoride ion source based on the combination of cost and availability versus its reactivity.
Slide 7/2/2011 -40
Dr. S.Iyengar, R & D Chennai, 14th JUly.
40 .
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R OH O R R'
R F
R CF2-R' R CF3
R CO 2H
SF4 by itself is not a fantastic fluorinating agent, but in the presence of hydrogen fluoride it is highly active.
Slide 7/2/2011 -41
Dr. S.Iyengar, R & D Chennai, 14th JUly.
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Reaction of Alcohols
The mechanism of R-OH p R-F can be represented by the following:
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The technique is used in commercial synthesis of Desflurane ( CF3CHF-O CHF2) from CHCl2OCHClCOCl .
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SF4 Alternatives
Recently, friendlier fluorodeoxygenation reagents have become commercially available. These are really just substituted sulfur fluorides. The most common one being DAST (Diethylaminosulfur trifluoride). (CH3CH2)2N-SF3 DAST DAST is a milder fluorinating agent that can convert hydroxyl to fluorine and carbonyls to CF2s. It cannot convert carboxylic acids to trifluoromethyls.
Slide 7/2/2011 -45
Dr. S.Iyengar, R & D Chennai, 14th JUly.
45 .
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DAST
DAST is a liquid that is stable to distillation, and can be stored in plastic bottles, and is stable in dry conditions at room temperature or with refrigeration for long periods of time. It has a boiling point of 45-46 degree C at 10mm Hg. DAST will decompose at 50oC, and can explode if heated to much higher temperatures . Normal reaction is done lower than 20 deg C in presence of solvents like MDC, Toluene or THF. It is highly moisture sensitive. It is widely used in carbohydrate chemistry for converting OH to F.
Slide 7/2/2011 -46
Dr. S.Iyengar, R & D Chennai, 14th JUly.
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Preparation of DAST
DAST is prepared by reaction of sulfur tetrafluoride with diethylaminotrimethylsilane at 78oC, followed by warming to room temperature, and then distillation.
(CH3CH2)2NSi(CH3)3+
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Bis(2-methoxyethyl)aminosulfur trifluoride. BAST is thermally more stable and decomposes less exothermically and with less gaseous byproducts.
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Other Fluorinating agents TAS Fluorides Modification of the DAST preparation can lead to a useful alternate product: SF4 + (CH3CH2)2NS(CH3)3 p DAST SF4 +3 (CH3)2NS(CH3)3 p ((CH3)2N)3S+ (CH3)3SF2Tris(dimethylamino)Sulphonium (TAS) salts are usually very soluble in organic solvents. The (CH3)3SF2- anion acts as a fluoride ion source.
Slide 7/2/2011 -50
Dr. S.Iyengar, R & D Chennai, 14th JUly.
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Trifluoromethylating Agents
Trifluoromethyl radicals can be generated by various means
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