C-F Bond Formation Methods in Aliphatic Compounds

C-F Bond formation in aliphatic Compounds
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Dr. S.Iyengar, R & D Chennai, 14th JUly.
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We always find a better way
2011
C-F Bond formation in aliphatic

There are 2 ways in which organo- fluorine compounds can be prepared . A. One is to convert existing organo fluorine compound into another by group transformation CF3CH2CN
H2O/ H+
CF3CH2COOH
C-F bond are strong and are not cleaved by most of the reagents used for transformation of other groups
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B. Second way is to introduce fluorine at specific sites example:(CH3CH2CH2)3N ECF (CF3CF2CF2)3N
We do not cover the first type but would focus on the Second type only.
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In general organic reactions can be classified into: Substitution reaction Elimination reaction. Addition reaction. Rearrangement Or a combination of these to reach a goal. Synthesis of organo fluorine compound follow similar pattern but catalyst and reactant differ from other aliphatic halocompounds in one way or other. Substitution and addition rtn are by far most important for synthesis of organo fluorine compounds.
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General Methods of Fluorination

Fluorine Gas Hydrogen Fluoride Alkali Metal Fluorides Metal Fluorides Fluorination Electrophilic Transition Sulfur Tetrafluoride and Safer Equivalents Trifluoromethylating Agents
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Fluorination with Fluorine gas
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Sources of Fluorine
CaF2 (Fluorspar)
HF (anhydrous)
F2 (gas)
Metal Fluorides
Transition Metal Complexes
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Direct Fluorination using Fluorine Gas

Fluorine, F2, is a diatomic molecule existing as a pale yellow gas. It liquefies at 188oC to produce a yellowish orange liquid, and solidifies at 220oC to give a yellow solid. Its name derives from the Latin verb fluere (to flow) that explains the given name to fluorite (fluorspar) since CaF2 exhibits good fluxing abilities. Fluorine is the most reactive element, and the most powerful oxidizing element. It readily reacts with almost all organic and inorganic materials.
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Typically reaction with elemental fluorine is an exothermic, free radical chain process
CH4 F CH3 + H-F F2 CH3F + F
Further fluorination becomes progressively more difficult

Fy is an electrophilic radical, and therefore as we increase the fluorine content in the molecule, further fluorination becomes progressively difficult
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CF4 (difficult to proceed this far along)

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Reaction steps of Free radical

Initiation:F2 F2 + RH Propagation :-
. 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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Consider the thermodynamics of the reaction
C-H +F2
C-F
+H-F (H = -99kcal/mol
Compare this to C-H +Cl2 p C-Cl +H-Cl (H = -23 kcal/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.
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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.
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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
Again sufficient to smash C-C bonds when using elemental fluorine.
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Why HF is not used for Fluorine Generation?

Fluorine gas is generated by the electrolysis of anhydrous potassium bifluoride (KHF2, or KF.HF) in HF. The fluoride anion is oxidized at the anode to liberate F2 gas. At the cathode, protons are reduced to hydrogen gas.
(Best to make sure the two compartments are kept separate!)

Anhydrous HF has a very low electrical conductivity, and so cannot be used as the electrolyte by itself. Thats why the molten fluoride salt electrolyte is used.
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Some Industrial example CF3-CO-CF3 (Hexafluoroacetone is used for ANESTHETICS) CH3-CO- CH3
C3 H8
C3F8
(C3F8 is used in electronic industry for plasma etching )
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Fluorination using AHF
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Fluorinations using Hydrogen Fluoride
These can be divided into two sections

Halogen Exchange Reactions (HALEX)
Oxidative Fluorinations
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Halogen Exchange using Hydrogen Fluoride (HALEX)

C-X p C-F
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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Flourination using AHF A. Halogen exchange C- X to C-F

( Where X= Cl, main preoccupation commercially), Br, I
AHF/ SbCl5 using liquid phase methodology.
The order of reactivity of Sb Halide is SbF5>SbF3Cl2>SbF3/SbCl5
Example :CCl4 CCl3F CCl2F2 CClF3
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Flourination using AHF

AHF/ Chromia catalyst ( vapour phase)
Reaction at the surface of catalyst.
Active species is chromium oxyfluoride. Reaction at High temperature . Reaction of per-fluorination/ higher fluorination. Example :CCl3 CCl3 CFCl2- CCl3 CFCl2- CF2Cl CF3- CF2Cl
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Fluorination using AHF

B. In Allylic activated position
Allylic chlorine is exchanged more readily than chlorine in polychlorination. Vinylic chlorine is seldom exchanged. Example :-
CCl3CCl=CCl2 C6H5CCl3
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CF3CCl=CCl2 C6H5CF3
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Fluroro dehydroxylation - AHF

In general the classic reaction of R-OH + HX R-X + H2O
Fails or gives low yield when X- Cl, and when X- F tarry material is produced. Use of AHF in conjugation with Lewis base such as pyridine, THF improves the yield remarkably. The ease of handling gets improved due to solvent. Example :C8H17OH C8H17F
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Fluorination with Olah s Reagent

Fluoro Dehydroxylation :-

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
(CH3)2CHCH(NH2)COOH (CH3)2CHCHFCOOH + (CH3)2CFCH2COOH

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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.
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Examples of Electro chemical fluorination.

O H3C C Cl E C.F. O F3C C F H2O O F3C C OH
O H3C S Cl O
E.C.F.
O F3C S F O
H2O
O F3C S OH O tri ili i ry strong organi aci
N(CH3)3
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E.C.F.
N(CF3)3
shows no signi icant basic character - is used as an inert fluid

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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
Actually NiF3 was later shown to be NiIVNiIIF6

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N iF 3
/2 F 2
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E.g. allylic / benzylic chlorides
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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The Swarts Reaction

This reaction is industrially important in the manufacture of Refrigerants (i.e. CFCs / Freons).
, C
5
CCl
CCl 9%
CCl 9 %
CCl tr
Systems that dont easily form cations require a Lewis Acid Catalyst
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The Swarts Reaction

Since Fluorine is so electronegative and a powerful inductive electron withdrawing substituent, it makes successive Chlorines worse donors to the Lewis Acid catalyst (SbF5), hence halogen exchange becomes progressively difficult. There is also a decrease in steric assistance to ionization as each larger chlorine is replaced by a smaller fluorine.
+ 109.
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o
120o
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Industrial Use of Swarts Reagent

The Bayer Company developed a one-pot synthesis of trifluorotoluene from benzene based on this type of reaction
H F , S b F C
6
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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General Mechanistic Process:

R Cl + SbF5 _ + R Cl SbF5 (ionic) R+ (SbF5Cl)-
(concerted)
H-F
Cl R F SbF4
H-F
R-F + H+(SbF5Cl)-
H-F
H-Cl +
H+(SbF6)32
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Alternatives to using Elemental Fluorine

Transition Metal Fluorides Oxidation Fluorination
C H
C F
is a formal oxidation on the carbon

Some transition metal fluorides can accomplish this type of transformation, with cobalt trifluoride CoF3 being one of the most commonly used.
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Mechanism of Oxidative Fluorination

Co3+ goes to Co2+, i.e. Co (III) to Co (II), which is a gain of electrons. Cobalt is reduced the organic gets oxidized CoF3 is an Oxidizing agent.
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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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Saturated Systems
C H -1e C H -H+ C
Co(III) Co(II)
Co(III) -1e Co(II)
etc. C F
FC+
Recall 2CoF3
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+ C-H
C-F + H-F + 2 CoF2

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Unsaturated Systems
- 1e
-
- 1e
F
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14th JUly.
F
2011
F-
+
F
37
Dr. S.Iyengar, R & D Chennai,
Alkali Metal Fluorides for Creating C-F bonds

Typically:
F

C X
F C
Fluoride ion is a very poor nucleophile in aqueous solution, but a very strong nucleophile in aprotic solvents.
The difference is the solvation of the fluoride ion.
If the fluoride ion is solvated it is much less accessible to perform nucleophilic attack.
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Common Aprotic Solvents include:

H 3C n "g ly m es " n = 2 d ig ly m e n = 3 trig ly m e n = 4 te trag ly m e CH3 N s ul h o lan e (s u lfo la n ) CH3 S
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.
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Metal Fluoride Reactivity in aprotic solvents:

CsF > KF >> NaF > LiF
As the lattice energy of the solid increases the reactivity decreases. (CsF has the lowest lattice energy, whilst LiF has the larger lattice energy
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.
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Sulfur Tetrafluoride and Safer Equivalents

Sulfur Tetrafluoride is best known for its fluorodeoxygenation ability.
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.
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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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Reaction of Carboxylic Acids

The conversion of carboxylic acid to trifluoromethyl is the most demanding of the fluorodeoxygenation transformations The mechanism of this transformation is as above, with the reaction proceeding from carboxylic acid p acid fluoride p trifluoromethyl. Use of high temp and plenty of HF as solvent and Lewis acid is required to perform this transformation.
The technique is used in commercial synthesis of Desflurane ( CF3CHF-O CHF2) from CHCl2OCHClCOCl .
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Drawbacks of using sulfur tetrafluoride

It is a gas ( Boiling point -38 degC) Its inhalation toxicity is comparable to that of phosgene On exposure to moisture (air, skin) it liberates HF Reaction with SF4 usually requires HF as solvent / LA (which precludes use of glassware)
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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.
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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.
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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+
SF4 p(CH3CH2)2NSF3 + FSi(CH3)3
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DAST operates by a similar mechanism to that for sulfur tetrafluoride:
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Other Fluorinating agents

Whilst DAST is still the market leader of this type of reagent, safer versions of DAST are currently being marketed. E.g. BAST (CH3OCH2CH2)2NSF3
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.
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Trifluoromethylating Agents
Trifluoromethyl radicals can be generated by various means
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THANKS FOR YOUR ATTENTION.
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C-F Bond Formation Methods in Aliphatic Compounds

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C-F Bond Formation Methods in Aliphatic Compounds

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C-F Bond formation in aliphatic Compounds

Dr. S.Iyengar, R & D Chennai, 14th JUly.

C-F Bond formation in aliphatic

Dr. S.Iyengar, R & D Chennai, 14th JUly.

C-F Bond formation in aliphatic

Dr. S.Iyengar, R & D Chennai, 14th JUly.

C-F Bond formation in aliphatic

General Methods of Fluorination

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Fluorination with Fluorine gas

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Transition Metal Complexes

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Direct Fluorination using Fluorine Gas

Further fluorination becomes progressively more difficult

CF4 (difficult to proceed this far along)

Reaction steps of Free radical

Slide 7/2/2011 -10

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Consider the thermodynamics of the reaction

Compare this to C-H +Cl2 p C-Cl +H-Cl (H = -23 kcal/mol

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Again sufficient to smash C-C bonds when using elemental fluorine.

Slide 7/2/2011 -13

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Why HF is not used for Fluorine Generation?

(Best to make sure the two compartments are kept separate!)

Slide 7/2/2011 -14

Dr. S.Iyengar, R & D Chennai, 14th JUly.

(C3F8 is used in electronic industry for plasma etching )

Slide 7/2/2011 -15

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Fluorination using AHF

Slide 7/2/2011 -16

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Fluorinations using Hydrogen Fluoride

These can be divided into two sections

Slide 7/2/2011 -17

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Halogen Exchange using Hydrogen Fluoride (HALEX)

Slide 7/2/2011 -18

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Flourination using AHF A. Halogen exchange C- X to C-F

Example :CCl4 CCl3F CCl2F2 CClF3

Slide 7/2/2011 -19

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Flourination using AHF

Fluorination using AHF

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Fluroro dehydroxylation - AHF

Fluorination with Olah s Reagent

Slide 7/2/2011 -23

Dr. S.Iyengar, R & D Chennai, 14th JUly.

(CH3)2CHCH(NH2)COOH (CH3)2CHCHFCOOH + (CH3)2CFCH2COOH

Examples of Electro chemical fluorination.

O F3C S OH O tri ili i ry strong organi aci

shows no signi icant basic character - is used as an inert fluid

Dr. S.Iyengar, R & D Chennai, 14th JUly.

Actually NiF3 was later shown to be NiIVNiIIF6

We always find a better way

E.g. allylic / benzylic chlorides

Slide 7/2/2011 -28

The difference is the solvation of the fluoride ion.