Fluoro-alkane, -alkenes, -alkynes and –aromatics
Fluoroalkanes
Properties of fluoroalkanes Consider these typical bond strengths:
C-C bond 88kcal/mol
C-F bond 111kcal/mol
C-H bond 106kcal/mol
This implies that the carbon – carbon bonds are the weakest link in fluoroalkanes.
1 Features to bear in mind:
(i)Bond Strengths tend to increase as the total number of fluorines increases
I.e.
Bond strengths
F F F F F < < F
C-F bond shortens (strengthens) as more F's are added
2 The C-F bond shortens (gets stronger) as more fluorines are added due to an increase in back bonding (halo effect).
BDE
Fluorine makes the atoms close to it bond stronger also !!
↑ shorter ↑ stronger no significant changes
Some C-C bond strengthening also occurs on substitution of F for H.
For example the CF3-CH2CH3 bond is ~5kcal stronger than the CF3CH2-CH3 bond.
(i)-(CF2)n- is more stable than -(CH2)n- due to better chemical stability.
PTFE shows resistance to oxidation and microbial attack. (Generally related to BDE’s of C-H and C-F). 3 (iii) Electron Pair Repulsions (Intramolecular) are important to PTFE.
1,3 repulsions force the F atoms out of linearity, which is in contrast to the hydrogen containing polymer analogue.
4 Boiling Points Fluorocarbons are obviously heavier than their hydrocarbon counterparts, and thus we might initially expect them to have correspondingly higher boiling points.
However, the boiling points of hydrocarbons and perfluorocarbons are very similar.
(B.Pts in oC) # of Carbons 1 2 3 4 5 6 FC -128 -78 -38 -1 29 57 HC -161 -88 -42 -0.5 36 69
The increase in molecular weight that increases the boiling point, therefore must be offset by the decrease in attractive intermolecular bonding forces in the fluorocarbon systems.
(I.e. the electron pairs on fluorines in one molecule have a tendency to repel the other fluorinated molecules).
5 Surface properties Fluorinated solids / surfaces display unusual properties.
PTFE has a coefficient of friction described as “wet ice sliding on wet ice”.
This low friction and oil repellency is almost certainly due to the electron pair repulsions.
Chemical Inertness The electron clouds of the fluorines “screen” the carbon atoms of the chain, and thus discourage the approach and attack of incoming reactants. (The carbons are the weakest link).
Thus fluorocarbons find uses as inert fluids (see later).
Carbon tetrafluoride is fantastically stable and inert.
But the hydrolysis of CF4 is predicted to be exothermic by 73kcal/mol. (i.e. very thermodynamically favorable).
6 So it is a large kinetic barrier to hydrolysis (i.e. a high activation energy) that causes the stability.
In fact under the right conditions perfluorocarbons like PTFE can generate a lot of heat (e.g. for use in pyrotechnics or car airbag inflation).
Usually this is achieved using metals → metal fluorides; an exothermic reaction).
Solubility Perfluorocarbons have a profound ability to dissolve partially fluorinated compounds.
Also certain fluorocarbons have excellent oxygen and nitrogen solvating ability, and prompted their application as artificial blood.(“Oxygen transport fluids”)
7 Reactions of Perfluorocarbons Generally perfluorocarbons are very inert and unreactive.
The only reaction they are prone to undergo, usually under forcing conditions, is Defluorination
(Note that in hydrocarbon systems, reduction = increasing saturation In fluorinated systems, reduction = increasing unsaturation)
Birch Reduction
Heating with strong reducing agents (electron donors) can afford defluorination.
CF3 CF3 Fe F F 500oC
These include zero valent metals and also organic electron transfer agents, like Thiolate. 8 The product with Thiolate anion was a little unexpected.
SPh SPh PhS- PhS SPh F F PhS SPh SPh SPh
9 Electron donation to Perfluorodecalin gives a radical anion, which expels fluoride anion to leave a tertiary radical.
Further reduction produces an anion which expels fluoride ion to generate a new C=C double bond.
This process continues until pefluoronaphthalene is generated.
As you will see later, such compounds are prone to nucleophilic attack (more precisely, Nucleophilic Aromatic Substitution), and Thiolate, being a good nucleophile, ends up substituting at every fluorinated position.
10 Fluoroalkenes
Unsaturation tends to increase reactivity of fluorocarbon systems.
E.g. CF3
F3C CF2 FF F3C PerFluoroIsoButene Perfluoromethyldecalin
PFIB is ten times more toxic than phosgene, whereas perfluoromethyldecalin is used as artificial blood. (A slight difference !!!)
11 Preparation of Fluoroalkenes
Synthesis of CF2=CF2 HF / SbF5 Industrially: CHCl3 CHF2Cl Pt, 700oC 2 CHF2Cl F2C=CF2
via carbene :CF2 dimerisation
H-Cl
Laboratory: By controlled heating of PTFE under vacuum, you can trap TFE.
Heat, vacuum PTFE F2C=CF2
This is a unique “unzipping” of a polymer back to a monomer.
12 At greater temperatures (700°C) and pressures, higher mass compounds are formed.
PTFE → CF2=CF2 + CF2=CFCF3 + CF2=C(CF3)2
F2C=CF2 HFP F2C=CF2 :CF2 F2C=CFCF3
:CF2
PFIB F2C=C(CF3)2
13 HexafluoroPropene HFP is a very important fluoroalkene for synthetic reactions since it does not homopolymerise (one of the few).
Commercially is produced by the controlled pyrolysis of CF2=CF2 (see previous).
In the lab it can be generated via the following synthetic scheme:
O E.C.F. O 1) H2O O F2 F2 C C 2) NaOH Cl HF F3C C F F3C C O- +Na F2 F2
heat -CO2
- F - F F F CCF2 C F C F3C CF2 3 _
14 Reactions of Fluorinated Alkenes Fluorinated alkenes are typically electrophilic, and therefore they react readily with nucleophiles.
E.g.
The reaction can either be nucleophilic addition or substitution.
Notice that in both cases, this reaction is Regiospecific.
(CH3O- attached to the CF2 end).
It is important to be able to explain what factors influence the reactivity of the fluoroalkenes, and thus why these reactions are regioselective. 15 General Rules for Ionic Reactions of Fluoroalkenes
F is more Cl δ+ reactive δδ+
than _ CCF strongly stabilizing
inductive withdrawal CF offset by lp repulsions
This highlights the different substituent effects of “fluorine” and “fluoroalkyl”. 16 Orientation of Attack
The nucleophilic reactions are very specific for attack at the terminal =CF2 group.
If we consider the two possible intermediate anions which would be produced by attack at either end of HFP, and consider their relative stabilities, we can explain the regioselectivity of these reactions.
The RHS reaction has two favorable fluoroalkyl stabilizations and one fluorine destabilization
The LHS reaction has one favorable fluoroalkyl stabilization and two fluorine destabilizations.
Clearly the RHS reaction pathway is preferred.
17 This also explains the following regiochemistry with CTFE:
- Cl Nuc- F Nuc - F Cl 2C CF C NucFC C F CFCl F _ F
Relative Reactivity Among Fluoroalkenes
CF2=CF2 < CF2=CFCF3 < CF2=C(CF3)2 TFE HFP PFIB Their corresponding intermediates (and approximately their transition states) are:
→ Increasing in Anion stability → Which show an increasing stability.
Hence PFIB is more reactive than HFP than TFE.
(PFIB reacts with neutral methanol). 18 Nucleophilic Epoxidation
Sodium Hypochlorite (NaOCl) is a good nucleophilic epoxidising agent (Recall mcpba is an electrophilic epoxidising agent)
19 “Mirror Image” Chemistry
Reactions with Fluoride Ion create a Mirror Image Organic Chemistry. (Nothing to do with chirality!)
- (CF ) C- Chemistry Compare: F F2CC(CF3)2 3 3
+ Chemistry H H2CC(CH3)2 (CH3)3C+
Oligomerisation Alkenes can be polymerized by acid, whereas fluoroalkenes can be oligomerised using fluoride ion.
20 And even for the generation of strained bicyclic systems.
Such systems can give rise to long lived anions.
E.g. F CsF _ F F Cs+ F
21 The anions can be observed at low temperature by 19F NMR.
Negative sigma complexes can be formed and observed by NMR.
E.g.
FF N N N N F CsF _ N FFN Cs+
22 Negative Friedal Crafts Processes Fluorinated systems can be used for a process analogous to FC alkylations, but using anions / nucleophiles instead of cations / electrophiles. E.g. CF3 F3C CF F F- N F2CCFCF3 (CF3)2FC- F N
C3F7 C3F7 C3F7 C3F7 C3F7- F F F N C3F7 N C3F7 C3F7 N C3F7 thermodynamic kinetic
(See fluoroaromatic section later for more detail.) 23 Electrophilic Attack On Fluorinated Alkenes
Consider the following reaction:
F3C H HSO3F CF CH CH (DIMER) 3 2 H CF3 H3C H
When the reaction was performed with Deuterio-fluorosulfonic acid, there was no D incorporation.
F3C H DSO3F CF CH CH 3 2 H CF3 H3C H
This implies the mechanism does not involve proton (or D+) transfer from the acid.
24 Here there was no change in the location of the deuterium, which again implies that the reaction is induced by the acid, but there is no H+ transferred.
F3C H HSO3F CF CD CH 3 2 D CF3 H3C D
...... So how does this reaction proceed?
25 26 Notice that the +ve charge stays well away from the powerfully electron withdrawing CF3 group.
There is a Hydrogen shift (hydride, :H-) to produce a more stable allylic cation.
Certain fluorinated cations are observable by NMR.
E.g.
F CF CF SbF5 F 3 F pC H OCH SO , -60oC 6 4 3 2 + F F OCH3
The NMR shifts imply (confirm) that the +ve charge lies almost totally at C1 and C3.
27 Notice that for a positive charge:
α Fluorine is strongly stabilizing β Fluorine is strongly destabilizing
Therefore we would (correctly) predict that the cation derived from HFP is less stable than that derived from pentafluoropropene.
F F F less stable CF3CF CF2 + F F +ve charge at C1 and C3, so an F at C2 is a β F = destabilizing H F F more stable CF3CH CF2 + F F 28 Free Radical Additions
For reactivity towards free radicals we observe:
CHCl=CHCl << CH2=CH2 << CCl2=CH2
This implies that substituents tend to enhance the reactivity towards free radical addition if the substituents are at the same end of the double bond.
This is a combination of steric and electronic factors.
For the radical addition of HBr to fluoroethene: H-Br H CCFH 2 Peroxides BrCH2-CFH2
(ROOR → 2 RO• then HBr→ ROH and Br• which adds to the alkene)
29 This regiochemistry indicates an intermediate radical of BrCH2CFH•
And thus it seems that an α F is more stabilizing to radicals than an α H.
Tetrafluoroethene can be easily polymerized under free radical conditions (which is unusual for a tetrasubstituted ethene).
In C2F4 (CF -CF ) F2CCF2 InCF2-CF2 2 2 n PTFE
The ΔH for polymerization for TFE is about 17kcal/mol more exothermic than for ethene. (This has to do with hybridization - see later).
30 Other Commercial Polymers Commercial homopolymers are
PVDF -(CH2CF2)-n
Kel-F. -(CF2CFCl)-n
HFP will not homopolymerize (for steric reasons), but can form useful commercial co-polymers with TFE, and VDF:
FEP -(CF2CF2)-x-(CF2CFCF3)-y
Viton -(CH2CF2)-x-(CF2CFCF3)-y
31 Cycloaddition Reactions
Fluoroalkenes show an unusual propensity for forming 4 membered rings via thermal 2+2 cycloaddition.
E.g. o 200 C Cl Zn F F2CCFCl F Dechlorination Cl
We shall discuss the matter of why the “head to head” dimer is formed later.
Hydrocarbon ethene derivatives do not form in analogous fashion.
(Recall that a 2+2 concerted cycloaddition is thermally forbidden).
A common feature of successful 2+2 cycloadditions is a terminal =CF2 group.
32 Mixed Cycloadditions can occur: E.g. F F2CCF2 F
H2CCH2 F F
The observed stereochemistry of these reactions reveals the likely mechanism.
200oC F2CCF2 F2C CF2 F2C CF2 and DD H H H D CC DD DH H H
pure mixtureof isomers syn & cis anti
The fact that stereochemistry is lost implies a diradical pathway as the most likely mechanism. (i.e.NOT CONCERTED). 33 The fact that stereochemistry is lost implies a diradical pathway as the most likely mechanism.
F CCF concerted F C CF 2 2 2 2 stereochemistry DD H H maintained CC DD H H
stepwise diradical
Rotation F C CF2 F2C CF2 F2C CF2 2 and DHC CHD before H H H D closure DD DH
stereochemistry lost
34 This diradical pathway helps explain why we observed the head to head dimer of CTFE earlier.
Cl CFCl F2C 2 CF2=CFCl F F2C CFCl Cl
This implies that to a radical center, an α Chlorine is more stabilizing that an α fluorine.
We will later prove that the stability order is:
CCl > CF > CH
more stable 35 We also see a surprising difference in butadiene / cyclobutene isomerization between fluorocarbon and hydrocarbon systems.
Δ F6 F
whereas
Δ
This behavior will be explained later.
Note that [2+2] thermal cycloaddns can and do occur, BUT NOT IN A CONCERTED PERICYCLIC MANNER.
36 For compounds with a terminal =CF2, (2+2) cycloadditions generally proceed in preference to (4+2) cycloadditions.
475oC CF2 CF2 CF2 CF2 CF CF2 2
(60%) (30%)
2+2 4+2
Another example is very revealing:
80oC CCl2 CCl2 CF 2 CF2 F2C CCl2 F2C CCl2
(2%) (15%) (83%)
2+2 2+2 4+2
37 Clearly the (2+2) is preferred over the (4+2) cycloaddition.
The ratio of the (2+2) cycloadducts reflects the stability of the diradical intermediates.
Firstly the dienophile generates a dichloro (not difluoro) radical.
CCl2 F2C F2C CCl2 CCl2 CF2 (15%)
CCl2 F2C F2C CCl2
more stable allylic radical (83%)
The allylic radical with a methyl on C-3 is the more highly substituted in the important places (i.e. C-1 and C-3), and thus is more stable, and leads to the major product.
38 Thermodynamic Effects of Perfluoroalkyl Groups
There is a strong thermodynamic driving force for Fluorine to be attached to an atom of high p character.
I.e. F prefers a carbon to be sp3 rather than sp2 rather than sp.
C F prefered over CF
sp2 sp3
Recall the exothermicity of the polymerization of TFE to PTFE was almost 17kcal/mol higher versus the non-fluorinated ethene.
This is probably attributed to the relief of electron/electron repulsions in the starting fluoroalkene to the saturated product polymer.
39 A fluorine on an sp2 (C=C) both inductively withdraws and resonance donates.
These opposing features essentially cancel each other out, and F-C=C and H-C=C are about the same bond energy.
Notice the difference between F and RF as double bond substituents:
RF-C=C significantly lower the orbital energies (stronger bond).
In double bond competition reactions F-C=C is slightly more electron rich than H-C=C. (F is better π donor than σ withdrawer). H F O O H CF2 F H CF2 H F F
DA is best with e- rich diene and e- poor dienophile, so we can tell which is more e- poor. 40 Recall perfluorobutadiene / cyclobutene.
Δ F 6 F
In this reaction we are reducing the number of sites where F is bound to sp2 carbon
(That’s 4 → 2)
Another example of this is the fluoride ion catalyzed isomerization of hexafluorobutadiene to hexafluorobutyne.
CsF F6 F3CCFCC 3 (100oC)
H+ H3CCHCC 3
ΔH = + 10kCal/mol 41 The fact that hybridization is so important to fluorocarbons is shown by the following experimentally observed bond angles for difluoromethylene groups: sp3 = 109.5o sp2 = 120o
“sp3” C-F { “sp2”C-F { {
This implies even sp2 C-F’s are not really sp2, but more “sp3-like”.
All the above examples highlight the fact that fluorine prefers not to be attached to unsaturated carbon.
42 Fluoroalkynes By definition, a fluoroalkyne has Fluorine bound to an sp hybridized carbon.
Fluorine prefers high p character atoms (e.g. sp3), thus sp is highly disfavored.
Consequently fluoroalkynes are generally very reactive. (I.e. potential for boom!)
It is tempting to attribute this to π / lone pair electron repulsions between the triple bond and fluorine atom.
sp C-F bond = short = e-s all close together
Difluoroethyne is “treacherously unstable”, and whilst it has not been isolated, it has been trapped from the pyrolysis / photolysis of difluoromaleic anhydride. 43 Monofluoroethyne polymerizes rapidly to give trifluorobenzene.
O F F Δ trimerization O FH H FF O dangerously explosive
44 Bulky groups can be used to help (kinetically) stabilize reactive compounds. Dewar Benzene t-Bu t-Bu t-Bu t-Bu Br CH3 - HBr x 3 H3C C CCF HF CH 3 FFF
x 3 Δ
t-Bu
t-Bu t-Bu F F t-Bu t-Bu
t-Bu F FF Benzvalene F
Δ
F This lead to the formation of stable t-Bu t-Bu Dewar benzenes and benzvalene
FF t-Bu 45 In contrast to fluoroalkynes, fluoroalkyl substituted alkynes are very stable.
RF CCRF
Hexafluorobutyne is the most readily (commercially) available.
via allylic cation Cl Cl2C SbF3, Cl2, HF Cl3C Cl F3C Cl CC Cl CCl Cl CF Cl CCl2 3 3
allylic fluorination Zn 1,4 Cl2 addn 1,2 Dechlorination
F3C CCCF3
46 Reactions of Hexafluorobut-2-yne 1) Trimerization Heating the alkyne to 400oC generates hexakis(trifluoromethyl) benzene.
CF3 F3C CF3 3 F3C CCCF3
F3CCF3 CF3
This benzene derivative shows some interesting chemistry, including the fact that is able to form numerous benzene isomers upon photolysis.
47 2) Nucleophilic Attack The powerful electron withdrawing groups render the triple bond electrophilic.
This means these systems react with nucleophiles.
Reaction with Methoxide gives products of nucleophilic addition.
48 Fluoride ion reacts to give carbanions that can either be trapped, or continue to oligomerize / polymerize.
49 The polymer generated by anionic polymerization is a trifluoromethyl-polyacetylene.
It is unusual that this conjugated polymer is white – normal conjugated polyenes are colored.
UV spectra indicate that the double bonds in this polymer are not conjugated.
This is attributed to the steric requirements of the bulky trifluoromethyl groups, which force the polyene out of planarity.(so cannot be conjugated)
(Side note about the trifluoromethyl group and sterics: Steric size and steric effect are two different things:
Steric size is an intrinsic molecular property, an absolute term.
Steric effect is an extrinsic property, and depends on the nature of the transition state for a particular process.
50 *
EQ
AX
Steric parameters for the trifluoromethyl group shown above, imply that the CF3 group is much larger than a methyl, and in fact has a steric effect, at the least, comparable to that of a hydrocarbon iso-propyl group.)
51 …Back to nucleophilic additions to C4F6. Addition of allyl alcohol is accompanied by the Claisen rearrangement.
OH F3CO F3CO F3CCFCC 3 NaOH HCF3 HCF3
The classic Claisen Rearrangement is
allyl aryl ether → ortho allyl aryl
•• ••
52
A 6 electrocyclic process.
Tautomerization of the ketone (actually a dienone) to the more stable aromatic enolic form, which we know as a phenol.
The acyclic version is:
53 There is no reason for keto/enol tautomerization in the acyclic case, and the product is a rearranged ketone.)
This type of reaction is correctly labeled as a concerted pericyclic [3,3] sigmatropic rearrangement.
A sigmatropic rearrangement is defined as migration, in an uncatalyzed intramolecular process, of a σ bond, adjacent to one or more systems, to a new position in a molecule, with the π systems becoming reorganized in the process.
The order of a sigmatropic rearrangement is expressed by two numbers set in brackets: [i, j].
These numbers are determined by counting the atoms over which each end of the σ bond has moved.
54 R R 2 2 1 O 3 1 O 3 sigma bond new sigma bond that breaks 1 3 1 3 2 2 a [3,3] sigmatropic rearrangement
Each of the original termini is given the number 1.
55 Cope Rearrangement ([3,3] sigmatropic )
56 57 3) Cycloaddition Reactions These fluoroalkyl-alkynes are also reactive dienophiles for cycloaddition reactions.
58 Fluoro-aromatic Systems
(Fluoroaromatic is used to refer to aromatic compounds with a C-F on the aromatic ring.
C6H5F is a fluoroaromatic
CF3-C6H5 is fluoroalkylaromatic.)
Fluoroaromatic compounds have only recently seen a large growth in their commercial applications.
Fluoroaromatic compounds now are considering key components in the pharmaceutical, agrochemical, dye and advanced materials industries.
Generally speaking there is not a great “universal” route to making fluoroaromatics.
59 There are a variety of different ways that are capable for synthesizing molecules with one or two ‘aromatic’ fluorines:
a) Elemental Fluorine / Electrophilic N-F reagents
b) Balz-Schiemann
c) Fluoride anion HALEX
To create perfluoro aromatics, the strategy of Perfluorination (saturation) followed by reduction (aromatization) is still the best.
d) High Valency Metal Fluorides (followed by reduction)
e) ECF (followed by reduction)
60 We have seen examples of most of these in the previous chapters:
a) Direct fluorination with F2 / N2, or Selectfluor:
61 c) Halex – nucleophilic aromatic substitution using fluoride.
The Sanger Reagent 2,4-dinitrofluorobenzene, C6H3F(NO2)2, used to identify the end amino acid in a protein chain. It is named after Frederick Sanger (1918- ).
N A S
why this N ?
62 The two nitro groups enable nucleophilic aromatic substitution to occur very easily.
NO2 NO2
KF
NO2 NO2 Cl F
This compound can be made simply via NAS with fluoride ion.
63 Without appropriate activating groups, multiple exchanges require very forcing conditions indeed.
KF Cl F autoclave
Cl Cl KF Cl F + F N autoclave N N
major product hard to force it with Cl meta to this product to N remaining
d+e)
CH3 CF3 CF3
CoF3 Fe F F F F High Temp. 64 b) The Balz-Schiemann Reaction
Covered in organic II.
+ - + - NO2 NH2 N2 Cl N2 BF4 F
NaNO2 HBF4 heat C6H6 HCl
N2 BF3
Perhaps still the best/simplest/easiest way to put a fluorine onto an aromatic ring.
This is still the way that most of the chemical industry does it.
65 There are some slight variations which can offer some advantages:
i) the use of HPF6 instead of HBF4.
Heating gives Ar-F + N2 + PF5
ii) Photochemical decomposition of the aryldiazonium tetrafluoroborate salt (eliminates the need to heat)
iii) The use of NaNO2 / HF (or Py-HF) to convert + - Ar-NH2 → Ar-N2 F , followed by heating.
The mechanism for the Balz-Schiemann reaction is not fully understood, and it is generally believed there are several competing processes occurring...
66 Normally we might imagine a slow RDS of aryl cation formation, followed by trapping with a nucleophile.
Ar+
Ar•
67 Fluoroaromatics and Nucleophilic Aromatic Substitution
Hexafluorobenzene undergoes NAS with nucleophiles via the addition / elimination mechanism.
Notice the ‘mirror image’ analogy of hydrocarbon systems:
68 For Example
F OCH3 F F F F NaOCH3
F F CH3OH F F F F
F F F F
F F F CH3 CH3Li
F F F F F F F F
69 But what about multiple attacks, relative rates and directing effects? Electron Donating Groups (Deactivating for NAS)
CH3 CH3 F F F F CH ONa 3 Rel rates
F F CH3OH F F 0.63 (deact) F OCH3
Hydrogen as a Substituent: H H F F F F CH ONa 3 1 (control)
F F CH3OH F F F OCH3
Electron withdrawing Substituents (Activating for NAS)
CF3 CF3 F F F F CH3ONa 5,000 (act)
F F CH3OH F F F OCH3 70 These reactions all proceed at 60oC. The relative rates for these reactions are 0.63 : 1: 5,000
Electron withdrawing substituents enhance the rate for these NAS, and electron-donating substituents lower the rate.
This is of course easy to explain by considering the relative stabilities of the intermediate carbanions formed in the endothermic RDS of these NAS processes.
But do you notice a pattern in directing effects? All three situations show a major preference for a para substitution.
This implies that it is not the substituent, BUT THE FLUORINES, that govern the position of attack and substitution.
So we should consider the basis of the orientating/directing preferences of Fluorine atoms.
It has to do with the effects of the fluorine atoms around the ring on the negatively charged σ intermediate.
71 We can determine these from the relative rate constants for the following systems: Para Attack F H F F F F para F ~ para H F F ~ F F F F kobs /6 6 identical sites
Ortho Attack H 20x H F F F F ortho F 20 x faster ortho H F F > F H F F kobs /2
Meta Attack H 100x H F F F H meta F 100 x faster meta H F F > F F F F kobs /2 Meta Fluorine is powerfully activating over meta H Ortho Fluorine is activating over ortho H Para Fluorine is similar to para H 72 Remember the different effects of α and β fluorines on a carbanion center:
So when a nucleophile attacks and forms a negative sigma complex:
73 A meta F is β to the –ve charge, and thus stabilizing
A para F α to the –ve charge, and thus slightly destabilizing
This explains the 100x preference, and equivalence exhibited in relative rates.
One could assume an ortho F should also be destabilizing – however we determined it to be 20x more active!
The full picture about ortho F is a little more involved…
The initial state effects are also important.
74 The ortho Fluorine enhances the ion dipole effect – which means the approach of a nucleophile is electrostatically encouraged.
δ- F δ+ δ- Nuc- F δ+F
F F F
The amount that this impacts the reactivity of the fluoroarene depends on the fluoroarene itself.
More precisely the initial state effects impact the transition state: if it is a highly reactive system the T.S. will be early, and this will be encouraged by the ortho fluorine.
A late transition state (less reactive system) is far less impacted by initial effects and so an ortho Fluorine would just show its destabilizing effect of F α to an anion.
However, almost all of these fluoroarenes are considered to be reactive systems.
75 Also, there has been evidence that implies that for these fluorinated sigma complexes, most of the negative charge really lies at the position para to attached nucleophile.
That is to say Lewis structure (A) is more significant / important than (B) for these systems.
Nuc F Nuc F ortho ortho ortho _ ortho _ meta meta meta meta para para
(A) (B)
This would also explain the activating effect of ortho fluorine (takes advantage of its withdrawing ability).
76 So overall, wrt NAS:
Ortho F considered slightly activating
Meta F considered very activating
Para F considered deactivating (slightly) / comparable to H
PARA Attack ORTHO Attack META Attack all activating mostly activating mostly activating X X X Dm mD Dm Up oD F F F o o DD p o D Dm U m o D D
two meta, two ortho
Para attack is generally preferred. 77 Pentafluoro pyridine Pyridine is inherently activated toward NAS due to the electronegative nitrogen.
Nuc Nuc F - Nuc- -F F _F F N N N
Attack at the 4 position (para to N) is strongly preferred since (a) it can place the –ve charge on the electronegative N, and (b) it avoids the para fluorine situation.
Hence from before the trapping of carbanions by pentafluoropyridine:
- F3CF F F3CFC4F6 _ F3C F3C CCCF3 C(CF3)=C(CF3) _ CCF3 n CF3 CF3
F N
F F3C F F C F C 3 3 CF3
CF3 CF3 F F N N 78