The Anomalous Reactivity of Fluorobenzene in Electrophilic Aromatic

Research: Science and Education

The Anomalous Reactivity of Fluorobenzene in Electrophilic Aromatic Substitution and Related Phenomena Joel Rosenthal† and David I. Schuster* Department of Chemistry, New York University, New York, NY 10003; *[email protected]

Introduction In discussions of the reactivity of halobenzenes (PhX) in electrophilic aromatic substitution (EAS) reactions in most introductory and advanced textbooks, it is usually stated that the halogens, as a group, act as deactivating substituents. Thus, substitution is said to be slower on halobenzenes than on benzene because of inductive electron withdrawal from the ring by the halogen atom (1–4). The fact that substitution is directed selectively to the ortho and para positions is attributed to stabilization of an adjacent positive charge in the intermediate benzenonium ion (sigma complex) by resonance, involving the lone pairs of electrons on the halogen atom, X (Figure 1; ref 5). The profound differences in the behavior of fluorobenzene compared with the other halobenzenes (chloro-, bromo-, and iodobenzene) are not discussed in any contemporary introductory organic chemistry texts to our knowledge and are barely suggested in advanced texts. One of us (DIS) has for some years been quizzing knowledgeable organic chemists and students about the rank order of reactivity of the halobenzenes in typical electrophilic substitution reactions (e.g., nitration) and has found that the vast majority have either no idea what the correct answer is or, more typically, get it backwards. On the basis of electronegativity considerations and the common conception that halogen substituents inductively deactivate aromatic rings, most people, in our experience, conclude that iodobenzene should be the most reactive and fluorobenzene the least reactive of the halobenzenes. The correct order of reactivity is given schematically in a figure in McMurry’s undergraduate text (6), namely PhF > PhCl > PhBr > PhI, together with the (correct) implication that fluorobenzene is almost as reactive as benzene. Anyone who closely examines this figure might well ask if this order is correct, and if so, why? No explanation for this order of reactivity can be found in McMurry’s textbook, or for that matter in any other textbook that we have consulted. The typical instructor is usually not prepared to provide an adequate explanation for these observations. McMurry also indicates in a table that the percent yield of para-substituted product (86%) on nitration is much higher for fluorobenzene than for the other halobenzenes, which are all 55–65%. Actually, according to the original literature, the difference is even greater, that is, the yield of p-nitrofluorobenzene in fact exceeds 90% (7). It is not our intention to pick on McMurry, especially since at least he is aware of the facts. No other introductory textbook that we have consulted even bothers to deal with this problem, typically lumping all of the halobenzenes together in discussions of EAS reactions. Clearly, something interesting and unusual is going on with †

Current address: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139.

fluorobenzene, which ought to be brought to the attention of teachers and students of organic chemistry. In his text, Mechanism and Structure in Organic Chemistry (8), which was the ‘bible’ in this field for those of us of an earlier generation, Gould notes that the relative reactivity toward NO2⫹ of halobenzenes relative to benzene (PhH) is 0.15 for PhF, 0.03 for PhCl, and 0.03 for PhBr, citing the experimental data of Ingold from the 1930s (9). While correctly indicating the overall reactivity of PhF relative to PhH, Gould fails to note that the partial rate factor, fp, for nitration at the para position of PhF, based on Ingold’s data, is actually 0.8 (5, 9)! Thus, the reactivity at the para position of PhF is only slightly less than that at a single position in benzene, which comes as a shock to most organic chemists. In his discussion Gould notes that (his italics) “these values need not be considered at length here, for, qualitatively speaking, they reflect a combination of the inductive and resonance effect of substituents”. He notes that “when the I (inductive) and R (resonance) effects of a substituent are in opposite directions (as in the case of the halogens as well as the ⫺OH, ⫺NR2, and ⫺SR groups) we cannot predict, in the absence of further information, whether that substituent will activate or deactivate the ring”. Gould then embarks on a classic discussion of the activated complexes (σ-complexes) resulting from attack of the electrophile, noting (his italics) that “the complex having the lowest energy is that associated with the ‘favored’ position for attack”. Orientation effects are rationalized in terms of the energies of the various intermediate arenium ions. Conspicuously, the fact that electrophilic substitution occurs with unusually high selectivity at the para position of PhF is completely ignored. Additional relevant experimental data are worth noting. Citing the results of Eaborn and Taylor from 1961, Carey and Sundberg (C&S) in their Advanced Organic Chemistry text present a table of partial rate factors for hydrogen exchange in substituted aromatic compounds (10) that includes the following provocative entries: for PhCH3, fo, fm, and fp are 330, 7.2, and 313, respectively. Thus, reaction of toluene occurs at about the same rate at ortho and para positions, and at a much slower rate at the meta position. For PhCl, the values are 0.035, 0.0, and 0.16; thus, for chlorobenXⴙ

X

ⴙ

H

E

H

E

Figure 1. Schematic illustration of para electrophilic aromatic substitution on halobenzenes where X is a halogen atom and E is an electrophile.

JChemEd.chem.wisc.edu • Vol. 80 No. 6 June 2003 • Journal of Chemical Education

679

Research: Science and Education ⴙ F

F

ⴙ

H

CH3

ⴙ

ⴙ

F H

H

H

H

H

H 1'

1

H

H

H H

Hⴙ

F

ⴙ

H

H

ⴙ F

H

H

H

H

H

H

H 3

2

Figure 2. Cations of 4-fluorobenzene 1, benzene 2, and 4methylbenzene 3.

Scheme I. Protonation of fluoroethene to form a resonance-stabilized carbocation.

zene reaction is inhibited at all positions, but nonetheless takes place at the ortho and para positions, with a slight preference for para. By contrast, the data for PhF are surprising if not shocking; fo is 0.136 while fp is 1.79 (11)! Thus, addition of a proton to the para position of fluorobenzene occurs almost twice as fast as to a single position of benzene itself. Moreover, there is a huge difference in reactivity of PhF at the ortho and para positions. No commentary upon these data is provided by C&S. The Hammett ρ value for this reaction is about ᎑8, depending on the precise reaction conditions, indicating that substituents play a major role in this reaction (12). In contrast to the other halogens, fluorine activates the aromatic ring toward electrophilic substitution at the para position, while it simultaneously inhibits reaction at the ortho position. Furthermore, while the ortho position for PhF is deactivated relative to a single position in benzene, it is still about four times more reactive than the corresponding position in PhCl. These observations are difficult to reconcile with the widely accepted description of EAS reactions in virtually every organic chemistry textbook.

The calculations show that the 4-fluorobenzenonium ion 1 is more stable than the parent ion 2 but is less stable than the corresponding 4-methyl cation 3 (Figure 2). Thus, fluorine clearly behaves as a π-donor in 1, that is, stabilization of 1 versus 2 must be the result of a resonance effect. This also explains why FCH2⫹ is more stable than CH3⫹ (13–15) and why protonation of fluoroethene results in the formation of the cation with positive charge on the carbon bearing fluorine (Scheme I; ref 16). Neither observation can be reconciled by electronegativity considerations. This resonance effect of fluorine is further demonstrated by data for the ionization of substituted cumyl chlorides (Table 1; ref 17–19). It can be seen that the order of stability of benzenonium ions 1–3 is mirrored by the cumyl cations, 5–7 (Scheme II). Most striking is the fact that the rate of ionization of 4 with X = p-F is about ten times faster than for the other cumyl chlorides bearing para-halogen substituents despite the extreme electron-withdrawing inductive effect of fluorine. Fluorine clearly stabilizes appropriately located positive charge on carbon better than the other halogens. These phenomena can be rationalized in terms of the size and electron density of the p orbitals of the respective atoms (20, 21). There is an excellent match between the sizes of the 2p orbital of fluorine and the vacant 2p orbital of carbon, resulting in excellent π-overlap and significant delocalization of positive charge onto the fluorine atom. This resonance stabilization clearly overrides the significant destabilizing inductive effect of fluorine (13). Analogous π-overlap with the vacant 2p orbital of carbon is much less effective with the increasingly diffuse 3p, 4p, and 5p orbitals of Cl, Br, and I, respectively. The C⫺Cl, C⫺Br, and C⫺I bonds are also much longer than C⫺F bonds, which further serves to reduce π-overlap (see Table 7; ref 22). As a consequence, the larger halogens are much less effective than fluorine in stabilizing carbocations by π-electron donation. Thus, all the

Electrophilic Substitution on Fluorobenzene: Resonance and Inductive Effects A clear indication of what is happening with fluorobenzene is provided by Wiberg and Rablen (13). The enthalpy changes for the hypothetical isodesmic reactions (eqs 1–4), calculated at the MP3兾6-311++G**兾兾MP2兾6-31G* level, show that fluorine stabilizes an adjacent positive charge better than hydrogen, but not as well as methyl. H

ⴙ

F + C2H6

H

H

ⴙ

CH3 + CH3F

H

1

(1)

3

∆H = -4.3 kcal/mol H

H

ⴙ

F + C2H6

H

1

ⴙ

Table 1. Relative Rates of Ionization of Selected Cumyl Chlorides

H + C2H5F

H

(2)

2

∆H = 9.3 kcal/mol FCH2

ⴙ

+ C 2H 6

C2H5ⴙ + CH3F

∆H = -21.4 kcal/mol FCH2ⴙ + CH4

CH3ⴙ +

CH3F

∆H = 18.3 kcal/mol

680

(3)

(4)

Compound

krel

Compound

krel

o-F

0.0502

o-Br

0.0061

m-F

0.025

m-Br

0.0144

p-F

2.14

p-Br

0.208

o-Cl

0.0079

o-I

0.011

m-Cl

0.0157

m-I

0.0233

p-Cl

0.305

p-I

0.244

NOTE: The rate of ionization for unsubstituted cumyl chloride is taken as 1.0.

Journal of Chemical Education • Vol. 80 No. 6 June 2003 • JChemEd.chem.wisc.edu

Research: Science and Education Cl H3C

H3C ⴙ CH3

H3C

CH3

H3C

H3C

CH3

CH3

CH3 ⴚ Clⴚ

ⴙ ⴙ F

F

Fⴙ

F

F

5 Cl H3C

H3C ⴙ CH3

H3 C

H3C

CH3

CH3

CH3

ⴙ

ⴚ Clⴚ

Scheme II. Ionization of substituted cumyl chlorides.

ⴙ Cl H

H

H

H

H3C

CH3

6 Cl H3C

H3C ⴙ CH3

H3C

CH3

H3C

CH3

X

CH3

ⴙ

ⴚ Clⴚ

4 ⴙ

CH3

CH3

CH3

CH3

7

positions on the benzene ring are deactivated toward electrophilic substitution by Cl, Br, and I substituents. The fact that these halogens are nonetheless ortho and para directing indicates that resonance effects of Cl, Br, and I can not be totally ignored; that is, the ortho and para positions of PhCl, PhBr, and PhI are deactivated less than the meta positions. The same considerations hold for ionization of the phalocumyl chlorides. A major anomaly is the extraordinary directing effect of fluorine in EAS: reactions on PhF occur with very high selectivity (> 90%) at the para position. The resonance effect already discussed would stabilize σ-complexes and the transition states (TSs) leading to them for electrophilic attack at positions ortho and para to fluorine. The small size of F compared to Cl, Br, and I, coupled with π-donation as discussed above, might lead one to anticipate greater proportions of ortho-substitution products for PhF than for the other halobenzenes, contrary to experimental observations. Other electronic effects are clearly operating. The extent to which the halogen inductively withdraws electrons from the aromatic ring in halobenzenes must play a crucial role in the directing effects for attack by electrophilic species. The fact that all halogens activate the para position more than the ortho positions upon nitration (Tables 2 and 3) indicates that resonance cannot be the sole mode of stabilization of the corresponding σ-complexes. If resonance were the sole factor, one would expect nearly twice as much ortho-substitution as para-substitution, since steric effects should be minimal. The idea that halogens can stabilize routes for electrophilic substitution at the ortho and para positions of an aromatic substrate seems counterintuitive since classic electron withdrawing groups (EWGs; e.g., cyano, nitro, and trifluoromethyl) deactivate the aromatic ring and dictate the site of electrophilic attack as meta solely by

their inductive effects (23). In these cases electrophilic addition at the ortho and para positions is energetically destabilized by coulombic repulsion (Scheme III). The TS for meta substitution is favored by the absence of a resonance form in the σ-complex in which two adjacent atoms are positively charged. Thus, in the case of classic EWGs such as CN and CF3, meta substitution is driven not by inductive interactions or resonance effects that stabilizes the TS, but rather

N C δⴙ ⴙ

E

N

N

N

δⴙ C

δⴙ C

δⴙ C

E

E

ⴙ

E H

H

H

ⴙ

ⴙ

Repulsion ⇒ Higher Energy

N C δⴙ

N

N

N

δⴙ C

δⴙ C

δⴙ C

ⴙ

ⴙ

Eⴙ

E

E H N

N

N

δⴙ C

δⴙ C

δⴙ C

N C δⴙ

E

ⴙ

H

H

ⴙ

Eⴙ

ⴙ

ⴙ H

E

H

E

H

E

Repulsion ⇒ Higher Energy

Scheme III. Resonance structures of σ-complexes formed upon electrophilic attack of benzonitrile.


681

682

0.15

0.033

0.03

0.18

PhF

PhCl

PhBr

PhI

1.8

1.2

1.9

0.0

3.2

m

60

62

69

87

40

p

NA

0.072

0.1

0.74

3400

Rel. Rate


0.054

0.030

0.033

0.205

PhF

PhCl

PhBr

PhI

NA

1

1

0

4

m

NA

62

69

91

37

p

NA

0.133

0.215

0.28

2.5

Rel. Rate

NA

24

42

43

42

o

NA

22

16

14

19.5

m

Ethylationb

NA

54

42

43

38.5

p

0.010

0.001

0.002

0.000

2.35

m

Nitrationb

0.648

0.112

0.137

0.783

58.8

p

NA

0.08

0.09

0.20

6018

o

NA

0.00

0.00

0.00

408

m

Chlorinationb

NA

0.268

0.414

4.04

7548

p

NA

0.10

0.271

0.361

3.15

o

NA

0.088

0.103

0.118

1.463

m

Ethylationb

NA

0.431

0.542

0.722

5.775

p

The data shown was aquired from ref 11 or extrapolated from the data available.

The data shown was aquired from ref 9 or extrapolated from the data available.

b

All rate data is relative to reaction on unsubstituted benzene. Cases in which data was not available denoted with NA.

a

41.9

o

PhCH3

Compound

c

NA

37

30

9

59

o

Chlorinationb

NA

NA

0.0115

0.25

110

Rel. Rate

NA

NA

0.0

0.0

9.3

o

NA

NA

0.0

0.0

30.69

o

NA

NA

0.0

0.0

4.62

m

Benzoylationb

NA

NA

0.0

0.0

1.4

m

Benzoylationb

Table 3. Partial Rate Factors for Various Reactions with Substituted Benzenesa

Data from ref 11 or extrapolated from the data available.

Data from ref 9 or extrapolated from the data available.

b

c

38

37

30

12

57

o

Nitrationb

All rate data is relative to reaction on unsubstituted benzene. Cases in which data was not available denoted with NA.

a

24.5

Rel. Rate

PhCH3

Compound

NA

NA

0.069

1.50

587.4

p

NA

NA

100

100

89

p

Table 2. Relative Rates and Percent of Products for Various Reactions with Substituted Benzenesa

0.043

0.027

0.035

0.136

3 30

o

0.08125

0.06875

0.1170

1.575

NA

Rel. Rate

0.0

0.0

0.0

0.0

3. 0

m

0.0

0.0

0.0

0.0

7.2

m

Protonationc

43.8

35.1

30.4

13.2

66

o

Protonationc

0.11

0.10

0 . 16

1 . 79

313

p

56.2

64.9

69.6

86.8

31.0

p



by the absence of destabilizing coulombic repulsions that are present in the ortho- and para-substitution pathways (24, 25). The electron withdrawing halogens stabilize the TSs leading to addition of electrophiles at the ortho and para positions and not the meta position, because the electron polarization in the C⫺X bonds in PhX is opposite to that for benzenes linked to classic EWGs (Figure 3). The C⫺X bond for PhX is polarized so that the electron-withdrawing halogen bears a partial negative charge, while the ipso carbon (the carbon adjacent to substituent) bears a partial positive charge: this effect is of course greatest for PhF. In contrast with compounds such as benzonitrile or nitrobenzene, the ipso carbon bears greater electron density than the atom of the EWG to which it is bonded (Scheme III). Polarization of charge on the aromatic ring induced by the halogen atom in PhX has a profound effect on the way in which electrophiles interact with these substrates, as illustrated in Figure 4. In his seminal studies on EAS, Ingold fully recognized that substituents that withdraw electron density from the aromatic ring inductively (I ↓) and donate electrons by resonance (R ↑) stabilize the TSs for addition at the ortho and para positions (9, 26, 27). Indeed, prototypical activating ortho–para directors such as amino (NH2) and methoxy (OCH3) function in this way: the electronegative heteroatom inductively withdraws electrons from the aromatic ring, while simultaneously helping to stabilize adjacent positive charge in benzenonium ions by resonance (9, 26, 27). In his early papers, Ingold categorized the halogens along with other classical EWGs possessing lone pairs as ortho–para directors. The halogens, fluorine in particular, are special members of the group described as (I ↓, R ↑) since the extent to which electrons are donated to the aromatic ring by resonance is greatly reduced when compared with NH2 or OCH3, while the inductive electron-withdrawing effect is much greater. This was illustrated by Wiberg and Rablen (13) who noted the similarity in the electron-density difference plots for PhF, PhCl, PhNH2, and PhOH. Although the para interaction (i.e., R ↑) is much greater in the cases of aniline and phenol, inductive withdrawal of electrons from the ipso carbon is seen for all four cases (Figure 5). This effect is greatest for fluorobenzene, which has an electron-density difference plot that is stunningly similar to that for phenyl cation with a nearby negative charge (Figure 6; ref 13). Hence, the increase in electron density at the ortho positions for PhF, and to a lesser extent for PhCl, is not the result of π-electron donation by the halogen substituent. Rather, it reflects the perturbation of electron density in the aromatic ring in response to the polarization of the C⫺X bond and the positively charged ipso carbon. This effect is obviously greatest in the case of fluorine. Pauling (28) noted that fluorine attracts electrons to a much greater extent than the other halogens, such that covalent bonds to fluorine have a much greater percent of ionic character as compared to those for the other halogens (i.e., H⫺F vs H⫺Cl, Cl⫺F vs Br⫺Cl). The extent to which fluorine serves to polarize covalent bonds to electropositive atoms is so great that Pauling termed fluorine the “superhalogen” (Table 4). Since the C⫺F bond has a much greater amount of ionic character as compared to C⫺N, C⫺O, and C⫺Cl bonds, polarized resonance structures for PhF in which electron density is directed to the ortho positions must be considered (Fig-

X δⴚ

X

Y δⴙ

Y

δⴙ

δⴚ

X = OH, NH2, F, Cl, etc.

Y = CN, NO2, CO2H, SO3H, etc.

Figure 3. Inductive effect of various substituents on aromatic rings. Fⴚ ⴙ

F

F δⴚ δⴙ

F δⴚ

F δⴚ δⴙ

δⴙ

ⴚⴙ

ⴙ

ⴚ

F δⴚ δⴚ'

δⴙ

δⴚ'

Figure 4. Charge-separated resonance forms of fluorobenzene.

Figure 5. Electron-density difference plots calculated by subtracting the electron-density plot for benzene from each aromatic derivative. Darkened contours indicate a gain in electron density. Lightly shaded areas indicate a loss of electron density. The contour level is 2.0 × 10᎑3 e/au3. Plots reproduced from ref 13.

Figure 6. Electron-density difference plots for (A) fluorobenzene and (B) phenyl cation. Darkened contours indicate a gain in electron density. Lightly shaded areas indicate a loss of electron density. The contour level is 2.0 × 10᎑3 e/au3. Plots reproduced from ref 13.


683


tive charge is forced onto the positions ortho to fluorine. This is particularly unfavorable as (a) it destroys the pre-existing coulombic stabilization of the ortho–ipso C⫺C bonds, and (b) introduces electrostatic repulsion between the ortho and ipso positively charged carbons. The latter effect resembles the repulsive forces created in the TSs for σ-complex formation following addition of electrophiles ortho or para to metadirecting groups such as CN or NO2. Thus, in meta addition to PhF, repulsive forces destabilize the TS leading to the σcomplex, strongly disfavoring meta substitution (see Figure 9b). Therefore, it is not surprising that less than 1% of mfluoronitrobenzene is formed in nitration of PhF (7). While addition of electrophiles ortho to fluorine does not create such destabilizing electrostatic repulsions, it adversely effects the coulombic stabilization of the bond between the electron-poor ipso carbon and the electron-rich ortho carbon. Therefore, the TS for ortho attack on PhF, while lower in energy than for meta attack, is higher in energy than that for para attack. In summary, perturbation of electron density in formation of the σ-complexes explains why addition to the ortho and meta positions is less preferable than addition to the para position. The addition of electrophiles to aromatic substrates to form σ-complexes is an endothermic process (23, 29). According to the Hammond postulate, the higher the energy of the σ-complex, the later the TS leading to this intermediate along the reaction coordinate (Figure 7; ref 25). Therefore, the TS leading to σ-complexes should be more closely related structurally and energetically to the σ-complexes than to the starting aromatic compounds (30–32). Thus, upon ortho attack of electrophiles on PhF, the stabilizing forces present in PhF would be disrupted, if not destroyed, raising the activation energy for this process (Figure 8; ref 33). Nonetheless, the yield of the ortho product far exceeds that of the meta product upon nitration of PhF (7), demonstrating that the TS for meta substitution must be significantly higher in

Table 4. Effects of Electronic Polarization by Fluorine Cpd

Bond Energy/ kcal mol᎑1

∆χP

Cpd

BondEnergy/ kcal mol᎑1

∆χP

H⫺F

134.6

64.2

Cl⫺F

60.6

13.3

H⫺Cl

103.2

22.1

Br⫺Cl

52.3

0.2

H⫺Br

87.5

12.3

I⫺Cl

50.3

3.2

H⫺I

71.4

1.2

I⫺Br

42.5

1.4

NOTE: Data taken from ref 28, p 81.

ure 4). Thus, the extreme polarization of the C⫺F bond and the resultant positive charge at the ipso carbon increases the electron density at the ortho positions by inductive reorganization of the electrons in the aromatic ring. This redistribution of electron density in turn provides coulombic stabilization of the ortho–ipso C⫺C bonds. Thus, the C⫺F bond and both ortho–ipso C⫺C bonds in PhF are stabilized by inductive effects. Most importantly, this interaction has no effect on the electron density at the para position, in accordance with Wiberg’s electron density plots (13). If the electron density in PhF is selectively enhanced at the ortho positions, why is the para position the preferred target of electrophilic attack by a factor of about 45 upon nitration? Indeed, based on the above arguments, it would seem that electrophilic attack at the ortho positions should be kinetically favored over attack at the para position! To rationalize the curious behavior of PhF, the electron distribution in the σ-complexes following electrophilic addition to the aromatic substrate must be analyzed. The resonance structures for the σ-complexes arising from electrophilic attack at the ortho, meta, and para positions of PhF, respectively, are shown in Scheme IV. The key factor is the extent to which stabilizing inductive interactions are disrupted or coulombic repulsion are enhanced in each mode of attack. Thus, in the charge-separated resonance forms for the σ-complex following addition of electrophiles meta to fluorine, posi-

δⴚ

δⴚ

δⴙ F δⴚ

Scheme IV. Resonance structures corresponding to the σ-complexes formed upon electrophilic attack of fluorobenzene.

δⴚ

E

H

E

H

δⴙ F E δⴚ

H

E

H

E

δⴙ F δⴚ

δⴚ

ⴙ δⴚ

δⴙ F δⴚ

H

δⴙ

F

δⴚ

684

δⴚ

δⴚ

ⴙ δⴚ

E

δⴙ

F

δⴚ

δⴙ F δⴚ

H

E

H

E δⴚ

ⴙ δⴚ

H

δⴙ F δⴚ

E

ⴙ

ⴙ δⴚ

δⴚ

δⴙ F δⴚ

H

E

Eⴙ δⴚ

δⴚ

ⴙ

ⴙ

ⴙ

δⴙ F δⴚ

δⴚ

ⴙ

δⴚ

Eⴙ

δⴚ

δⴚ ⴙ δⴚ δⴙ

F

δⴚ


δⴚ

δⴙ

F

δⴚ

δⴚ


energy than that for ortho substitution. Therefore, while ortho substitution is not the favored process for EAS on PhF, this pathway is still heavily favored energetically over the corresponding meta-substitution process (Figure 7). From the above arguments, one can understand why para substitution is so highly favored energetically over ortho and meta substitution in PhF. The resonance structures for the σ-complex formed upon addition of an electrophile to the para position of PhF are depicted in Scheme IV. In this process, positive charge is generated at the carbons meta and ipso to fluorine, reinforcing the inductive stabilization present in PhF without introducing any destabilizing interactions. In fact, additional stabilizing interactions are created on the aromatic ring in the para substitution process (Figure 9c). This stabilization arises from an increased dipolar contribution to the ortho–meta C⫺C bonds not present in ground state PhF, as well as an increase in the dipolar character of the ipso– ortho C⫺C bonds and the C⫺F bond. Since electrophilic addition to aromatic substrates is an endothermic process, the electrophile can have a profound effect on the distribution of products in EAS reactions (9). The later the TS leading to σ-complex formation (i.e., the more endothermic the process), the more pronounced this effect will be (see Figure 7; ref 32). Thus, for reactive electrophiles such as CH3CH2+ (Friedel–Crafts alkylation) where the TS should be relatively early, ortho:para ratios for PhF and PhCl are close to one, while for PhBr this ratio is close to 0.5 (possibly as a result of steric factors; ref 9). In addition, more than 10% meta product is seen in each of these cases. The relative amount of meta product obtained in the alkylation reactions increases as one proceeds from PhF to PhI since both resonance and inductive effects decrease for the less electronegative halogens. Conversely, for less reactive electrophiles, such as PhCO+, where the TS for addition is especially late, the para substitution product is formed exclusively with both PhF and PhCl (Tables 2 and 3; ref 9, 17, 34–37 ).

F

tetrahedral-like carbon is neutral in charge; mostly sp3 character in transition state

δⴙⴙ E δⴚ

H δⴙ'

Figure 8. Electronic nature of the transition-state leading to σ-complex formation upon or tho attack of an electrophile on fluorobenzene.

new inductive destabilizing interactions

inductive stabilization lost F δⴚ

F δⴚ E

(ⴙ) δⴙ

δⴙ

δⴚ

(ⴙ)

H

(ⴙ)

δⴚ

δⴚ

(ⴙ) E

(ⴙ) (ⴙ)

H

new inductive stabilizing interactions (b) meta transition state

(a) ortho transition state

F δⴚ

enhanced stablilizing inductive interaction

(ⴙ) δⴙ

new inductive destabilizing interactions

δⴚ

new inductive stabilizing interactions

δⴚ

(ⴙ)

(ⴙ)

H E (c) para transition state Figure 9. The electronic nature of the transition states formed upon electrophilic attack of fluorobenzene.

1

N

δⴙ

δⴙ

F

F δⴙ

N

path B

1

δⴙ

N

δⴙ

δⴙ

F Figure 7. Activation-energy diagram for EAS with fluorobenzene for the ortho, meta, and para positions.

F δⴙⴙ

path A

N

N

δⴙ

F

Scheme V. Rearrangements of (top) 2-fluorophenyl nitrene and (bottom) 4-fluorophenyl nitrene.


685


A completely analogous argument based upon σ-bond polarization was used recently by Platz and coworkers (38) to rationalize the preferential insertion of 2-fluorophenyl nitrene on the side of the ring away from the fluorine substituent (Scheme V). Computations show that insertion towards fluorine (path A) introduces larger coulombic repulsion between the ortho and ipso carbons than for the alternative insertion pathway (path B). Thus, the energy of the TS for path A is higher than that for path B. However, both insertion pathways for 2-fluorophenyl nitrene are energetically disfavored compared to the corresponding insertion reaction of 4-fluorophenyl nitrene (see Scheme V). This is completely understandable on the basis of the coulombic interactions in of PhF discussed above.

F OH

OH OH

O

δⴚ

δⴚ

F

δⴙ

ⴚ δⴚ

δⴚ

ⴙ

ⴚH

F

δⴙ

δⴚ

δⴚ

8

9

F

F

10

F

ⴙ

NH3

NH3ⴙ 11

Acidities of Fluorinated Aromatic Compounds The presence of strong inductive stabilization in fluorobenzene also readily explains the relative acidities of fluorinated aromatic compounds, as well as the reactivity of fluorinated aromatic compounds in nucleophilic substitution reactions. For the series of acids shown in Figure 10 (fluorophenols 8, 9, 10 and fluoroanilinium ions 11, 12, 13), the chief determinant of relative acidity is inductive stabilization, which depends on the relative orientation of the fluorine and the acidic group. The respective pKa values are shown in Table 5 (39, 40). Analysis of the coulombic interactions in the conjugate bases of 8, 9, and 10 and acids 11, 12, and 13 illustrates how inductive stabilization of the aromatic ring functions in these systems (Scheme VI and Figure 12). As shown for both 8 and 10, delocalization of negative charge onto the aromatic ring places partial negative charge ipso to fluorine, disturbing the stabilizing inductive interactions discussed earlier between the positively charged ipso carbon, the fluorine substituent, and both ortho carbons. In the conjugate base of m-fluorophenol 9, the negative charge is delocalized to the

OH

F

F

NH3ⴙ

12

13

Figure 10. Fluorophenols 8, 9, 10, and fluoroanilium ions 11, 12, 13.

Table 5. pKa Data for Fuorinated Acid Derivatives Compound

pKa

Compound

pKa

2-Fluorophenol

8.7

2-Fluoroanilinium

3.2

3-Fluorophenol

9.21

3-Fluoroanilinium

3.5

4-Fluorophenol

9.91

4-Fluoroanilinium

4.65

NOTE: Data taken from ref 39 and 40.

ortho positions that already bear a partial negative charge, reinforcing the coulombic stabilization already present between the ortho and ipso carbons (Scheme VI). On this basis, it is clear why meta-fluorophenol 9 is seven times more acidic than the para isomer 10. The pKa data for orthofluorophenol 8 is anomalous, probably owing to hydrogen bonding between the F and OH groups. The pKa data for the fluorinated anilinium derivatives (11–13) can also be understood using the induction model.

O δⴚ

δⴚ

F

δⴙ

ⴚ

O δⴚ

ⴚ

δⴚ

O

δⴚ

δⴚ

δⴚ

δⴙ

F ⴚ δⴙ

δⴚ

δⴚ

F

8

OH

O δⴚ

δⴚ

ⴚ

ⴙ

O δⴚ

δⴚ

ⴚH

δⴙ F δⴚ

δⴚ

9

OH

O

δⴙ F δⴚ

ⴚ

ⴚ

δⴚ

δⴙ F δⴚ

δⴙ F δⴚ

δⴚ

δⴚ

ⴚ δⴚ

O

ⴚ

δⴙ F δⴚ

δⴚ

δⴚ

δⴙ F δⴚ

δⴚ

δⴙ F δⴚ

δⴚ

δⴚ

δⴙ F δⴚ

δⴙ F δⴚ

ⴚ

ⴚ δⴚ ⴚ

δⴚ

O

O

ⴚHⴙ δⴚ

O

O

δⴚ

δⴚ

δⴙ F δⴚ

δⴚ

10

Scheme VI. Charge-separated resonance forms for the conjugate bases of 2-fluorophenol 8, 3-fluorophenol 9, and 4-fluorophenol 10.

686



The positively charged NH3+ group polarizes the aromatic ring in a manner opposite to that of fluorine, placing a partial negative charge on the carbon ipso to the NH3+ group (Figure 12). As a consequence, p-fluoroanilinium ion 13 is less acidic than 12 because inductive perturbation in 13 induced by the NH3+ reinforces the positive charge at the carbons ipso to fluorine, thus stabilizing 13. In contrast the inductive effect of the NH3+ substitution in 12 places the negative charge on the carbon ortho to fluorine and positive charge on the ortho carbons, thus reducing inductive stabilization present in PhF lacking the ammonium group. This raises the energy of 12 relative to 13 and makes the loss of a proton thermodynamically more favorable (41). The ortho derivative 11 is the most acidic, owing presumably to steric effects and hydrogen bonding.

F

X

Nu NO2

NO2

ⴚ

NO2 17

O

N

ⴙ

O

ⴚ

18

Figure 11. Substituted 2,4-dinitrohalogenated aromatics.

1-Substituent

δⴚ

δⴚ

ⴙ

3300

Cl

4.3

Br

4.3

I

1

NOTE: Data compiled from ref 43. Table 7. Selected Data for the Carbon–Halogen Bond of Halobenzenes Bond Strength/ Bond Length/ Electronegativity Å of Halogen kcal mol᎑1

C⫺halogen C(Ar)⫺F

1.134

4.0

C(Ar)⫺Cl

126 96

1.73

3.0

C(Ar)⫺Br

81

1.88

2.8

C(Ar)⫺I

65

2.10

2.5

NOTE: Data compiled from ref 1, pp 7, A.3.

δⴚ

ⴚ

Relative Rate

F

NH3 ⴙ

NH3 ⴙ

δⴚ F δⴚ ⴚ ⴙ δⴙ

F δⴚ

NO2 16

Table 6. Rate of Reaction of 1-Substituted 2,4-Dinitrobenzenes with Piperidine

δⴙ

δⴚ

NO2

NO2 15 I

Additional experimental support for the postulated charge-polarized structure for PhF comes from kinetic data for nucleophilic substitution on 2,4-dinitrohalogenated aromatics, 14–17 (Figure 11; ref 42). The relative rates at which a typical nucleophile, piperidine, displaces the various halogens are summarized in Table 6. This reaction proceeds about 750 times faster for the fluorinated substrate 14 than for the other halogenated derivatives, 15–17, which all react at similar rates (43). This occurs despite the fact that the C⫺F bond in PhF is about 30 kcal兾mol stronger than the C⫺Cl bond in PhCl (Table 7; ref 1). The reason for this apparent discrepancy is that the rate-determining step for this addition– elimination reaction is nucleophilic attack at the ipso carbon to give intermediate 18 (so-called Meisenheimer complex; ref 43). Since the electrophilicity of the ipso carbon ultimately determines the rate at which 18 is formed (Scheme VII), the strength of the C⫺X bond has a minimal effect on the rate of reaction. The ipso carbon in PhF has a unique electronic NH3 ⴙ

Br NO2

NO2 14

Properties of Other Organofluorine Compounds

NH3ⴙ

Cl NO2

δⴚ

F δⴚ δⴙ δⴚ

ⴚⴙ

NH3 ⴙ δⴚ

F δⴚ δⴙ δⴚ

F δⴚ δⴙ

ⴙⴚ δⴚ

11

NH3 ⴙ δⴚ

δⴚ

δⴙ F δⴚ

NH3 ⴙ

NH3 ⴙ

ⴚ δⴚ ⴙ

ⴚ

δⴚ

12

NH3 ⴙ

δⴚ

δⴙ

F

δⴚ

δⴚ

δⴚ

δⴙ F δⴚ

ⴙ

δⴚ

δⴙ F δⴚ

NH3 ⴙ

ⴚ ⴙ

ⴚ

F

δⴚ

δⴚ


F

δⴚ

NH3 ⴙ

δⴚ

δⴚ

NH3 ⴙ

δⴙ

NH3 ⴙ

ⴚⴙ

δⴚ

δⴙ F δⴚ

NH3 ⴙ

ⴚ


F

δⴚ

δⴚ

ⴙⴚ δⴚ

δⴙ F δⴚ

NH3 ⴙ

ⴚ


F

δⴚ

13

Figure 12. Charge-separated resonance forms for 2-fluoroanilinium 11, 3-fluoroanilinium 12, and 4-fluoroanilinium 13.


687

Research: Science and Education Nu

X

ⴚ

Nu O Nⴙ

X

NO2

NO2

X

O

Nu

X

NO2

ⴚ

NO2

ⴚ

NO2

ⴚ

O

Nⴙ 18

Oⴚ

Nu

Nu

NO2

NO2

NO2

Scheme VII. Mechanism for nucleophilic aromatic substitution of 2,4-dinitrohalobenzenes.

X F

19

21

20

F

F

22

23

Figure 13. Monohalogenobullvalene derivatives.

favored (78%) over the other isomers, as shown by NMR studies at ᎑25 ⬚C (45, 46). In 21, the carbon ipso to fluorine is allylic with respect to all three C⫺C double bonds of the bullvalene moiety and can most readily accommodate a positive charge. Thus, the partial positive charge induced by the electronegative fluorine atom can be delocalized by the ethene bridges, as shown by the resonance structures in Figure 14. This is not possible for isomers 22 and 23. Calculations by Wiberg (15) on substituted cyclopropanes have shown that EWGs prefer to bond to carbon orbitals having high p character, in which case the remaining orbitals on that carbon have increased s character. This effect is especially pronounced for fluorine, as illustrated in the isodesmic reaction shown in eq 5

δⴙ δⴙ

δⴙ

F

δⴚ

δⴙ

F

F

δⴚ

δⴙ

Figure 14. Charge-separated representation of fluorobulvalene isomer 21.

F

F

δⴙ

δⴚ

Figure 15. Charge-separated representation of fluorobulvalene isomer 23.

character similar to that of the charged carbon in phenyl cation (Ph+), so it is hardly surprising that the addition of nucleophiles to 14 is much faster compared with additions to 15, 16, and 17. Another example illustrating the extreme polarized nature of C⫺F bonds comes from studies of monohalogenobullvalene derivatives (Figure 13). While unsubstituted bullvalene 19 is a fluxional molecule in which all carbon atoms become equivalent via a series of rapid degenerate Cope rearrangements, the presence of a single substituent on the bullvalene core 20 creates a situation in which monosubstituted isomers are no longer energetically identical (44). In the case of fluorobullvalene, isomer 21 is strongly 688

F

F

F

+

+

∆HMP2 = 13.3 kcal/mol

(5)

Wiberg’s calculation shows that there is a stronger preference for bonding of fluorine to the ∼ sp3 hybrid orbitals of propane, rather than to the ∼ sp2 orbitals of cyclopropane (47, 48). Therefore, fluorobullvalene isomer 22 should be of higher energy than 21, since in 22 fluorine is attached to a cyclopropane moiety. Fluorobullvalene isomer 23 is also expected to be much less stable than 21, since C⫺F polarization would place positive charge at a vinylic position (Figure 15; ref 49, 50) Conclusions Students and instructors of organic chemistry need to recognize that fluorobenzene, PhF, behaves very differently in EAS reactions compared with the other halobenzenes (PhCl, PhBr, and PhI). Indeed, PhF reacts much faster in typical EAS reactions than the other halobenzenes, and partial rate factors for electrophilic attack on PhF are close to, and sometimes even greater than, unity. PhF also displays a significantly different directing effect from the other halobenzenes in that ∼ 90% of the substitution product with PhF is the para isomer, while the ortho:para ratio for the other halobenzenes is closer to unity. These facts should be mentioned in introductory as well as advanced textbooks of organic chemistry in place of the more customary generalization that all the halobenzenes behave in a similar manner. As shown above, these observations are not anomalous, but can be explained using accepted theoretical and mechanistic paradigms, which are summarized below.


Research: Science and Education 1. Analogous to PhNH2 or PhOH, PhF exhibits a dichotomy in terms of π-electron donation to the benzene ring (resonance effect) and inductive electron withdrawal. The resonance effect is much stronger for fluorine than for the other halogens and acts to stabilize adjacent positive charge on the ring as well as from the para to the benzylic position. While the halobenzenes are fundamentally different from other aromatic substrates, organic chemists should recognize that PhF and the other halobenzenes are members of the Inductive–Resonance group as originally classified by Ingold that includes PhNH2 and PhOH. 2. Textbooks usually explain the directing effect of the halogens solely in terms of resonance effects. However, it is clear that inductive effects play a major role in the course of electrophilic addition to the halobenzenes, particularly in the case of PhF. 3. The strong inductive effects of fluorine and the polarization of the C⫺F bond in PhF can be used to explain the enhanced reactivity of PhF and the difference in isomer ratios compared with the other halobenzenes in electrophilic substitution. Introduction of such concepts to students at an early stage (i.e., in a sophomore-level organic chemistry course) may be beneficial, as dealing with charge-separated resonance forms is frequently a stumbling block for undergraduate students. Familiarity with such concepts and associated structural representations should lead to a better understanding of the chemistry of aromatic compounds as well as organofluorine chemistry. 4. As shown, pK a data on isomeric fluorophenols and fluoroanilinium ions provide insight into the electronic structure of fluoroaromatic compounds using these concepts. Thus, it is common for organic chemistry textbooks to cite acidity data in illustrating the effects of electron withdrawing groups in saturated acyclic substrates (e.g., CF3CO2H versus CH3CO2H). 5. Relatively few undergraduate organic texts engage in detailed discussions of aromatic nucleophilic substitution reactions. It is clear that parallel forces control both nucleophilic and electrophilic substitution reactions on fluorinated aromatic compounds. We believe that discussion of these topics together should help students to understand the special role that fluorine plays in aromatic systems and to better appreciate the interplay between kinetic and thermodynamic effects of substituents. As an example, most textbooks cite the use of 2,4-dinitrofluorobenzene in the Sanger degradation of peptides, but provide no explanation as to why the fluoro- and not the chloro- or bromo-derivative is the reagent of choice. 6. Fluorinated aromatics in particular, and fluorine chemistry in general, provides the instructor of organic chemistry with a vehicle to discuss the effects that strong electron-withdrawing groups have on carbon orbital hybridization and bond polarity. Although of the topics discussed in this article may be too complicated or advanced for introductory undergraduate organic classes, they would certainly be appropriate in honors sections, courses designed graduate-level course. The apparently anomalous chemistry of fluorobenzene and its derivatives provides a fine illustration of the fascinating interplay between chemical structure and reactivity in organic chemistry.

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The Anomalous Reactivity of Fluorobenzene in Electrophilic Aromatic

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