Subscriber access provided by NEW YORK MED COLL

Article
Quantifying Reactivity for Electrophilic Aromatic
Substitution Reactions with Hirshfeld Charge
Shubin Liu
J. Phys. Chem. A, Just Accepted Manuscript DOI: 10.1021/acs.jpca.5b00443 Publication Date (Web): 27 Feb 2015
Downloaded from http://pubs.acs.org on March 1, 2015

Just Accepted

Just Accepted manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides Just Accepted as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. Just Accepted manuscripts
appear in full in PDF format accompanied by an HTML abstract. Just Accepted manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI). Just Accepted is an optional service offered
to authors. Therefore, the Just Accepted Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the Just
Accepted Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these Just Accepted manuscripts.

The Journal of Physical Chemistry A is published by the American Chemical Society.

1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.
Page 1 of 15 The Journal of Physical Chemistry

1
2
3
4 Quantifying Reactivity for Electrophilic Aromatic Substitution
5
6 Reactions with Hirshfeld Charge
7
8 Shubin Liu*
9
10 Research Computing Center, University of North Carolina, Chapel Hill NC 27599-3420, USA
11
12
13
14 Abstract
15
16 An electrophilic aromatic substitution is a process where one atom or group on an aromatic ring is
17
18 replaced by an incoming electrophile. The reactivity and regioselectivity of this category of reactions is
19 significantly impacted by the group that is already attached to the aromatic ring. Groups promoting
20
21 substitution at the ortho/para and meta position are called ortho/para and meta directing groups,
22
23 respectively. Earlier, we have shown that regioselectivity of the electrophilic aromatic substitution is
24
25
dictated by the nucleophilicity of the substituted aromatic ring, which is proportional to the Hirshfeld
26 charge on the regioselective site. Ortho/para directing groups have largest negative charge values at the
27
28 ortho/para positions, whereas meta directing groups often have the largest negative charge value at the
29
30 meta position. The electron donation or acceptance feature of a substitution group is irrelevant to the
31
regioselectivity. In this contribution, we extend our previous study by quantifying the reactivity for this
32
33 kind of reactions. To that end, we examine the transition state structure and activation energy of an
34
35 identity reaction for a series of mono-substituted-benzene molecules reacting with hydrogen fluoride
36
37 using BF3 as the catalyst in the gas phase. A total of 18 substitution groups will be considered, nine of
38 which are ortho/para directing and the other nine groups meta-directing. From this study, we found
39
40 that the barrier height of these reactions strongly correlates with the Hirshfeld charge on the
41
42 regioselective site for both ortho/para and meta-directing groups, with the correlation coefficient R2
43
44
both better than 0.96. We also discovered a less accurate correlation between the barrier height and
45 HOMO energy. These results reconfirm the validity and effectiveness of employing the Hirshfeld charge
46
47 as a reliable descriptor of both reactivity and regioselectivity for this vastly important category of
48
49 chemical transformations.
50
51
52
53
54
55
56
57 * E-mail address: shubin@email.unc.edu. Tel: (919)962-4032
58
59
60 1
ACS Paragon Plus Environment
 The Journal of Physical Chemistry Page 2 of 15

1
2
3 I. INTRODUCTION
4
5
6 As one of the most fundamental organic transformation processes, an electrophilic aromatic
7
8 substitution replaces an atom or a group, usually hydrogen, which is attached to an aromatic system, by
9
10 an incoming electrophile.1-4 Prominent examples of such reactions include nitration, halogenation,
11
12
13 sulfonation, and acylation and alkylating FriedelCrafts reactions. The dominant determinant of the
14
15 reactivity for this category of reactions should be the nucleophilicity of the carbon atoms on the
16
17 aromatic ring, i.e., the capability for the carbon atom on the aromatic ring to donate electrons to the
18
19
20
attacking electrophile. If the six carbon atoms on the benzene ring have different nucleophilicity
21
22 (electron-donating) properties, then the electrophile will preferably attack the one or ones with the
23
24 largest nucleophilicity. The outcome of this selective attack is the origin of regioselectivity.
25
26
Relevant to the reactivity and regioselectivity of these reactions is the so-called substituent
27
28
29 effect. It has long been known5 that both reactivity and regioselectivity of an electrophilic aromatic
30
31 substitution are affected by the substituents that are already attached to the aromatic ring. The group
32
33 that promotes substitution at the ortho/para and meta position is, respectively, called ortho/para and
34
35
36 meta directing group. Typical ortho/para directing groups are alkyl, amino, amide, aryl, ether, halogen,
37
38 hydroxyl, and ether, and common meta-directing groups are aldehyde, cyano, carboxylic acid, ester,
39
40 ketone, nitro, nitroso, quaternary amine, sulfonate, and trihalide. Resonance and inductive effects are
41
42
43
often employed to explain and justify these phenomena in textbooks and in the literature,1-4 yet a
44
45 satisfactory quantitative explanation is still lacking.
46
47 Very recently, a novel explanation has been proposed by us,6 based on a recent quantification of
48
49
nucleophilicity,7-9 which should be the root cause of the above substituent effect, using the Hirshfeld
50
51
52 charge10 in the framework of density functional reactivity theory (DFRT).11-14 This work was based on our
53
54 recent efforts in understanding information-theoretic quantities`15-23 in DFRT. We found that
55
56 regioselectivity of the electrophilic aromatic substitution is determined by the nucleophilicity of the
57
58
59
60 2
ACS Paragon Plus Environment
Page 3 of 15 The Journal of Physical Chemistry

1
2
3 aromatic ring, which is inversely proportional to the Hirshfeld charge on the regioselective site.
4
5
6 Ortho/para directing groups have largest negative charges on the ortho/para positions, whereas meta
7
8 directing groups often have the largest negative charge on the meta position. We also showed that the
9
10 feature of electron donation or acceptance of a substitution group is irrelevant to the phenomenon of
11
12
13 ortho/para and meta directing. It is the electron redistribution of the aromatic ring after a group is
14
15 introduced that matters. In addition, strong linear correlations between the Hirshfeld charge on the
16
17 regioselective site and the HOMO energy have been disclosed, providing the first link between the
18
19
20
frontier molecular orbital theory and DFRT. We also predicted ortho/para and meta group directing
21
22 behaviors for a list of groups whose regioselectivity is previously unknown.6
23
24 Our previous work unambiguously determined the root of regioselectivity, which should be the
25
26
nucleophilicity of carbon atoms on the aromatic benzene ring. However, it is limited by the fact that,
27
28
29 from the reactivity perspective, it is still of qualitative nature. This is because chemical reactivity should
30
31 ultimately be determined by the activation energy or barrier height of the transition state. To overcome
32
33 this limitation, in this work, we provide a quantitative account of this new explanation. To that end, we
34
35
36 at first choose nine systems with ortho/para directing groups and another nine systems with meta-
37
38 directing groups, and then investigate their kinetic behaviors for an identity reaction. The transition
39
40 state structure of this system has been well studied in the literature,24,25 which was found to be a one-
41
42
43
step reaction in gas phase. The barrier height represented by the total energy difference between the
44
45 reactant and transition state is compared with the Hirshfeld charge and HOMO energy of the mono-
46
47 substituted benzene derivatives. What we are interested in observing in this work is to see whether or
48
49
not there exist strong linear correlations between the barrier height and the Hirshfeld charge in systems
50
51
52 with different directing groups.
53
54
55
56
57
58
59
60 3
ACS Paragon Plus Environment
 The Journal of Physical Chemistry Page 4 of 15

1
2
3 II. COMPUTATIONAL DETAILS
4
5
6 The electrophilic aromatic reaction to be considered in this work is the following identity
7
8 reaction of mono-substituted-benzene molecules reacting with hydrogen fluoride using BF3 as the
9
10 catalyst in the gas phase (Scheme 1).
11
12
13
14
15
16
17
18
19
20
21 Scheme 1. Electrophilic aromatic substitution reaction studied in this work.
22
23
24
25 The nine ortho/para groups chosen are X= -F, -Cl, -CH3, -C2H5, -C3H7, -tBu, -NH2, -NMe2, and -OH. The
26
27
nine meta-directing groups picked are X= -CCl3, -CF3, -CHO, -CN, -COF, -NH3+, -NO2, -NO, and -SO3H.
28
29
30 Following the literature,24,25 we represent the catalyst by one BF3 molecule. The reactant complex
31
32 consisting of one mono-substituted benzene ring with one hydrogen fluoride (HF) and one BF3 was fully
33
34 optimized at the M062X/aug-cc-pVDZ level of theory.26,27 For each system studied, no matter if it
35
36
37 contains either an ortho/para or a meta directing group, we examined its electrophilic substitution at
38
39 both meta and para positions. The QST2 technique was employed to obtain the optimized transition
40
41 state structure of the reaction. After a transition-state search is accomplished, a single-point frequency
42
43
44 calculation was performed to ensure that the final structure obtained (i) has only one imaginary
45
46 frequency and (ii) the vibration mode of the negative frequency corresponds to the anticipated bond
47
48 formation and breaking. In addition, intrinsic reaction coordinates (IRCs) were calculated to verify the
49
50
relevance of transition-state structures. All calculations were performed with the Gaussian 09 DO1
51
52
53 package28 with tight SCF convergence and ultra-fine integration grids. The Hirshfeld charge was obtained
54
55 by the population analysis. We also calculated other charges such as Mulliken, NPA (Natural Population
56
57 Analysis), and CHELPG (CHarges from Electrostatic Potentials using a Grid based method) charges from
58
59
60 4
ACS Paragon Plus Environment
Page 5 of 15 The Journal of Physical Chemistry

1
2
3 the population analysis and compared them with the results from the Hirshfeld charge. We employed ab
4
5
6 initio Hartree-Fock and MllerPlesset perturbation theory (MP2) methods as well as density functional
7
8 theory (DFT) methods with Poples standard triple-zeta split-valence basis set and Dunnings augmented
9
10 correlation consistent basis set.27,29 B3LYP30,31 and M062X functionals were used in DFT calculations. No
11
12
13 qualitatively different result among these methods was observed. We will only show the results from
14
15 the M062X/aug-cc-pVDZ level of theory below.
16
17
18
19
20
III. RESULTS AND DISCUSSION
21
22 Table 1 displays the results for the systems with an ortho/para directing group, where the
23
24 HOMO energy, Hirshfeld charges of mono-substituted benzene derivatives at both meta and para
25
26
positions, and barrier heights of the identity reaction at both meta and para positions are tabulated for
27
28
29 the nine systems. As can be seen from the Table, (i) the Hirshfeld charge at the para position is always
30
31 more negative than that at the meta position, indicating that for the systems with para-directing groups,
32
33 the para position is invariably more nucleophilic, and (ii) the barrier height at the para position is always
34
35
36 smaller than that at the meta position, suggesting that the preferred, i.e., regioselective, site of the
37
38 electrophilic substitution of these systems should be at the para-position. These results agree well with
39
40 the fact that these groups are indeed ortho/para directing groups. These results are also consistent with
41
42
43
what we have observed in our previous work.6 That is, benzene derivatives with ortho/para-directing
44
45 groups possess the most negative Hirshfeld charges, and thus the strongest nucleophilicity, at the
46
47 ortho/para positions, and their regioselective reaction sites of electrophilic substitution should therefore
48
49
be at the ortho/para positions.
50
51
52 Shown in Fig. 1 are the two strong correlations about the barrier height for the systems with
53
54 ortho/para directing groups in Table 1. Figure 1a is a reasonably strong, inversely linear relationship
55
56 between the barrier height of the substitution occurring at the para position and the HOMO energy. This
57
58
59
60 5
ACS Paragon Plus Environment
 The Journal of Physical Chemistry Page 6 of 15

1
2
3 correlation shows that the higher the HOMO level of a system, the easier it donates the electron pair
4
5
6 from HOMO to the incoming electrophile, and thus the faster the electrophilic substitution process. This
7
8 relationship agrees well the frontier orbital theory.32,33 However, since the HOMO distribution is
9
10 delocalized over the entire molecule, this correlation does not contain the information of
11
12
13 regioselectivity. That is, it does not tell us which carbon atom will be the preferred reaction site. Plus, for
14
15 post-Hartree-Fock methods, where more than one Slater determinants are employed, the picture of
16
17 frontier orbitals makes no more physiochemical sense. Figure 1b shows a stronger linear relationship
18
19
20
between the same barrier height and the Hirshfeld charge at the para position with the correlation
21
22 coefficient R2 equal to 0.966. This latter relationship not only illustrates that the more negative Hirshfeld
23
24 charge on the para position, the smaller the barrier height for the reaction to take place, but also
25
26
distinguishes the preferred reaction site from other possible spots. This strong linear correlation
27
28
29 between the barrier height and Hirshfeld charge on the para position unambiguously demonstrates that
30
31 the Hirshfeld charge is an accurate descriptor of both reactivity and regioselectivity for the electrophilic
32
33 aromatic substitution of systems with ortho/para directing groups. A similar good correlation between
34
35
36 the reaction barrier height and the Hirshfeld charge on the ortho position has also been obtained (not
37
38 shown). In addition, we tried to correlate the barrier height with other charges, but much worse results
39
40 were obtained (not shown).
41
42
43
Table 2 exhibits the results for the systems with a meta directing group, from which we can see
44
45 that (i) the Hirshfeld charge at the meta position is always more negative than that at the para position,
46
47 suggesting that the meta carbon is able to donate more electrons, and (ii) the barrier height of the
48
49
reaction happening at the meta position is always smaller than that at the para position, indicating that
50
51
52 the reaction prefers to take place at the meta carbon. These results suggest that for the mono-
53
54 substituted benzene systems with meta-directing groups, the meta position is most nucleophilic and
55
56 most reactive. Figure 2 shows the two strong linear correlations for the barrier height of the reaction
57
58
59
60 6
ACS Paragon Plus Environment
Page 7 of 15 The Journal of Physical Chemistry

1
2
3 occurring at the meta position, similar to Fig. 1, one with the HOMO energy (Fig. 2a) and the other with
4
5
6 the Hirshfeld charge at the meta position (Fig. 2b). Again, these results confirm that for systems with
7
8 meta-directing groups, it is the meta position that possesses the most negative Hirshfeld charge, the
9
10 strongest nucleophilicity, and thus the smallest barrier height for the electrophilic aromatic substitution.
11
12
13 It clearly demonstrates that the Hirshfeld charge is a quantitatively accurate descriptor of both reactivity
14
15 and regioselectivity for electrophilic aromatic substitution of systems with meta directing groups.
16
17 We notice in passing that the results obtained from this work should also be applicable to
18
19
20
traditional aromatic electrophilic substitutions, where a cyclohexadienyl cation (arenium ion) is formed
21
22 as the reactive intermediate, which is often called the Wheland intermediate34 (sigma complex or -
23
24 complex). In this case, besides the impact from the substitution group, the delocalization of the positive
25
26
charge in this intermediate is also important. We anticipate that the kinetic of the first step, i.e., the
27
28
29 formation of the arenium ion, is dictated by the nucleophilicity of the substituted benzene, but the
30
31 subsequent step is governed both by the nucleophilicity of the benzene ring and by the nature of the
32
33 incoming electrophile. Since the formation of the sigma complex is an endothermic and energetically
34
35
36 unfavorable process, the first step should therefore be the rate determining step of this process.
37
38
39
40 IV. CONCLUSIONS
41
42
43
Put together, the statement that reactivity and regioselectivity properties of electrophilic
44
45 aromatic substitution reactions are governed by the nucleophilicity of carbon atoms in the aromatic ring
46
47 has been rigorously examined and thoroughly verified. With the new quantification approach of
48
49
nucleophilicity (and electrophilicity) we recently proposed using the Hirshfeld charge, we are able to
50
51
52 determine these properties simultaneously. Above numerical results from the transition state
53
54 perspective for a list of mono-substituted benzene + HF + BF3 reaction systems with both ortho/para
55
56 and meta-directing groups have clearly demonstrated that point. The strong linear correlations of the
57
58
59
60 7
ACS Paragon Plus Environment
 The Journal of Physical Chemistry Page 8 of 15

1
2
3 reaction barrier height with both the HOMO energy and Hirshfeld charge establish a novel and reliable
4
5
6 approach to quantify reactivity and predict regioselectivity for this vastly important category of chemical
7
8 transformations. This new view of reactivity and regioselectivity provides us with an improved
9
10 understanding about these reactions and should therefore be incorporated in future textbooks.
11
12
13
14
15 AUTHOR INFORMATION
16
17 Corresponding Author
18
19
20
* E-mail: shubin@email.unc.edu.
21
22 Telephone: (919)962-4032
23
24
25
26
Notes
27
28
29 The authors declare no competing financial interest.
30
31
32
33 ACKNOWLEDGMENTS
34
35
36 The author is grateful to an anonymous referee of Ref. [6], who correctly pointed out the
37
38 importance to work on the transition state structure reported in this work. For that, the author
39
40 acknowledges and appreciates. The author is also grateful to Research Computing Center, University of
41
42
43
North Carolina at Chapel Hill, for accessing needed computing facilities for the present study.
44
45
46
47 References
48
49
1. Solomons, T. W. G. ; Fryhle, C.B. ; Snydeer, S.A. Organic Chemistry; Wiley: New York, 2013.
50
51 2. Wade Jr., L.G. Organic Chemistry; Prentice-Hall: New Jersey, 2003.
52
53 3. Carey, F.A. ; Sundberg, R.J. Advanced Organic Chemistry Part A: Structure and Mechanism;
54
55 Kluwer/Plenum: New York, 2000.
56 4. Klein, D.R. Organic Chemistry; Wiley: New York, 2012.
57
58
59
60 8
ACS Paragon Plus Environment
Page 9 of 15 The Journal of Physical Chemistry

1
2
3 5. Crum Brown, A; Gibson, J. A rule for determining whether a given benzene mono-derivative shall
4
5 give a meta-di-derivative or a mixture of ortho- and para-di-derivatives, J. Chem. Soc. Trans. 1892,
6
7 61, 367 - 369.
8
9 6. Liu, S.B. Where does the electron go? The nature of ortho/para and meta group directing in
10 electrophilic aromatic substitution, J. Chem. Phys. 2014, 140, 194109.
11
12 7. Liu, S.B. ; Rong, C.Y.; Lu, T. Information conservation principle determines electrophilicity,
13
14 nucleophilicity, and regioselectivity, J. Phys. Chem. A 2014, 118, 3698 - 3704.
15
8. Zhou, X.Y.; Rong, C.Y.; Lu, T.; Liu, S.B. Hirshfeld charge as a quantitative measure of electrophilicity
16
17 and nucleophilicity: Nitrogen-containing systems, Acta Phys.-Chim. Sin. 2014, 30, 2055 - 2062.
18
19 9. Rong, C.Y. ; Lu, T.; Liu, S.B. Dissecting molecular descriptors into atomic contributions in density
20
21 functional reactivity theory, J. Chem. Phys. 2014, 140, 024109.
22 10. Hirshfeld, F.L. Bonded-atom fragments for describing molecular charge densities, Theor. Chim. Acc.
23
24 1977, 44, 129 - 138.
25
26 11. Parr, R.G.; Yang, W.T. Density Functional Theory for Atoms and Molecules; Oxford University: London,
27
28 1989.
29 12. Geerlings, P.; De Proft, F.; Langenaeker, W. Conceptual density functional theory, Chem. Rev. 2003,
30
31 103, 1793 - 1873.
32
33 13. Chattaraj, P.K.; Sarkar, U.; Roy, D.R. Electrophilicity index, Chem. Rev. 2006, 106, 2065 - 2091.
34
14. Liu, S.B. Conceptual density functional theory and some recent developments, Acta Phys.-Chim. Sin.
35
36 2009, 25, 590 - 600.
37
38 15. Nalewajski, R.F.; Parr, R.G. Information theory, atoms in molecules, and molecular similarity, Proc.
39
40 Natl. Acad. Sci. USA 2000, 97, 8879 - 8882.
41 16. Nalewajski, R.F.; Parr, R.G. Information theory thermodynamics of molecules and their Hirshfeld
42
43 fragments, J. Phys. Chem. A 2001, 105, 7391 - 7400.
44
45 17. Parr, R.G.; Ayers, P. W.; Nalewajski, R. F. What is an atom in a molecule? J. Phys. Chem. A 2005, 109,
46
47
3957 - 3959.
48 18. Ayers, P. W. Information theory, the shape function, and the Hirshfeld atom, Theor. Chem. Acc. 2006,
49
50 115, 370 - 378.
51
52 19. Kullback, S. Information Theory and Statistics; Dover: Mineola, N.Y., 1997.
53
20. Nalewajski, R.F. Information Theory of Molecular Systems; Elsevier: Amsterdam, The Netherlands,
54
55 2006.
56
57 21. Nalewajski, R. F. Information origins of the chemical bond; Nova Science: Hauppauge, N.Y., 2010.
58
59
60 9
ACS Paragon Plus Environment
 The Journal of Physical Chemistry Page 10 of 15

1
2
3 22. Rong, C.Y.; Lu, T.; Chattaraj, P.K.; Liu, S.B. On the relationship among Ghosh-Berkowitz-Parr entropy,
4
5 Shannon entropy and Fisher information, Indian J. Chem. A 2014, 53, 970 - 977.
6
7 23. Rong, C.Y.; Lu, T.; Ayers, P.W.; Chattaraj, P.K.; Liu, S.B. Scaling properties of information-theoretic
8
9 quantities in density functional reactivity theory, Phys. Chem. Chem. Phys. 2015, 17, 4977 - 4988.
10 24. Alagona, G.; Scrocco, E.; Silla, E.; Tomasi, J. The catalytic effect of BF3 on the electrophilic hydrogen
11
12 exchange reaction in benzene, Theoret. Chim. Acta, 1977, 45, 127 - 136.
13
14 25. Heidrich, D. The transition state of electrophilic aromatic substitution in the gas phase, Phys. Chem.
15
Chem. Phys. 1999, 1, 2209 - 2211.
16
17 26. Zhao, Y.; Truhlar, D.G. The M06 suite of density functionals for main group thermochemistry,
18
19 thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new
20
21 functionals and systematic testing of four M06-class functionals and 12 other functionals, Theor.
22 Chem. Acc. 2008, 120, 215 - 241.
23
24 27. Dunning Jr., T. H. Gaussian basis sets for use in correlated molecular calculations. I. The atoms boron
25
26 through neon and hydrogen, J. Chem. Phys., 1989, 90, 1007 - 1023.
27
28 28. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani,
29 G.; Barone, V.; Mennucci, B.; Petersson, G. A.; et al. Gaussian 09, Revision D.01, Gaussian, Inc.,
30
31 Wallingford CT, 2009.
32
33 29. Ditchfield, R.; Hehre, W.J.; Pople, J.A. Self-consistent molecular-orbital methods. IX. An extended
34
gaussian-type basis for molecular-orbital studies of organic molecules, J. Chem. Phys. 1971, 54, 724 -
35
36 728.
37
38 30. Becke, A. D. A new mixing of HartreeFock and local density-functional theories , J. Chem. Phys.,
39
40 1993, 98, 1372 - 1377.
41 31. Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti correlation-energy formula into a
42
43 functional of the electron density, Phys. Rev. B, 1988, 37, 785 - 789.
44
45 32. Fukui, K.; Yonezawa, T.; Shingu, H. A molecular orbital theory of reactivity in aromatic hydrocarbons,
46
47
J. Chem. Phys. 1952, 20, 722 - 725.
48 33. Fukui, K. Recognition of stereochemical paths by orbital interaction, Acc. Chem. Res. 1971, 4, 57 - 64.
49
50 34. Wheland, G.W. A Quantum Mechanical Investigation of the Orientation of Substituents in Aromatic
51
52 Molecules, J. Am. Chem. Soc. 1942, 64, 900 908.
53
54
55
56
57
58
59
60 10
ACS Paragon Plus Environment
Page 11 of 15 The Journal of Physical Chemistry

1
2
3 Table 1. Results for nine mono-substituted benzene derivatives, Ar-R, with para-directing groups, R.
4
5 Shown here are their HOMO energy, Hirshfeld charges at meta- and para-positions, and barrier heights
6
7 of electrophilic aromatic substitution, Eq. (1), for these species at both meta- and para-positions. Units
8
9 of HOMO and Hirshfeld charges are in atomic unit, and barrier heights in kcal/mol.
10
11
12
13 Hirshfeld Charge Barrier Height
14
15 -R HOMO Meta Para Meta Para
16
-H -0.3080 -0.0498 -0.0498 28.41 28.41
17
18 -Cl -0.3039 -0.0414 -0.0488 31.57 27.35
19
20 -Et -0.2947 -0.0506 -0.0554 27.79 25.23
21
22 -F -0.3069 -0.0419 -0.0560 31.64 25.38
23
24 -Me -0.2947 -0.0506 -0.0558 28.45 24.59
25
26 -NH2 -0.2595 -0.0501 -0.0717 30.29 11.09
27
28
-NMe2 -0.2430 -0.0525 -0.0748 29.83 12.18
29 -OH -0.2818 -0.0474 -0.0658 29.56 16.69
30
31 -Pr -0.2939 -0.0508 -0.0554 28.49 24.69
32
33 -tBu -0.2945 -0.0514 -0.0554 27.63 25.34
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60 11
ACS Paragon Plus Environment
 The Journal of Physical Chemistry Page 12 of 15

1
2
3 Table 2. Results for nine mono-substituted benzene derivatives, Ar-R, with meta-directing groups, R.
4
5 Shown here are their HOMO energy, Hirshfeld charges at meta- and para-positions, and barrier heights
6
7 of electrophilic aromatic substitution, Eq. (1), for these species at both meta- and para-positions. Units
8
9 of HOMO and Hirshfeld charges are in atomic unit, and barrier heights in kcal/mol.
10
11
12
13 Hirshfeld Charge Barrier Height
14
15 -R HOMO Meta Para Meta Para
16
-H -0.3080 -0.0498 -0.0498 28.41 28.41
17
18 -CCl3 -0.3206 -0.0417 -0.0387 31.10 31.89
19
20 -CF3 -0.3293 -0.0399 -0.0368 32.23 33.16
21
22 -CHO -0.3234 -0.0449 -0.0337 31.16 32.96
23
24 -CN -0.3273 -0.0380 -0.0326 33.47 33.94
25
26 -COF -0.3329 -0.0408 -0.0292 33.00 34.90
27
28
-NH3+ -0.4752 -0.0082 -0.0048 53.02 54.92
29 -NO2 -0.3392 -0.0365 -0.0296 34.29 35.37
30
31 -NO -0.3032 -0.0420 -0.0298 31.85 34.08
32
33 -SO3H -0.3394 -0.0356 -0.0296 33.68 35.33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60 12
ACS Paragon Plus Environment
Page 13 of 15 The Journal of Physical Chemistry

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36 Figure 1. Strong correlations of the electrophilic substitution barrier height for mono-substituted
37
38 benzene derivatives with para-directing groups with (a) HOMO energy and (b) Hirshfeld charge at the
39
40 para-position.
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60 13
ACS Paragon Plus Environment
 The Journal of Physical Chemistry Page 14 of 15

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36 Figure 2. Strong correlations of the electrophilic substitution barrier height for mono-substituted
37
38 benzene derivatives with meta-directing groups with (a) HOMO energy and (b) Hirshfeld charge at the
39
40 meta-position.
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60 14
ACS Paragon Plus Environment
Page 15 of 15 The Journal of Physical Chemistry

1
2
3
TOC Graphic
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60 15
ACS Paragon Plus Environment