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Comments on the Treatment of Aromaticity and Acid–Base Character of Pyridine and Pyrrole in Contemporary Organic Chemistry Textbooks Hugh J. Anderson Department of Chemistry, Memorial University, St. John’s, NF A1B 3X7, Canada;
[email protected] Ludwig Bauer College of Pharmacy, M/C 781, University of Illinois at Chicago, 833 S. Wood Street, Chicago IL 60612-7231;
[email protected] A survey of some of the chemistry of pyridine (1) and pyrrole (3) in a number of contemporary organic chemistry textbooks (1–18) revealed considerable disparity in the presentations of acid–base properties of pyrrole. Because of the interrelated nature of aromatic character and acid–base behavior of these monoaza heteroarenes, we briefly review some of the problems associated with the teaching of aspects of their chemistry. All the texts presented the aromatic structure of pyridine well, in words and orbital pictures, starting with the assembly of an aromatic (Hückel) sextet consisting of five electrons, one each from the p orbitals of the five sp2-hybridized carbons, and one electron from the p orbital of the pyridine type of sp2hybridized nitrogen. The basic and nucleophilic character of pyridine is attributed correctly to the remaining two nonbonded electrons in the sp2 orbital of the pyridine nitrogen which lies in the plane of the ring and does not overlap with the 6 π-electron system. The texts correctly label pyridine as a base (pKb about 8.8 [9, 13, 17 ]) considerably weaker than a typical secondary aliphatic amine (e.g., piperidine has a pKb = ~3 [9, 13, 17 ]). Furthermore, the pyridinium cation is a stronger acid (pKa = ~5 [9, 14, 17 ]) than a typical aliphatic ammonium ion (pKa = ~11 [9]). This difference in basicity is attributed by one author to “the lone-pair electrons of the sp2 hybridized nitrogen of pyridine [that] are held more tightly than those of the approximately sp 3 nitrogen of a simple secondary amine like piperidine, and therefore are less basic” (9). The surveyed texts illustrate neutralization of structure 1 by H+X{ to form a colorless pyridinium salt 2 (eq 1).
stating that the electron pair on the ring nitrogen in pyrrole is unavailable for protonation on nitrogen, for a reversible neutralization, many texts dwell on discussions of pyrrole’s “relative basicity”. Amidst efforts to explain the virtual lack of basic properties, it is disconcerting to find that little or no emphasis is placed on the fact that pyrrole is a weak acid, pKa = ~15 (6 ) or 23 (9), whereas it is often reported as a weak base (pKb = ~14 [7, 17 ] or 15 [13]; Kb ~2.5 × 10{14 [12]). More positively, several texts (2, 6, 9) succinctly describe the neutralization of pyrrole by statements like “The proton on the nitrogen atom can be removed by hydroxide ion to give the conjugate base of pyrrole. Salts containing the pyrrole anion are easily prepared this way” or “The corresponding lithium and sodium salts are made by warming pyrrole with either lithium or sodium hydrides in tetrahydrofuran.” In fact, 3 is readily deprotonated by strong bases to generate an aromatic resonancestabilized and highly reactive nucleophilic anion 4 (eq 2). Alkylation of ambident ion 4 usually takes place on nitrogen. H -
Base N-
N
N
H 3
H
(2)
H
N
N
H
N
4
+ HX N 1
+ N H
X-
(1)
2
The aromatic character of pyrrole (3) is also portrayed clearly (although the bond angles in that five-membered ring are not 120° [12]) and is based in part on a heat of combustion about 25 kcal/mol less than calculated for a diene structure (7 ); resonance energy of ~22 kcal/mol (3, 6, 17 ); proton resonances in the 1H NMR spectrum in the aromatic region (7, 9); and the fact that pyrrole undergoes electrophilic aromatic substitution. All texts clearly state that the aromatic sextet is made up of four p electrons, one from each of the four sp2hybridized carbons, and two electrons from the p orbital of the pyrrole type of sp2-hybridized nitrogen. In spite of repeatedly
Instead of simply acknowledging that the basicity of pyrrole (3) is “virtually nonexistent”, most texts devote a great deal of space to this problem. Ironically, calling pyrrole a base is like calling ethanol (pKa = 15–18 [15]; 16 [11]) a base! Alcohols, like pyrrole, are neutralized by strong basic reagents (e.g., hydride ion, organometallics) to form stable anions. Furthermore, alcohols are also attacked by strong acids in strictly anhydrous media, to form first oxonium salts and then carbocationic intermediates. Many of the circuitous statements relating to the alleged basicity would be unnecessary if the reader were simply informed that pyrrole does not undergo reversible neutralization on nitrogen. The problem can be judged by examining excerpts from some texts. Many authors attempt to compare organic amines and pyridine with the “virtually non-basic” pyrrole. While nuances of such comparisons may be appreciated by seasoned
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chemists, they might well be lost on undergraduate students. Some selected sections, not quoted in toto, illustrate the problem: “Unlike pyridine and the amines, pyrrole (pKb = ~14) is not basic under the usual conditions” (7 ) assumes that the student has a feeling for “usual conditions”! and, “Pyridine and pyrrole are both weak bases, but pyridine is much more basic than pyrrole” (5) assumes that students understand the full meaning of “much more basic”. Other authors attempt to quantify this matter: “Pyrrole (pKb = 13.6) is a much weaker base than pyridine (pKb = 8.8)” (17 ); and “Pyrrole is an exceedingly weak base, pKb = 15” (compared to pyrrolidine, pKb = 2.73) (12). Frequently, beginning organic chemistry students have difficulty grasping differences between “weak”, “relatively weak”, “extremely weak,” and “relatively strong” organic bases. Having mastered reversible neutralizations of “regular” organic bases to form ammonium salts (usually well before heteroarenes are presented), beginning students have a tendency to neutralize nitrogens possessing a free electron pair, be it on 3 or another nitrogen-bearing functional group, (amides are prime examples). All warnings that the two electrons on the ring nitrogen of 3 are not available for protonation because of their utilization for the aromatic π-electron sextet may go unheeded. The impulse to form the wrong and nonexistent salt 5 is real, and eq 3 (1, 8, 17) should perhaps best be omitted, even if this reaction is stated not to take place. HX
+ N
3 H
XH
(3)
5
There are other statements that may not help students comprehend some of the essentials related to the acid–base properties of 3. “Because the nitrogen atom in pyrrole contributes two electrons to the aromatic π cloud, the nitrogen atom is electron-deficient and therefore not basic. The pyrrole ring, however, has six π electrons for only five ring atoms. The ring is electron-rich and therefore partially negative” (7). Another text links the pyrrole ring’s “negativity” to dipole moments, comparing that of pyrrolidine, µ = 1.57 D, with that of pyrrole, µ = 1.80 D, which are opposite in direction, pointing out that “This indicates that nitrogen’s ability to donate electrons into the ring by resonance more than makes up for its inductive electron withdrawal” (4). The fallacy is that one electron pair from the aromatic sextet is readily available during electrophilic attack on the pyrrole ring, as is elaborated below. Electrophilic attack of a proton on pyrrole takes place in a nonreversible manner and therefore is not a neutralization. The attachment is to one of the ring carbons, which some authors specify while others are ambivalent about it. Some texts show pictures, others just words. Parenthetically, it is written that “Pyrrole can be protonated by strong acids— however, protonation occurs on one of the ring carbon atoms, not on the nitrogen atom” (1); “When it [pyrrole] accepts a proton, it does so on one of the carbon atoms adjacent to the nitrogen atom” (6 ). Such sweeping statements as “Because pyrrole and indole look like amines, it may come as a surprise that neither of the two heterocycles has appreciable basicity. These compounds are protonated only in strong acid, and protonation occurs on carbon, not nitrogen” are followed by an equation correctly depicting pyrrole being protonated at 1152
C-2 and showing the appropriate three contributors to the resonance hybrid 6 (10). However, the author fails to tell the student that indole is protonated preferentially at C-3. In other texts, only the resonance hybrid contributor due to attack at C-2 of 3 is drawn (6, 9 16 ). Protonation on the ring carbon of 3 does disrupt the π -electron system, but results in the resonance-stabilized cation 6 (see eq 4).
3
H+
+
H H
N H
H
H
+
H
N
H
H
H H
+ N
H
(4)
H
6
Having established that pyrrole reacts with a proton to form a C–H, and not an N–H, bond, what meaning can be attached to the values quoted for pKa of such “conjugate acids”? Some texts imply C-protonation and provide pKa’s of {3.8 (4, 6 ), {4 (9, 10), and {4.4 (14, 16 ). There is also a value reported for the unknown N-protonated species, 5, of 0.4 (17). A similar value is shrouded in this somewhat mysterious, yet in part correct, statement: “Because the nitrogen lone pair is a part of the aromatic sextet, it is less available for bonding with acids. Pyrrole is therefore less basic and less nucleophilic (pKa = 0.4). By the same token, however, the carbon atoms of pyrrole are more electron rich and more nucleophilic than typical double-bond carbon atoms. The pyrrole ring is therefore reactive towards electrophiles in the same way that activated benzene rings are reactive” (11). The reaction of pyrrole with mineral acids is fast and indeed extremely complex. Most textbooks ignore the facts that pyrrole itself, plus many substituted pyrroles, is extremely sensitive to strong aqueous acids, and that the action of dilute hydrochloric acid on 3 produces an amorphous orange substance that has been named pyrrole red (19). Also not mentioned is the sensitivity of pyrrole to strong acids as is evident when “the vapor of pyrrole turned a pine splinter dipped in hydrochloric acid a purple-red color”, detecting even one part in 300,000 of pyrrole (20). The fact that 3 is protonated initially at C-2 has been established by succinct 1 H NMR experiments in aqueous sulfuric acid (21). A later paper reported that neutralization of some di- and tri-tertbutyl pyrroles with tetrafluoroboric acid led to the isolation of the corresponding relatively stable (several months) pyrrolium tetrafluoroborates (22). C-Protonation is corroborated by a number of molecular orbital calculations using the PM3 and AM1 methods (23), thus supporting the previous conclusion (21) that there is no protonation on the nitrogen of pyrroles. March (18) succinctly states that “pyrrole is neutral in aqueous solution”. Some authors might wish to modify their position on the lack of “basicity” of pyrrole and emphasize its weak acid character in subsequent editions of their texts. Literature Cited 1. Baker, A. D.; Engel, R. Organic Chemistry, 1st ed.; West: St. Paul, MN, 1992; p 743. 2. Beyer, H.; Walter, W. Handbook of Organic Chemistry, 1st English ed.; Prentice Hall: Englewood Cliffs, NJ, 1996; pp 705–707. 3. Brown, W. H. Organic Chemistry, 1st ed.; Saunders: Fort Worth, TX, 1995; p 562. 4. Bruice, P. Y. Organic Chemistry, 1st ed.; Prentice Hall: Englewood Cliffs, NJ, 1995; p 921.
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5. Carey, F. A. Organic Chemistry, 3rd ed.; McGraw-Hill: New York, 1996; pp 455–456. 6. E¯ge, S. N. Organic Chemistry, 3rd ed.; Heath: Lexington, MA, 1994; p 1061. 7. Fessenden, R. J.; Fessenden, J. S. Organic Chemistry, 5th ed.; Brooks-Cole: Pacific Grove, CA, 1994; pp 795–797. 8. Fox, M. A.; Whitesell, J. K. Organic Chemistry, 1st ed.; Jones and Bartlett: Boston, MA, 1994; pp 95–96. 9. Jones, M. Organic Chemistry, 1st ed.; Norton: New York, 1997; pp 1301–1307. 10. Loudon, G. M. Organic Chemistry, 3rd ed.; Benjamin-Cummings: Redwood City, CA, 1995; p 1182. 11. McMurry, J. Organic Chemistry, 4th ed.; Brooks-Cole: Pacific Grove, CA, 1996, pp 553, 943, 1131, 1169. 12. Morrison, R. T.; Boyd, R. N. Organic Chemistry, 6th ed.; Prentice Hall: Englewood Cliffs, NJ, 1992; p 1060. 13. Ouelette, R. J.; Rawn, J. D. Organic Chemistry, 1st ed.; Prentice Hall: Upper Saddle River, NJ, 1996; p 962.
14. Schmidt, G. H. Organic Chemistry, 1st ed.; Mosby: St. Louis, MO, 1996; p 900. 15. Solomons, T. W. G. Organic Chemistry, 6th ed.; Wiley: New York, 1995; p 638. 16. Vollhardt, K. P. C.; Schore, N. E. Organic Chemistry, 2nd ed.; Freeman: New York, 1994; p 998. 17. Wade, L. G. Jr. Organic Chemistry; 3rd ed.; Prentice Hall: Englewood Cliffs, NJ, 1995; pp 731–732. 18. March, J. Advanced Organic Chemistry, 3rd ed.; Wiley: New York, 1985; p 235. 19. The Merck Index, 11th ed.; Budavari, S., Ed.; Merck: Rahway, NJ, 1989. 20. Anderson, H. J. J. Chem. Educ. 1995, 72, 875–878. 21. Chiang, Y.; Whipple, E. B. J. Am. Chem. Soc. 1963, 53, 2763–2767. 22. Gassner, R.; Krumbholz, E.; Steuber, F. W. Liebigs Ann. Chem. 1981, 789–791. 23. Nakajima, Y.; Sakagishi, Y.; Shiibashi, M.; Suzuki, Y.; Kato, H. J. Mol. Structure (Theochem) 1993, 288, 199–205.
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