Lecture 12 (2/17/17) Phenols. Chapter 18 in Loudon, M.; Parise, J. Organic Chemistry, 6th Ed. W. H. Freeman: New York, NY, 2016

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1 J. G. Rudick CHE 322: rganic Chemistry IIA Lecture 12 (2/17/17) Phenols Chapter 18 in Loudon, M.; Parise, J. rganic Chemistry, 6th Ed. W. H. Freeman: New York, NY, 2016 Prof. Jon Rudick ffice Hours: CHEM 775 Mondays 1:30 2:30p Tuesdays 1:30 2:30p Thursdays 2:30p 3:30p 1

2 Phenols are compounds in which an alcohol functional group is attached to an aromatic ring Natural Products H H 3 C H N capsaicin Pharmaceuticals Plastics H H H N H H H salbutamol bisphenol A 2

3 The enhanced acidity of phenol is due to stabilization of its conjugate-base anion by resonance Loudon, M.; Parise, J. rganic Chemistry, 6th Ed. W. H. Freeman: New York, NY, 2016 p. 913 H + B + B H phenol phenolate 3

4 The enhanced acidity of phenol is due to stabilization of its conjugate-base anion by resonance Loudon, M.; Parise, J. rganic Chemistry, 6th Ed. W. H. Freeman: New York, NY, 2016 p. 913 H + B + B H phenol pk a 9.95 (~10) H phenolate + B + B H cyclohexanol pk a ~17 phenolate evans.rc.fas.harvard.edu/pdf/evans_pka_table.pdf 4

5 J. G. Rudick icker Question Aryl H + B Aryl + B H What is the weakest base that is strong enough to deprotonate phenol? A. NaH (conjugate acid is H2, pka ~36) B. NaH (conjugate acid is H2, pka ~16) C. K2C3 (conjugate acid is KHC3, pka ~10) D. AcNa (conjugate acid is AcH, pka ~5) 5

6 H phenol pk a 9.95 (~10) Substituents on the aromatic ring can further shift the pka lower (i.e., stronger acid) F H phenol pk a 8.81 Et phenol pk a 8.5 H Stronger Acids Phenolate is Better Stabilized evans.rc.fas.harvard.edu/pdf/evans_pka_table.pdf 6

7 Substituents on the aromatic ring can further shift the pka lower (i.e., stronger acid) Et Et Et Et Et Charge is delocalized to an atom more electronegative than carbon! 7

8 Substituents on the aromatic ring can further shift the pka lower (i.e., stronger acid) F F F F Electronegativity of the substituent inductively stabilizes the negative charge. 8

9 J. G. Rudick icker Question Rank order the following compounds from lowest to highest pka. F F H H F H o-fluorophenol m-fluorophenol p-fluorophenol pk a 8.81 pk a 9.28 pk a 9.95 A. ortho < meta < para B. para < ortho < meta C. ortho < para < meta D. meta < ortho < para E. they are essentially the same (i.e., ± 0.1 pka units) 9

10 Substituents on the aromatic ring can further shift the pka lower (i.e., stronger acid) F F H H F H o-fluorophenol pk a 8.81 m-fluorophenol pk a 9.28 p-fluorophenol pk a 9.95 F F F Inductive effects decline as the electron withdrawing group (EWG) moves farther away from the negative charge on the phenolate 10

11 J. G. Rudick icker Question N H N H m-cyanophenol pk a 8.61 p-cyanophenol pk a 7.95 Which phenol is most acidic (i.e., has the lowest pka)? A. m-cyanophenol B. p-cyanophenol C. they are essentially the same (i.e., ± 0.1 pka units) 11

12 Substituents on the aromatic ring can further shift the pka lower (i.e., stronger acid) N H N N C p-cyanophenol pk a 7.95 Charge is delocalized to an atom more electronegative than carbon! N N N H m-cyanophenol pk a 8.61 Electronegativity of the substituent inductively stabilizes the negative charge. 12

13 J. G. Rudick icker Question Pre-lecture Quiz Question Which phenol is most acidic (i.e., has the lowest pka)? 2 N H H 2 N H p-nitrophenol o-chlorophenol pk a chloro-4-nitrophenol pk a 5.42 pk a 7.14 A. p-nitrophenol B. o-chlorophenol C. 2-chloro-4-nitrophenol D. A and C are essentially the same (i.e., ± 0.1 pka units) 13

14 Substituents on the aromatic ring can further shift the pka lower (i.e., stronger acid) 2 N H H 2 N H p-nitrophenol pk a 7.14 o-chlorophenol pk a chloro-4-nitrophenol pk a N 2 N N Resonance and inductive effects are cumulative 14

15 J. G. Rudick icker Question What is the most significant factor that contributes to the lower pka of 2-chloro-4-nitrophenol compared to 4-chloro-2-nitrophenol? N 2 2 N H H 2-chloro-4-nitrophenol pk a chloro-2-nitrophenol pk a 6.46 A. Steric interactions force o-nitro group out-of-plane so that there is less resonance stabilization of the o-nitrophenolate B. Repulsion between anions on the phenolate and o-nitro oxygens destabilize the o-nitrophenolate C. The inductive effect of the p-chloro group is much less than the o-chloro group 15

16 Substituents on the aromatic ring can further shift the pka lower (i.e., stronger acid) N 2 H H o-chlorophenol pk a 8.48 o-nitrophenol pk a 7.23 H 2 N H p-chlorophenol pk a 9.38 p-nitrophenol pk a evans.rc.fas.harvard.edu/pdf/evans_pka_table.pdf 16

17 J. G. Rudick icker Question Which site reacts faster (or first) with a radical (R )? R + B H H 3 C A C H 17

18 Phenols react with radicals to form more stable, resonance stabilized radicals (e.g., inhibition of free-radical reactions) R + H R H + 18

19 J. G. Rudick icker Question Pre-lab Quiz Question H H H 3 C H H 3 C A H B Which isomer reacts faster with a radical (R ) (i.e., which is a better antioxidant)? A. the 4-hydroxy isomer B. the 3-hydroxy isomer C. there is no difference between the two isomers 19

20 CH 3 CH 3 CH 3 CH 3 H H H H 20

21 H 3 C H 3 C H 3 C H 3 C H H H H H 3 C H 3 C H H 21

22 xidation of phenols to quinones H [] H 2 H [] R H 2 R [] = Na2Cr27/H2S4, Cr3 22 J. rg. Chem. 1983, 48,

23 J. G. Rudick Lecture 12 Ended Here icker Question Answers 5. C. 9. A. 11. B. 13. C. 15. C. 17. B. 19. A. 29. C. 23

24 Catechols are aromatic 1,2-diols Hydroquinones are aromatic 1,2-diols H Natural Products H urushiol Pharmaceuticals H H H epinephrin HN 24

25 Hydroquinones are readily oxidized to quinones H [] para-quinone H H H [] ortho-quinone [] = Ag2, Cr3, Na2Cr27/H2S4 25 J. Am. Chem. Soc. 1995, 117,

26 Hydroquinones are readily oxidized to quinones H B [] B H (H 2 ) H 1e H (H 2 ) Seminquinone [] 1e H H H H 26

27 Hydroquinones are readily oxidized to quinones H B [] B H (H 2 ) H 1e H (H 2 ) [] 1e 27

28 Laboratory Synthesis NH 2 HN N 2 Cu 2 Cu +2 H H 2 28

29 J. G. Rudick icker Question Which of these phenols has the lowest pka (i.e., is most acidic)? H H H o-chlorophenol pk a 8.48 m-chlorophenol pk a 9.02 p-chlorophenol pk a 9.38 A. ortho < para < meta B. para < meta < ortho C. ortho < meta < para D. meta < ortho < para E. they are essentially the same (i.e., ± 0.1 pka units) 29

30 Substituents on the aromatic ring can further shift the pka lower (i.e., stronger acid) or higher (i.e., weaker acid) H H H o-chlorophenol pk a 8.48 m-chlorophenol pk a 9.02 p-chlorophenol pk a 9.38 Inductive effects decline as the electron withdrawing group (EWG) moves farther away from the negative charge on the phenolate 30