`
`Department of Chemistry
`University of Virginia
`
`McGRAW-HILL BOOK COMPANY
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`Page 1 of 6
`
`SENJU EXHIBIT 2101
`LUPIN v. SENJU
`IPR2015-01097
`
`
`
`ABOUT THE COVER
`
`The cover depicts a new kind of molecular structure, one characterized by a spherical cluster of 60 car(cid:173)
`bon atoms. This compound, referred to as "buckminsterfullerene," has been described by Professor
`Richard E. Smalley and his coworkers in the Chemistry Department at Rice University. They suggest
`that it may be present among the products formed by high-vacuum laser vaporization of graphite. The
`interior oftbe molecule is large enough to accommodate other atoms and the+ sign represents an
`atom of lanthanum trapped within the spherical cavity. The colored dots indicate the approximate van
`der Waals surface of the molecule. Theoretical calculations indicate that buckminsterfullerene and its
`metal complexes should be quite stable, yet further research is needed to conclusively establish the
`proposed structure.
`In addition to Professor Smalley, I would also like to thank Professor Aorante Quiocho and John
`C. Spurlino of the Biochemistry Department at Rice for permission to reproduce their computer
`graphics depiction of buckminsterfullerene.
`
`ORGANIC CHEMISTRY
`Copyright© 1987 by McGraw-Hill, Inc. All rights reserved. Printed in the United States of America.
`Except as permitted under the United States Copyright Act of 1976, no part of this publication may be
`reproduced or distributed in any form or by any means, or stored in a data base or retrieval system,
`without the prior written permission of the publisher.
`
`2 3 4 5 6 7 8 9 0 OOWDOW 8 9 4 3 2 I 0 9 8 7
`
`ISBN 0-07-009831-X
`
`This book was Set in Serif by Progressive Typographers, Inc. The editors were Karen S. Mister, Randi
`B. Kashan, and David A. Damstra; the production supervisor was Leroy A. Young; the designer was
`Rafael Hernandez. The drawings were done by 1 & R Services, Inc. R. R. Donnelley and Sons Com(cid:173)
`pany was printer and binder.
`
`Library of Congress Cataloging-in-Publication Data
`
`Carey, Francis A. (date)
`Organic chemistry.
`
`Bibliography: p.
`Includes index.
`I. Chemistry, Organic.
`QD251.2.C364
`1987
`ISBN 0-07-009831-X
`
`I. Title.
`547
`
`86-10374
`
`Page 2 of 6
`
`
`
`24.4 BASICITY OF ARYlAMINES 917
`
`The direction of polarization is not revealed directly by dipole moment measure(cid:173)
`ts but can be deduced by examining the effects of substituents. The dipole
`moment of p-(trilluoromethyl)aniline, for example, is approximately equal to the
`sum of the separate dipole moments of aniline and (trilluoromethyl)benzene.
`
`r@
`
`Aniline
`J1 1.3 D
`
`1~ I~
`
`CF3
`(Trifluoromethyl)benzene
`Jl 2.9 D
`
`CF3
`p-(Trifluoromethyl)aniline
`).14.3 D
`
`The separate effects of the amino group and the trifluoromethyl group must rein(cid:173)
`force, rather than oppose, each other. Since the trifluoromethyl group attracts elec(cid:173)
`trons, the amino group must release them.
`
`PROBLEM 24.4 Which would you expect to have the greater dipole moment,
`p-dinitrobenzene or p-nitroaniline? Why?
`
`Because of its e!ectronegativity nitrogen tends to withdraw electrons from carbon
`by polarization of the electron distribution in a bonds. Because nitrogen has an
`unshared pair of electrons, it can donate them to adjacent n systems. Dipole moment
`data reveal that the n donor effect of an amino substituent on an aromatic ring
`substantially exceeds its electron-withdrawing effect on a bonds.
`
`24.4 BASICITY OF ARYLAMINES
`
`Aromatic amines are several orders of magnitude less basic than alkylamines; while
`Kb for most alkylamines is on the order of 10-s (pKb 5), arylamines have Kb's in the
`1 o- to range. The sharply decreased basicity of arylamines arises because the stabiliz(cid:173)
`ing effect of lone pair electron de localization is sacrificed on proto nation.
`
`H 07'-R + HO(cid:173)
`
`R'
`Lone pair electrons
`transformed to N-H bonded pair
`
`Amine is stabilized by
`delocalization of lone
`pair into n system of
`ring, decreasing the elc:ctron
`density at nitrogc:n
`
`..
`
`0'
`
`·<'
`
`. '
`
`I
`
`"
`
`The aromatic ring does very little to disperse the positive charge in the ammonium
`ion. Indeed, since the ring carbon attached to nitrogen is sp2 hybridized, it is electron
`withdrawing and destabilizes the ammonium ion. Stabilization of the amine and
`destabilization of the ammonium ion combine to make the equilibrium constant for
`amine proto nation smaller for arylamines than· for alkylamines. This relationship is
`depicted in Figure 24.3, .where the free energies of proto nation of cyclohexylamine
`
`. j . .
`
`Page 3 of 6
`
`
`
`----------------- - - -- - -----------------------------------------------------------------~--
`
`918 ARYLAMINES
`
`Destabilization of
`aniiinium ion due to
`electron withdrawal
`by benzene ring
`
`--T
`
`t.G0
`
`:::: 12.8 kcal/mol
`
`AG 0 = 4.6 kcal/mol
`
`T
`j__
`c::::r--- NH 2
`
`+ H2 0
`
`Stabilization of aniline due to
`electron de localization into 7T
`system of aromatic ring
`
`l
`
`Cyclohexylamine
`
`Aniline
`
`FIGURE 24.3 Free energy
`changes accompanying protonation
`of aniline and cyclohexylamine by
`water.
`
`and aniline are compared. As measured by their respective Kb's, cyclohexylamine is
`almost l million times more basic than aniline.
`
`@-NH,+ H,o=@-NH,+ Ho-
`
`Aniline
`
`Water
`
`Anilinium ion
`
`Hydroxide
`ion
`
`o-NH, +H,o= Q-NH, + Ho-
`
`Cyclohexylamine Water
`
`Cyclohexylammonium Hydroxide
`ion
`ion
`
`When the proton donor is a strong acid, arylamines can be completely protonated.
`Aniline is extracted from an ether solution into l N hydrochloric acid because it is
`converted to a water-soluble anilinium ion salt under these conditions.
`
`PROBLEM 24.5 The two amines shown differ by a factor of 40,000 in their Kb values.
`Which is the stronger base? Why?
`
`00 H
`
`Tetrahydroquinoline
`
`Tetrahydroisoquinoline
`
`Page 4 of 6
`
`
`
`24.4 BASICITY OF ARYLAMINES
`
`919
`
`conjugation of the amino group with a second aromatic ring, then a third, reduces
`basicity even further. Diphenylamine is 6300 times less basic than aniline, while
`lamine is scarcely a base at all, being estimated as 108 times less basic than
`and 10 14 times less basic than ammonia.
`
`C6HsNH 2
`Aniline
`(K11 3.8 X I o-•o;
`pK" 9.4)
`
`Diphenylamine
`(Kb 6 X tO-••;
`pKb 13.2)
`
`(C6HshN
`Triphenylamine
`(K"- t0-•9;
`pK•- 19)
`
`The effects of some representative aryl substituents on the basicity of arylamines
`are summarized in Table 24.2. In general, electron-donating groups increase the
`·. basicity of aniline slightly while electron-withdrawing groups decrease it, in some
`cases dramatically. Thus, the basicity constant Kb of p-toluidine is 5 to 6 times greater
`than that of aniline, but aniline is 220 times more basic than its p-trifluoromethyl
`· derivative.
`
`~ CH3
`
`p-Toluidine
`(Kb 2 X t0-9 :
`pK11 8.7)
`Most basic: methyl group
`donates electrons
`
`...
`
`TABLE 24.2
`Basicities of Some Arylamines
`
`Aniline
`(Kb 3.8 X 10- 10;
`pK" 9.4)
`
`CF3
`p-(Triftuoromethyl)aniline
`(Kb 1.7 X tO-•!:
`pK1• 11.5)
`Least basic: triOuoromethyl
`group withdraws electrons
`
`. ' :!. ,.
`
`..
`('
`
`I
`
`,.
`
`j
`. ]
`'
`I
`
`( ! I ;
`. i I i
`
`l
`t
`J.
`1'
`I
`
`-
`
`--
`
`Position of substituent X and Kb ( pKb)*
`- - - -- __ , ---
`- - -- - - - · - - - -
`Substituent in H2NC6H4X Ortho
`Meta
`Para
`~-:
`
`.
`
`. h. •
`
`• ":
`
`•
`
`·'
`
`• • <>,
`
`. . ,
`
`•
`
`:
`
`•
`
`)
`
`~·':'
`~.~7 -~.~d~ i';~;
`Standard of comparison ts. aniltne
`·. ,.,,-.;;~'"' .. . .
`'
`. • r_,
`.. . .
`3.8 X. ~ Q- 1~.(~.4) .. 3.8. X 1 o- 10 (9.4)
`
`H
`
`3 .. 8 X 10- 10 (9.4)
`
`Electron-releasing substituents· increase basicity slighUy
`3.8 x .1 o- 10 (9.4)
`3.3 X 1 <T"10 (9.5)
`
`1.6 X 10-10 (9.8)
`5.5 X 10- 10 (9.3)
`
`2.2 X 10- 9 (8.7)
`2 X 10- 9 (8.7)
`
`Electron-withdrawing substituents decrease basicity
`3.8 x 10- 11 (10.4)
`
`4.5 X 10- 12 (11.3)
`
`7.2 X 1<T" 11 (10.2)
`
`2.5 X 10- 12 (11.6)
`8.9 X 10- 14 (13.1)
`5.5 X 10- 15 (14.3)
`
`4 X 10- 11 (10.4)
`5.6 X 10-12 (11 .2)
`2.9 X 10- 12 (11.5)
`
`5 X 10- 12 (11.3)
`5.5 x 1 o- 13 (12.3)
`1 X 10- 13 (13.0)
`
`Cl
`0
`II
`CCH3
`CN
`N02
`·In water at 2s·c.
`
`Page 5 of 6
`
`
`
`920 ARYLAMINES
`
`The methyl group in p-toluidine donates electrons to the ring and helps disperse the
`positive charge in the derived anilinium ion. A trifluoromethyl substituent enhances
`the tendency ofthe aryl group to attract electrons from nitrogen, thereby lowering its
`basicity.
`Electron-withdrawing groups that are conjugated to the amine nitrogen have a
`very large base·weakening effect; Kb for p-nitroaniline, for example, is 3800 times
`smaller than Kb for aniline. A resonance interaction of the type shown leads to
`extensive delocalization of the unshared electron pair of the amine group and stabi(cid:173)
`lizes the free arylamine.
`
`,·;
`
`Electron delocalization in p-nitroaniline
`
`When the amine group is protonated, this type of resonance stabilization is no longer
`possible because the unshared electron pair of the amine nitrogen has been converted
`to a bonded pair of an ammonium ion. More resonance stabilization is lost when
`p-nitroaniline is protonated than when aniline is, which makes Kb smaller for
`p-nitroaniline.
`---~---------- -- ------- ------ ---
`PROBLEM 24.6 Each of the following is a much weaker base than aniline. Present a
`resonance argument to explain the effect of the substituent in each case.
`
`. 'l
`
`(a) o-Cyanoaniline
`(b) p-Cyanoaniline
`0
`II
`(c) C6H5NHCCH3
`(d) p-Aminoacetophenone
`
`SAMPLE SOLUTION
`(a) A cyano substituent is strongly electron-withdrawing. When
`present at a position ortho to an amino group on an aromatic ring, a cyano substituent in(cid:173)
`creases the delocalization of the amine tone pair electrons by a direct resonance interaction.
`
`This resonance stabilization is lost when the amine group becomes protonated, and
`o-cyanoaniline is therefore a weaker base than aniline.
`-----------------------------
`Multiple substitution by strongly electron-withdrawing groups diminishes the
`basicity of arylamines still more. As just noted, aniline is 3800 times as strong a base
`as p-nitroaniline; however, it is 109 times more basic than 2,4-dinitroaniline. A
`practical consequence of this is that arylamines that bear two or more strongly
`electron-withdrawing groups are often not capable of being extracted from ether
`solution into dilute aqueous acid.
`
`.,
`·'
`
`Page 6 of 6