RGANIC
`HEMISTRY
`
`FRANCIS A. CAREY
`
`Department of Chemistry
`University of Virginia
`
`MCGRAW-HILL BOOK COMPANY
`
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`Page 1 "f6
`
`SENJU EXHIBIT 2101
`
`LUPIN v. SENJU
`IPR20l5—01100
`
`

`
`ABOUT THE COVER
`
`The cover depicts a new kind of molecular structure, one characterized by a spherical cluster of 60 car-
`bon atoms. This compound, referred to as “buckrninstert'ulIerene,” 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 of the molecule is large enough to accommodate other atoms and the + sign rqaresents 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 buclcminsterfullerene 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 Florante Quioeho and John
`C. Spurlino of the Biochemistry Department at Rio: for pcnnission to reproduce their computer
`graphics depiction of buckminsterfullerene.
`
`ORGANIC CHEMISTRY
`Copyright © [987 by McGraw-Hill, Inc. All rights reserved. Printed in the United States of America.
`Except as permitted under the United States Copyright Act of I976, 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.
`
`234567890 D0wDow 8943210987
`
`ISBN n—n?-009531-x
`
`This book was set in Serif by Progressive Typographers, Inc. The editors were Karen S. Misler, Randi
`B. Kashan, and David A. Damstra; the production supervisor was I_eroy A. Young; the designer was
`Rafael Hernandez. The drawings were done by I & R Services, Inc. R. R. Donnelley and Sons Com-
`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.
`QD25 l.2.C364
`I987
`ISBN 0-07-0098} l—X
`
`1. Title.
`547
`
`86- l0374
`
`Page 2 of 6
`
`
`
`k..\-.(-I-T.‘-.~.4.-.r..‘.;~_-...=.:..-..‘;'xt.v_
`
`

`
`
`
`The separate effects of the amino group and the trifluoromethyl group must rein-
`force, rather than oppose, each other. Since the triiluoromethyl group attracts elec-
`trons, the amino group must release them. gm
`
`
`
`PROBLEM 24.4 which would you expect to have the greater dipole moment,
`p-dinitrobenzene orp-nltroaniline? why?
`
`
`
`Because of its electronegativity nitrogen tends to withdraw electrons from carbon
`by polarization of the electron distribution in 0 bonds. Because nitrogen has an
`unshared pair ofelectrons, it can donate them to adjacent 7: 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 0 bonds.
`
`24.4 BASICITY OF ABYLAMINES
`
`Aromatic amines are several orders of magnitude less basic than alkylamines; while
`Kb for most alkylamines is on the order of l0“ (pK,, 5), arylamines have Kb's in the
`10‘ ‘° range. The sharply decreased basicity of arylamines arises because the stabiliz-
`ing effect of lone pair electron delocalization is sacrificed on protonation.
`
`R
`
`/
`I_\_J\
`/ R’
`
`+H,0.-:.
`
`Amine is stabilized by
`delocalization oflone
`pair into it system of
`ring. decreasing the electron
`density at nitrogen
`
`/ \
`*‘
`
`H
`i+
`N—R
`it
`
`+Ho-
`
`Lone pairelectrons
`transformed to N-H bonded pair
`
`The aromatic ring does very little to disperse the positive charge in the ammonium
`ion. Indeed, since the ring carbon attached to nitrogen is sp’ hybridized, it is electron
`withdrawing and destabilize: the ammonium ion. Stabilization of the amine and
`destabilization of the ammonium ion combine to make the equilibrium constant for
`amine protonation smaller for arylamines than for alkylamines. This relationship is
`depicted in Figure 24.3..where the free energies of protonation of cyclohexylamine
`
`Page 3 of 6
`
`
`
`24.4 BASICITY or ARYLAMINES 917
`
`The direction of polarization is not revealed directly by dipole moment measure-
`cnts but can be deduced by examining the effects of substituents. The dipole
`‘moment of p-(trifluoromethyl)aniline, for example, is approximately equal to the
`sum of the separate dipole moments of aniline and (trilluorornethyubenzene.
`
`NH,
`
`Tot
`
`I
`
`NH,
`
`Aniline
`ll l.3D
`
`CF,
`(Trifluoromethyl)benzenc
`}l2.9D
`
`CF,
`p-(Trilluoromethyl)ani|inc
`y4.3D
`
`

`
`Destabilization of
`anilinium ion due to
`electron withdrawal
`by benzene ring
`J~~~- » —
`
`'*
`N”:
`- OH
`
`mi“;
`
`‘ OH
`
`T“—*r
`
`AG° = 4.6 kcal/mol
`
`_L__..__
`X‘“"2
`
`i—
`
`AG° = 12.8 kcal/moi
`
`+ H 0 Stabilization of aniline due to
`2
`electron delocalization into 11
`system of aromatic ring
`
`l J
`
`+_
`
`91 8 ARYLAMINES
`
`'
`
`i
`
`Cyclo hexylamine
`
` NH2
`
`+ H2 0
`
`Aniline
`
`FIGURE 24.3 Free energy
`changes accompanying protonaiion
`of aniline and cyolohexylamine by
`water.
`
`and aniline are compared. As measured by their respective K,,’s, cyclohcxylaminc is
`almost 1 million times more basic than aniline.
`
` NH,+H2 ;.—_—~.{<j>—NH,+ HO‘
`
`+
`
`(1<,,3.8><io-'0; pK,,9.4)
`
`Aniline
`
`Water
`
`Anilinium ion
`
`Hydroxide
`ion
`
`<:>+NH2+H2O: Gnu; + H0‘
`
`(K,,4.4><l0"‘;pK(,3.4)
`
`Cyclohexylamine
`
`Water
`
`Cyclohexylammonium
`ion
`
`Hydroxide
`ion
`
`When the proton donor is a strong acid, arylami nes can be completely protonated.
`Aniline is extracted from an ether solution into i N hydrochloric acid because it is
`converted to a water-soluble aniliniurn ion salt under these conditions.
`
`
`
`The two amines shown differ by a factor of 40,000 in their K, values.
`PROBLEM 24.5
`which is the stronger base? Why‘?
`
`(>1/,3
`
`Telrahydroquinoline
`
`Tetrahydroisoquinoline
`
`‘
`
`
`
`Page 4 of 6
`
`

`
`...-,,.-...~..-\,..,,__
`
`24.4 BASICITY OF ARYLAMINES
`
`9
`
`Conjugation of the amino group with a second aromatic ring, then a third, reduces
`ts basicity even further. Diphenylamine is 6300 times less basic than aniline, while
`;;‘-triphenylamine is scarcely a base at all, being estimated as 103 times less basic than
`
`
`
`gi-"aniline and 10" times less basic than ammonia.
`C6H5NH2
`(C6H5)2NH
`
`Aniline
`Diphenylamine
`(K), 3.8 X l0"°;
`(K, 6 X l0"‘;
`pI(,, 9.4)
`p[(,, l3.2)
`
`E_
`
`(C6H5)3N
`Triphenylaminc
`(K, ~- 10"’;
`pK,, ~ 19)
`
`The effects of some representative aryl substituents on the basicity of arylamines
`,
`3' 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 K,, ofptoluidine is 5 to 6 times greater
`than that of aniline, but aniline is 220 times more basic than its p-trifluoromethyl
`derivative.
`
`NH;
`
`NH2
`
`NH;
`
`CH3
`p-Toluidine
`(K, 2 X l0‘°:
`pK,, 8.7)
`Most basic; methyl group
`donates eiectrons
`
`Aniline
`(K,, 3.8 X l0““;
`pk’, 9.4)
`
`CF,
`;»(Trifluoromelhyl)aniline
`(K, L? X 10"":
`pI\',_ ll.5)
`Least basic: tritluoromcthyl
`group withdraws electrons
`
`TABLE 24.2
`
`Basicities ol Some Arylamlnes
`
`Position of substituent X and K,, (pKt,)' Substituem in H,NC5H,X Ortho
`
`Meta
`
`Para
`
`Standard ot comparison is aniline
`
`_
`
`h
`
`H
`
`3.8 ><1o-‘°(9.4)
`
`3.8 x 1o*'° (9.4)
`
`3.8 x10-‘°(9.4)
`
`Electron-releasing substituents increase basicity slightly
`
`OCH3
`CH,
`
`3.8 x 10"° (9.4)
`3.3 x1o~'°(9.5)
`
`1.6 x 1o-'° (9.8)
`5.5 x 10-‘° (9.3)
`
`2.2 ><10‘“(8.7)
`2 x to-9 (8.7)
`
`Electron-withdrawing substituents decrease basicity
`
`Cl
`ii’
`ccna
`cw
`No,
`
`4.5><to-'=(11.3) 3.8x1o-"(1o.4)
`
`7.2><1or"(1o.2)
`
`2.5><10“’(1t.6)
`a.9><1o-"(13.1)
`5.5x1o-'=(14.3)
`
`4x10-"(1o.4)
`5.6X10""(11.2)
`2.9x1o"*(11.5)
`
`5x1tT'=(11.3)
`5.5><1o-'°(12.a)
`1x1o*'°(13.o)
`
`' In water at 25'C.
`
`Page 5 of 6
`
`

`
`920 ARYLAMINES
`
`The methyl group in p-toluidine donates electrons to the ring and helps dispersc thé
`positive charge in the derived anilinium ion. A trifluoromethyl substituent enhances ‘ii
`the tendency of the aryl group to attract electrons from nitrogen, thereby lowering its
`basicity.
`Electron-withdrawing groups that are conjugated to the amine nitrogen havc a
`very large base-weakening effect; K, for p~nitroani1ine, for example, is 3800 times
`smaller than K, for aniline. A resonance interaction of the type shown leads to
`extensive delocalization of the unshared electron pair of the amine group and stabi-
`lizes the free arylamine.
`
`-
`
`0
`
`\
`
`K
`
`..
`
`O
`
`x,\ N / \ TNHZ ‘___) \ In
`
`/ + _
`
`C_)
`
`o_
`Electron delocalization in p-nitroaniline
`
`+
`
`“NH?
`
`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 convened
`to a bonded pair of an ammonium ion. More resonance stabilization is lost when
`p-nitroaniline is protonated than when aniline is, which makes K, smaller for
`p-nitroaniline.
`
`
`
`
`
`
`Each of the following is a much weaker base than aniline. Present a
`PROBLEM 24.6
`resonance argument to explain the effect of the substituent in each case.
`
`o-Cyanoaniline
`(a)
`(b) p-Cyanoaniline
`
`0 l
`
`l
`CG}-l5NHCCH3
`(c)
`(d) p-Aminoacetophenone
`
`SAMPLE SOLUTION (a) A cyano substituent is strongly electromwithdrawing. when
`present at a position ortho to an amino group on an aromatic ring, a cyano substituent in-
`creases the delocallzation of the amine lone pair electrons by a direct resonance interaction.
`
`=NH
`
`Q__
`
`2 C;/N;
`
`*
`
`":-
`
`NH2 C¢N.
`
`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 strongl)’
`electron-withdrawing groups are often not capable of being extracted from ether
`solution into dilute aqueous acid.
`
`Page 6 of 6
`
`mugs.