`
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`·''
`
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`~ .,
`
`FRANCIS A. CAREY
`
`Department of Chemistry
`University of Virginia
`
`McGRAW-HILL BOOK COMPANY
`New York St. Louis San Francisco Auckland Bogota
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`
`II
`
`PAGE10F6
`
`SENJU EXHIBIT 2101
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`
`
`-~
`
`·~ .
`
`~ . t:
`
`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. Tllis 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 grapbite. The
`interior of the molecule is large enough to accommodate other atoros and the + sign represents an
`atom of lanthanum trapped within the spherical cavity. The colored dots indicate the approx_imate 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 Florante Quiocho and John
`C. Spurlino of the Biocllernistry Department at Rice for pennission to reproduce their computer
`graphics depiction of buckminsterfullerene.
`
`ORGANIC CHEMISTRY
`Copyright© 1987 by McGraw-Hill, (nc. All rights reserved. Printed in tbe 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 follD 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 & 9 0 OOWDOW & 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.
`
`Libmry of Congr~ss Cataloging-in-Publication Data
`
`Carey, francis A. (date)
`Organic chemistry.
`
`Bibliography: p.
`Includes index.
`I. Chemistry, Organic.
`QD25 1.2.C364
`1987
`ISBN 0-07-009831-X
`
`I. Title.
`547
`
`86-10374
`
`Page 2 of6
`
`
`
`24.4 BASICITY OF ARYLAMINES 917
`
`The direction of polarization is not revealed directly by dipole moment measure(cid:173)
`nts but can be deduced by examining the effects of substituents. The dipole
`mou1cu• of p-(trifluoromethyl)aniline, for example, is approximately equal to the
`of the separate dipole moments of aniline and (trifluoromethyl)benzene.
`
`t@
`
`Aniline
`).11.30
`
`(Trifluoromethyl)benzene
`tt2.9 D
`
`p-(Trilluoromethyl)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 electronegati vity 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 w-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.
`
`ON/R
`/''R'
`
`Amine is stabili<:ed by
`delocalization of lone
`pair into rr system of
`ring, decreasing the el~<:tron
`density at nitrogen
`
`+HP ~
`
`H 07'-R
`
`R'
`Lone pair electrons
`transformed to N-H bonded pair
`
`+Ho-
`
`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
`
`. ~
`
`•' ·
`
`.;_;
`i
`
`.
`
`.. ; .. ,
`. ·.~
`·-f
`:~
`r~
`·j
`. ·~
`
`~ ..
`···~
`.~
`• i~
`- ~
`
`. · ~.
`.. ;_
`
`'
`I '
`
`' ~
`
`.
`' ;;
`
`h
`1
`
`; ~
`
`.il
`
`~.:.·
`
`y
`
`{.
`
`..
`
`Page 3 of 6
`
`
`
`·~
`
`918 ARVLAMINES
`
`Destabilization of
`anilinium ion due to
`electron withdrawal
`by benzene ring
`
`-T
`
`t.G0 ~ 12.8 kcal/mol
`
`t.C0
`
`- 4.6 kcal/mol
`
`T
`j__-r-
`c:::::r- NH 2
`
`+ H2 0
`
`Stabilization of aniline due to
`electron delocalization in to rr
`system of aromatic rina
`I
`
`\
`
`I i
`
`Cyclohexylamine
`
`Aniline
`
`FIGURE 24.3 Free Energy
`changes accompanying protonatiOn
`of aniline and cyclohexytamine by
`water.
`
`and aniline are compared. As measured by their respective K1/s, cyclohexylamine is
`almost 1 million times more basic than aniline.
`
`Aniline
`
`Water
`
`Anilinium ion
`
`Hydroxide
`ion
`
`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?
`
`©0 H
`
`Tetrahydroqunoline
`
`Tetrahydroisoquinoline
`
`Page 4 of6
`
`
`
`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
`!amine is scarcely a base at all, being estimated as 108 times less basic than
`" "''" ___ _
`and 10 14 times less basic than ammouia.
`
`C 6H 5NH2
`Aniline
`(Kb 3.8 X w-•o;
`pKb 9.4)
`
`(C6 H shNH
`Diphenylamine
`(Kb 6 X 10-••;
`pKb 13.2)
`
`(C6Hs)3N
`Triphenylamine
`(~ -I0-•9;
`pKb- 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
`])·Toluidine
`(Kb 2 X 10- 9:
`pK0 8.7)
`Most basic: methyl group
`donates electrons
`
`Aniline
`(K6 3.8 X I0-'0:
`pK~ 9.4)
`
`CF3
`p-(TriOuoromethyl)aniline
`(K. 1. 7 X tO-•):
`p/<:,, 11.5)
`Least basic: trilluoromethyl
`group withdraws electrons
`
`TABLE 24.2
`Basicities of Some Arylamines
`
`Position of substituent X and Kb (pKb)*
`
`- - - - -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`~
`
`.. \.;\
`
`Meta
`
`Substituent in H2NC6H4 X Ortho
`,..
`~-:. ... -: ·\1r .(~.
`<:...-·.
`• •
`- ~;.
`•.
`.. • .::-1
`Standard ~f. comP,arison is;a~~in~: ~~~>{ ;:· .
`~-B ·?< 10~:1~. {9,.1) . 3·.S X 1 Q- 10 (9.4)
`H
`'
`
`.. .
`
`Para
`
`3.8 X 10-lo (9.4)
`
`•
`
`•
`
`~ ''l'l' •
`
`' .
`
`'
`
`' t
`
`' ~:.,
`
`.... (•·
`::-.·
`
`Electron-releasing sub~tituents. increase basicity slighUy
`·.3·.8 X 10-10 (9.4)
`.1.6 X 10- 10 (9.8)
`5.5 X 1Q- 1o (9.3)
`3.3 X 1 Q-10 {9.5)
`
`2.2 X 1Q-9 (8.7)
`2 X 10-9 ·(8.7)
`
`Electron-wit hdrawing substituents decrease basicity
`
`4.5 X 10-12 (11.3) 3.8 X 10_ 1, (10.4) 7.2 X 10-11 {10.2)
`
`2.5 X 1 Q- 12 {11.6)
`8.9X1Q- 14 (13.1)
`5.5 X 10-15 (14.3)
`
`4 X 10-11 {1 0.4)
`5.6 X 10- 12 (1 1.2)
`2.9 X 10-'2 (1 1.5)
`
`5 X 10-12 (11.3)
`5.5 X 10- 13 (12.3)
`1 X 10-13 (13.0)
`
`Cl
`0
`II
`CCH3
`CN
`N02
`
`• In water at 25' C.
`
`Page 5 of6
`
`
`
`920 ARYLAMINES
`
`i
`{
`'
`
`1
`J
`
`·,
`
`~ z 'l
`
`( · ,
`~
`
`~' 6'
`~· !
`
`;·
`~
`
`}t
`,.
`t·
`I'
`I
`I I :
`
`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 of the 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 uoshared electron pair of the amine group and stabi(cid:173)
`lizes the free arylamine.
`
`-
`
`~~ ~\.~ .{). 0"-+=0+
`
`N
`/ +
`0
`
`NH2 ~ N
`/
`-
`-
`Q _
`Electron delocalization in p-nirroaniline
`
`NH2
`
`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 au ammonium ion. More resonance stabilization is lost when
`p-oitroaniline 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.
`
`(a) o-Cyanoaniline
`(b} p-Gyanoaniline
`0
`II
`(c) C6H5 NHCCH3
`(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 ling, a cyano substituent in(cid:173)
`creases the delocalization of the amine lone pair electrons by a direct resonance interaction.
`
`i
`f
`
`i'
`
`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-n itroaniline; 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 of6
`
`