SENJU EXHIBIT 2101
`LUPIN v SENJU
`IPR2015-01105
`
`PAGE 1 OF 6
`
`

`
`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 “buclrminstert'ullerene,” 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 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 buckminstetfullerene and its
`metal complexes should be quite stable, yet further research is needed to conclusively establish the
`proposed structure.
`In addition to Professor Srnalley, I would also like to thank Professor Florante Quiocho and John
`C. Spurlino of the Biochemistry Department at Rice for pennission to reproduce their computer
`graphics depiction of buckminsterfullerene.
`
`ORGANIC CHEMISTRY
`Copyright © 1937 by Mcfiraw-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 fonn or by any means, or stored in a data base or retrieval system,
`without the prior written permission of the publisher.
`
`23456?390 DOWDOW 8943210937
`
`ISBN EI—rJ?—DU‘lE.31—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 I & R Services, Inc. R. R. Donnelley and Sons Com-
`pany was printer and binder.
`
`
`
`Library of Congress Cataloging-in—Puhlic2tion Data
`
`Carey, Francis A. (date)
`Organic chemistry.
`
`Bibliography: p.
`Includes index.
`
`I. Chemistry, Organic.
`QD25l.2.C364
`I987
`ISBN 007-00933 1-K
`
`1. Title.
`547
`
`86-l03'.'4
`
`PAGEZOF6
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`,_.,,_;-.--=.__<--'~,.-e~_.;»_:*.r~_-_e;:-£j;"‘.r‘..":'--_'
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`._(_Im...J_‘.:u__.;:£____._...-.
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`PAGE 2 OF 6
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`The separate effects of the amino group and the trifluoromethyl group must rein-
`force, rather than oppose, each other. Since the trifluoromethyl group attracts elec—
`trons, the amino group must release them.
`
`'
`
`PROBLEM 24.4 which would you expect to have the greater dipole moment,
`' pointtrobenzene or p-nitroaniline? Why?
`
`Because of its electronegativity nitrogen tends to withdraw electrons from ca rbon
`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 R donor effect of an amino substituent on an aromatic ring
`substantially exceeds its electromwithdrawing effect on 0 bonds.
`
`24.4 BASIGITY OF ARYLAMINES
`
`Aromatic amines are several orders of magnitude less basic than alkylamines; while
`Kb for most alkylatnines is on the order of l0‘5 (pig, 5), arylamines have Kgs 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.
`
`
`
`/
`
` N\
`
`R
`
`R’
`
`+ H20 .~;~_:
`
`.
`
`H
`i+
`
`/ \ N—R
`__u
`lit
`
`+ H0-
`
`Amine is stabilized by
`delocalization of lone
`pair into II system of
`ring. decreasing the electron
`density at nitrogen
`
`Lone pair electrons
`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 spz hybridized, it is electron
`Withdrawing and destabilizes the ammonium ion. Stabilization of the amine and
`destabilization ofthe ammonium ion combine to make the equilibrium constant for
`amine protonation smaller for arylamines thanfor allcylamines. This relationship is
`depicted in Figure 24.3,-where the free energies of protonation of cyclohexylamine
`
`PAGE 3 OF 6
`
`24.4 BASlClTY OF AHYLAMNE5
`
`.' The direction of polarization is not revealed directly by dipole moment measure-
`ients but can be deduced by examining the effects of substituents. The dipole
`oment of p-(trifluoromethy1)aniline, for example, is approximately equal to the
`sum of the separate dipole moments of aniline and (trifluoromethyljbenzene.
`
`6
`
`NH?
`
`Aniline
`pt 1.3 D
`
`CF}
`(Trifluorornethmbenzene
`it 2.9 D
`
`CF,
`p-(Trilluoromethyl)aniline
`,u 4.3 D
`
`PAGE 3 OF 6
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`

`
`91 B ARYLRIIIINES
`
`Destabilization of
`anilinium ion due to
`
`t
`
`by benzene ring
`
`+
`
`[:fl""“3
`
`‘ OH
`
` /NH3
`electron withdrawal
`Le” e *1-
`
`-
`
`OH
`
`AC-'° -1 4.6 kcalirnol
`
`AG” = 12.3 kcalfmol
`
`J_w-fl
`mm 7
`
`+ H
`
`Stabilization of aniline clue to
`20 electron rlelocalization into 1!
`system of aromatic ring
`
`-
`
`Cyclohexylamine
`
`:
`
`FIGURE 24.3 Free energy
`
`+ H1 0
`
`Aniline
`
`changes accompanying protonation
`of aniline and cyclohexylamine by
`water.
`
`and aniline are compared. As measured by their respective Kgs, cyclohexylamine is
`almost 1 million times more basic than aniline.
`
`NI-£2+ H20: 0 E'4H,+
`
`I-IO‘
`
`(Kb3.8>< 10-'0; p1v;,,9.4)
`
`Aniline
`
`Water
`
`Anilinium ion
`
`Hydroxide
`ion
`
`-NHg+H2O::‘
`
`NH; + H0‘
`
`(K,,4.4Xl0““;pKg,3.4)
`
`+
`
`Cyclohexyiarnine
`
`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 1 N hydrochloric acid because it Is
`converted to a water-soluble anilinium 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?
`
`erg cm
`
`Tetrahydroquinoline
`
`Tetrahydroisoquinoline
`
`PAGE 4 OF 6
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`PAGE 4 OF 6
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`

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`'.
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`I
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`The effects of some representative aryl substituents on the basicity of arylarnines
`'-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), ofp-toluidine is 5 to 6 times greater
`' than that of aniline, but aniline is 220 times more basic than its p-trifluoromethyl
`derivative.
`
`NH;
`
`NH;
`
`NH;
`
`CH,
`p-Toluidine
`{K 2 X 10-‘*;
`pK,, 8.7)
`Most basic: methyl group
`donates electrons
`
`Aniline
`(K, 3.8 ><10-'0;
`pig 9,4)
`
`CF,
`p={Trifluoromethy|)ani1ine
`(K, 1.7 X :0--H;
`pk}, l|_5)
`Least basic". trilluornmethyl
`group withdraws electrons
`
`TABLE 24.2
`
`Basicities of Some Arylamines
`
`Position of substituent X and Kb (pK,,)*
`
`Para
`
`Meta
`Substituent in H,NC5H.,X Ortho
`_
`__
`_
`_-
`. Standard"
`comparison .irs'i-arii__Iii1e -
`H
`'
`-'
`-
`.
`_ "
`__.3.a ><_1_04_*f?_(9,_.-4)" " as >'<_ _1of'°(9.4)
`
`.
`"3.8 >'<10*‘°(9.4)
`
`Electron-releasing sub'stituen'ts'_ii1erease basieity slightly
`OCH3'
`'
`-
`'3.8\><.1o-_-'"1(9.4)
`1;'6><1o-1°{9.a)
`CH,
`3.3><10~1°(9.5)
`5.5><10-1°(9.3}
`
`'
`
`2.2><10j9(s.7)
`2x10-°(3.7)
`
`Electron-withdrawing substituents decrease basicity
`
`CI
`‘i
`CCH3
`CN
`N02
`
`4.5 ><10‘”{11.3)
`
`3.8 X10'" (10.4)
`
`7.2 X 10‘” (10.2)
`
`2.5 X 10“? (11.6)
`89X 10"‘ (13.1)
`5.5X10“5(14.3)
`
`4 X 10-" (10.4)
`5.6><10“"’{11.2)
`2.9X10“” (11.5)
`
`5 X 10“? (11.3)
`5.5)( 10”” (12.3)
`1 ><10“3(13.0)
`
`' In water at 25°C.
`
`PAGE 5 OF 6
`
`24A BASICITY OF ARYLAMINES
`
`9
`
`Conjugation ofthe amino group with a second aromatic ring, then a third, reduces
`ts basicity even further. Diphenylamine is 6300 times less basic than aniline, while
`fiphqnylamine is scarcely a base at all, being estimated as 103 times less basic than
`niline and 10" times less basic than ammonia.
`
`CGHSNHI
`Aniline
`(Kb 3.3 >( 10"”;
`pK,, 9.4)
`
`(C.sHs)aNH
`Diphenylamine
`(K), 6 X 10'”;
`pk’), 13.2)
`
`(C6Hs)3N
`Triphenylamine
`(K, ~ 10"”;
`pKb - 19)
`
`PAGE 5 OF 6
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`

`
`AFIYLAHINES
`
`The methyl group in p-toluidine donates electrons to the ring and helps disperse thé
`positive charge in the derived anilinium ion. A trifluorornethyl substituent enhances
`the tendency of the and 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 3300 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.
`
`'
`
`O
`
`Q
`
`‘L
`
`--
`
`O
`
`+
`
`of
`—
`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 ofthe amine nitrogen has been converted
`to a bonded pair of an ammonium ion. More resonance stabilization is lost when
`p-nitroaniline is protonatcd than when aniline is, which makes Kb smaller for
`p—nitroaniline.
`.-.._
`.__.~
`
`__..
`
`.—.__
`
`Each ol 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
`(0) C6H5NHCCH3
`(d) p-Aminoacetophenone
`
`(a) A cyano substituent is strongly electron-withdrawing. when
`SAMPLE 5€)LUTlON
`present at a position ortho to an amino group on an aromatic ring, a cyano substituent in-
`creases the delocalization of the amine lone pair electrons by a direct resonance interaction.
`
`QNH2
`
`E N:
`C’
`
`+NH2
`
`c
`
`4-?!
`
`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-nitroanilineg however,
`it
`is 109 times more basic than 2,4-dinitroanillne. A
`practical consequence of this is that arylarnines 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
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`PAGE 6 OF 6