SENJU EXHIBIT 2038
`INNOPHARMA v. SENJU
`IPR2015-00903
`
`Page 1 of 7
`
`

`
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`
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`
`Library of Congress Cataloging-in-Publication Data
`
`Loudon, G. Marc.
`Organic chemisuy.
`
`Includes index.
`
`1. Chemistry, Organic.
`QD251.2.L68
`1988
`ISBN []~80S5-6643-]
`
`1. Title.
`54?
`
`87-29996
`._
`
`Permission for publication herein of Sadtler Standard Spectra” has
`been granted, and all rights are reserved, by Sadtler Research
`Laboratories, Division of Bio-Rad Laboratories. Inc.
`
`Additional credits are listed starting on page C-1.
`
`Copyright © 1988 by Benjaniin./Cummings Pulflisliing Company, Inc.
`© 1984 by AtldiSoi1—Wcsley Publishing C0mp:iny,
`inc.
`All rights resen-'ed. No pm-r of this publicatioii n1;ty' be reproduced.
`stored in :1 retrieval system, or transniitted, in tiny funn or by any
`meunsa, electronic, n1e<:h:1i1ic:i{, plmtocopg-'ii1_g, 1-ccmdiitg, or
`0[l'Il'.’l'\'-\r’i.SC, without the prior written perIn1s.~sion oi" the publi:5I1eI'.
`l’1'in1etl in the Ul'Ii[L'(l States of An‘1eI‘iL':1. Ptlblislit-:tl siintlltuileotlsly
`in Cunaltia.
`
`.'—\_ll(:l)l;‘:l'_L}1U_l'\:"l I-H‘-J}-1*
`
`
`
`
`
`Tlic Hciiitllliin/tltimtnings l’ul3li5l1ing C0l1Ip:ti1y, Inc.
`3'.-'37 511116} Hill
`l{t‘1:lLl
`
`.Vl¢:nlu P'.I1'k. (T;tlil0I'I1i;l 9¢iU3‘.i
`
`
`
`
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`Page 2 of 7
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`
`24.2 Introduction to the Aromatic Heterocycles
`
`1051
`
`4 Propose 21 synthesis of the following compound from naphtltaiene. (The F1-iedel—
`Crafts reitction cannot be used because it gives a mixture of 1- and 2racetyl-
`l'1:'ipi'1[i‘l:I]('.‘1‘iI{:‘ thztt is difficult to Sf.’p2il':1l€'.)
`
`o\ /CH3
`
`A. Nomenclature
`
`The mines and structures of some common al'0l'I’1:1IiC heterocyclic compounds are
`given in Fig. 24.1. This figure also shows how the rings are numbered in systematic
`nomen<:Iatui'e. In all but a few cases, a heteroatom is given the number 1. (Iso-
`quinoiine is an exception.) As we see in thiazole and oxazole, oxygen and sulfur are
`given :1 lower number than nitrogen when a choice exists. Substituent groups are
`given the lowest number consistent with this scheme.
`
` N:
`
`H
`
`Bethylpyrrole
`
`5-methoxyindole
`
`(kc H
`
`0 -
`I
`
`"
`
`3 N03
`/ M
`
`s
`T
`
`5
`
`2-ethylfuran
`
`3—nitrothiophene
`
`(These are the same rules used in numbering and naming saturated heterocyclic
`compounds; see Sees. 8.1C and 23.13.)
`
`Page 3 of 7
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`;
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`Page 3 of 7
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`
`1052 Chapter 24: Chemistry 01 Naphthalene and the Aromatic Heterocycles
`
`Problems
`
`5 Draw the structure of (a) 4-(dimethylamino)py'ridine; (b) 4-ethyl-2-nitroim
`.—.—
`_.~.
`_._ _
`_
`
`6 Name the following compounds:
`
`-
`
`l
`
`\
`
`N/
`
`ocna
`
`(b)
`
`N02
`
`(C)
`
`\
`
`N 1
`
`H
`
`Br
`
`I
`
`(21)
`
`N
`
`Br—()—CH3
`5
`
`B. Structure and Aramaticity
`
`The aromatic heterocyclic compounds furan, thiophene, and pyrrole can be wi-i"
`resonance hybrids, illustrated here for furan.
`
`considerably more important than the others. Nevertheless, the irnportan
`other structures is evident if we compare the dipole moments of furan and te
`furan, a saturated heterocyclic ether.
`
`0
`
`tetrahydrofuran
`1.7 D
`67°
`
`O
`
`furan
`0.7 D
`31.4°
`
`dipole moment
`boiling point
`
`The dipole moment of tetrahydrofuran is attributable mostly to the bond dip H"
`polar C-0 single bonds. That is, electrons in the cr—bonci5 are pulled to
`oxygen because of its electronegativity. This same effect is present in fur"
`addition there is a second effect: the resonance delocaiization of the oxygen 3
`electrons into the ring shown in Eq. 24.12. This tends to push electrons
`oxygen into the 11-electron system of the ring.
`
`[/
`
`-¢—v- fig
`
`0-
`l-1——b —;€
`
`H
`
`§4——-Ir etc.
`
`9
`i
`"1
`
`9
`9
`\_..L._*.,?—.~.:__J
`+
`=
`
`dipole moment
`contribution of
`C—‘O tr-bonds
`
`dipole moment
`contribution of
`arr-electron
`delocalization
`
`r
`
`I161 (“P015
`moment of
`lllrilil
`
`Page 4 of 7
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`

`
`24.2 Introduction to the Aromatic Heterocycles
`
`electron pairs
`are part of the
`11'-system
`
`unshared electron pairs
`(not in -rr—system)
`
`Ure 24.5 The configurations of the unshared electron pairs and
`lectrons in pyridine, pyrrole, and furan. The o1'bit;1ls in each
`'+ 2-electron 1r-systeth are shown in grey; 1-r—inter:tctions are shown in
`or. Unshared electron pairs not in the 1r-system are shown in white.
`
`Because these two effects in furan nearly cancel, furan has a very small dipole mo-
`ment. We can see the effect of dipole moment on the relative boiling points of tetrahy—
`drofuran and furan.
`Pyridine, like benzene, can be represented by two equivalent neutral resonance
`structures. Three additional structures, although involving Separation of charge, have
`some importance because they reflect the relative electronegativity of nitrogen.
`
`\
`
`N’
`
`+—>
`
`/’
`
`‘N.
`
`+4» +
`
`__
`..
`
`._
`
`__
`
`(24.14)
`
`minor contributors
`
`The arornaticity of some heterocyclic compounds was considered in our discus-
`sion of the Hiickel 4n + 2 rule (Sec. 1S.6D). It is important to understand which
`unshared electron pairs in a heterocyclic compound are part of the 4:: + 2 aromatic
`tr-electron system, and which are not. Heteroatoms involved in formal double bonds-—
`such as the nitrogen of pyridine——contribute one tr-electron to the six tr-electron
`aromatic system, just like each of the carbon atoms in the 1r-system. The orbital con-
`taining the unshared electron pair of the pyridine nitrogen is perpendicular to the p
`orbitals of the ring and is therefore not involved in 1r—bonding (Fig. 2-4.5a). An on-
`shared electron pair on a heteroatom in a formally allylic position—such as the Lin-
`
`Page 5 of 7
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`Page 5 of 7
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`

`
`1054 Chapter 24: Chemistry of Naphthalene and the Aromatic Heterocycles
`
`
`
`
`
`‘='.-~r*.w-:e\»+..m~«r.*.«me
`
`TABLE 24.1 Empirical Resonance Energies of
`Some Aromatic Compounds
`- .--5
`-
`.
`-='
`. .-
`..
`-
`_-..': _l,;.=«,
`'.'..::-.,+-
`
`Compound
`
`benzene
`
`pyridine
`
`naphthalene
`
`Resonance energy,
`kcaiimol
`
`34-36
`
`23-28
`
`61
`
`Compound
`
`furan
`
`pyrrole _
`
`thiophene
`
`'
`Resonant:
`kcalremglla E '
`
`.\n_\_(._\\>._...,....»_».»~.\~mw.
`
`
`
`
`v'.-e‘.-5*.'.sV':‘-—.:
`
`
`
`
`
`"‘.\-'-Kv::-t.\x-‘!'".-'-Fix‘
`
`.'ih31‘(:‘£l pair on the nitrogen of py1'ro|e~is part of the aromatic 71'-systent.
`hyclrogen of pyrrole lies in the plane of the ring (Fig. 2-’i.5b). The Oxygen of
`.?.4.5c} contributes one unshared electron pair to the aromatic 'rr~e1ectron systg
`the other unsltared electron pair occupies a position analogous to the hy
`pyrrole—in the ring plane, pe1‘pent.liCulzt1‘ to the p orbitals of the ring.
`How much stability does each heterocyclic compound owe to its ‘cI1'OI113[lC
`ter? In Sec. 15.'.r'C we learned that the er-t-apfricczl resonance Qfielgjf can be‘
`estimate this st;tbility_ (Remember that this is the energy 2. contpountl “does '
`becausfi: of its 21t'o111:tticity'——that is,
`its arontatic stability.) The empiricztl re
`energies of benzene, naphthalene, and some heterocyclic compounds are
`Table 24.1. To the extent that resonance energy is 3 measure of :1l‘0I‘t1L1|.iC citartigz
`can see that furan has the least :1l‘Ol'l'l£i[lC character of the heterocyciic compo;
`the table.
`
`Problems
`
`7 (":1") The dipole rnoutents of pyrtole and p}-'r1'oliciine are similztr in tn;1gr1it
`have opposite directions. Explain, indicating the direction of the dipql
`ment in each compound.
`
`4;
`
`H
`
`[QI
`
`H
`
`u: i.80D u: i.S?D
`
`(ll) Explain win,’ the dipole moments of fttrztn and pyrrole hzwe oppofiif
`Lions.
`
`|1yt.lI'<)gt:|1 at curlmn-2 05
`3 Each of the ltallowing t.‘l‘lL‘l‘I1lL':ll sltiftré goes with at
`pwicliite. p_vt'rolit.lit1e. U1‘ p_\-’t't'ole. M'.itt'l1 |‘.?'.'lCl1 t.‘hemit.‘;tl sltift with the HPIE‘-‘Q
`|1etemL‘y‘clic C0li1[)f.JL|t1(l. and t:?iltl;1it1 Y"”" ‘“‘-“'W*-’1'- 5 3-5'1: 5 (3.--il: anti 0'
`
`C‘. Basicity and Acidity of the Nitrogen Heterocyctes
`
`Basicity l’yt'ic|ine and L[I_ilf1UllI1L‘ act 11:5 0l’(lit1alI'y2it‘()l11;ltlC;ll'1’ill'ti:l‘)21:-its: [1163-' 31"?‘
`2-is
`i_>:i.«:it:
`:15 '.1l'lllli'lL’.
`
`Pae 6 of7
`
`Page 6 of 7
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`

`
`\‘:g_\A.¢\..'
`
`.u...-r-.......,......-.t.................
`
`
`
`-:\-¢<~v<"
`
`
`
`-..‘;g--_.v.‘.
`
`I
`
`
`
`24.2 introduction to the Aromatic Heterocycies 1055
`
`\
`
`/
`
`P?
`
`‘\
`
`/'
`
`N
`
`+ I-I30" ‘# |
`
`‘\
`
`/
`
`If.
`
`H
`
`pK, = 5.2
`
`+ H30
`
`(24.15)
`
`+ H3O‘* “N
`
`\
`
`X
`
`If.
`
`H
`
`pK;, = 4.9
`
`+ H30
`
`(24.16)
`
`Pyridine and quinoline are less basic than aliphatic tertiary’ amines because of the sp‘’
`hybridization of their nitrogen unshared electron pairs. (Recall from Sec. 1/+..7A that
`basicity of an unshared electron pair decreases with increasing 5*Cl’lEll‘flCEEI".)
`Since pyrrole and indole look like amines, it may come as a surprise that the
`nitrogens of these two heterocycles are not basic at all! These compounds are proton-
`ated only in strong acid, and protonation occurs on carbon, not nitrogen.
`
`+1-I30 4.?
`
`i
`
`.. 4753
`1?!
`H
`
`..
`
`<—>- +
`
`in.
`
`05* Q51
`I‘|~l
`H
`I“~l+ H
`
`4-4»
`
`«t-1-120
`
`(24,170
`
`H
`
`H
`
`H
`
`pKa 2 "'4
`
`\
`
`..
`
`N IH
`
`/
`
`We can understand the marked contrast between the basicities of pyridine and
`pyrrole by considering the role of nitrogen's unshared electron pair in the aromztticity
`of each compound (Fig. 24.5). Protonation of the pyrrole nitrogen disrupts the aro-
`matic six -zr-electron system by taking the nitrogen’s unsltnrecl pair “out ofcirculation.”
`
`U +H30*
`
`/I U +H3O
`
`(24.13)
`
`N
`I
`H
`
`N+
`/\
`
`H
`
`H
`
`not aromatic;
`not observed
`
`F‘urtherrnore, the positive charge in nitrogen-protonated pyrrole C1-lt‘tl10t be clelocal-
`ized by resonzmce. Although p1‘OtOl‘l21[iOl‘l of the carbon of pyrrole (Eq. 24.17} also
`disrupts the ztromzttic 'rr—electron system, at least the restllting C:1ti(}l‘t
`is reson;-1nce
`stabilizetl. On the other hand, protonation of’ the pyridine unsltured electron pair
`occurs easily lvecntise this electron pttir is not pttrt of the 1r-electron systeltt. Hence
`protonation 0|" tltis electron pair does not destroy ;tt'o1n:tticity.
`Intidztzole, like pyridine, is l‘J;l:iiC, and is p1‘oto1”1zttetl to give :1 ctittjttgute acid with
`ljKJ = 6.9‘). Il‘|‘tl(i£1Z0lt‘ I135 two l1l.tl'C)gt’l"lHI one lttts the rslectronic L'ttt1Fi§:LI1';tti()t1 of pyri~
`(line, but the other is like the nitrogen of pyrrole. Protonzition of lI't'1l(l;1Z0lt3 occtlrs on
`the pyridine—like nitrogen——-—tI1e one who.~.-e (.°.ltSL‘I1‘0I’l pttit‘ is not part of the ;l:'t)In2Iti(.'
`SCXICI.
`
`Page 7 of 7
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`Page 7 of 7