Organic
`Chemistry
`
`SECOND EDITION
`
`G. Marc Loudon
`
`Purdue University
`
`The Benjamin/Cummings Publishing Company, Inc.
`Menlo Park, California • Reading, Massachusetts
`Don Mills, Ontario • Wokingham, U.K. • Amsterdam • Sydney
`Singapore • Tokyo • Madrid • Bogota • Santiago • San Juan
`
`SENJU EXHIBIT 2247
`LUPIN v. SENJU
`IPR2015-01097
`
`Page 1 of 7
`
`

`
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`
`Library of Congress Cataloging-in-Publication Data
`
`Loudon, G. Marc.
`Organic chemist1y.
`
`Includes index.
`1. Chemistry, Organic.
`QD251.2.L68 1988
`ISBN 0-8053-6643-1
`
`I. Title.
`547
`
`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 Benjamin/Cummings Publishing Company, Inc.
`© 1984 by Addison-Wesley Publishing Company, Inc.
`All rights reserved. No pan of this publication may be reproduced,
`stored in a retrieval system, or transmitted, in any form or by any
`means, electronic, mechanical, photocopying, recording, or
`othenvise, without the prior written pernussion of the publisher.
`Primed in the United States of America. Published simultaneously
`in Canada.
`
`AIICDEFliiii}VIl-K'JS-
`
`The Benjamin/Cummings Publishing Companv, Inc
`1727 Sand Hill Road
`;'vtenlo Park, California 9402'>
`
`Page 2 of 7
`
`

`
`24.2 Introduction to the Aromatic Heterocycles
`
`1051
`
`(cl
`
`+
`
`(d)o60H +6N IN
`'
`
`·---------------------·--·- -----------------------------------------------------
`
`4 Propose a synthesis of the following compound from naphthalene. (The Friedel(cid:173)
`Crafts reaction cannot be used because it gives a mixture of 1- and 2-acetyl(cid:173)
`naphthalene that is difficult to separate.)
`
`A. Nomenclature
`
`The names and stmctures of some common aromatic lleterocyclic compounds are
`given in Fig. 24.1. This figure also shows how the rings are numbered in systematic
`nomenclature. In all but a few cases, a heteroatom is given the number 1. (!so(cid:173)
`quinoline is an exception.) As we see in thiazole and oxazole, oxygen and sulfur are
`given a lower number than nitrogen when a choice exists. Substituent groups are
`given the lowest number consistent with this scheme.
`
`o,H, rn,U)
`'
`
`-.
`
`- -~
`
`I
`
`2
`
`N1
`H
`3-ethylpyiTole
`
`'
`
`N1
`H
`5-methoxyindole
`
`~C2Hs 02
`
`0
`
`..
`
`s
`
`,N02
`
`2-ethylfuran
`
`3-nitrothiophene
`
`(These are the same rules used in numbering and naming saturated heterocyclic
`compounds; see Sees. 8.1C and 23.1B.)
`
`i I,
`I
`!
`
`Page 3 of 7
`
`

`
`1052 Chapter 24: Chemistry of Naphthalene and the Aromatic Heterocycles
`
`Problems
`
`5 Draw the structure of (a) 4-(dimethylamino)pyridine; (b)
`
`6 Name the following compounds:
`gN
`(b)
`(a)
`Br-{s)-cH3
`
`N02
`Br-0 N
`~
`
`B. Structure and Aromaticity
`
`The aromatic heterocyclic compounds furan, thiophene, and pyrrole can be
`resonance hybrids, illustrated here for furan.
`
`-l;--Q-Q:-
`
`+
`
`+
`
`+
`
`..
`+
`
`Since separation of charge is present in all but the first structure, the first
`considerably more important than the others. Nevertheless, the
`other structures is evident if we compare the dipole moments of furan and
`furan, a saturated heterocyclic ether.
`
`Q 0 0
`
`tetrahydrofuran
`1.7 D
`67"
`
`furan
`0.7 D
`31.4°
`
`dipole moment
`boiling point
`
`The dipole moment of tetrahydrofuran is attributable mostly to the bond
`polar C-O single bonds. That is, electrons in the CT-bonds are pulled
`oxygen because of its electronegativity. This same effect is present in fu
`addition there is a second effect: the resonance delocalization of the oxygen
`electrons into the ring shown in Eq. 24.12. This tends to push electrons
`oxygen into the 7T-electron system of the ring .
`
`Q +-+a+-+ -:0 ._.etc.
`
`.('. -
`
`0
`+
`
`0
`
`0
`+
`
`j_
`
`I y
`
`+
`
`dipole moment
`contribution of
`C-0 cr-bonds
`
`t
`net dipole
`moment of
`furan
`
`dipole moment
`contribution of
`7T-electron
`deloealization
`
`Page 4 of 7
`
`

`
`24.2 Introduction to the Aromatic Heterocycles 1053
`
`electron pairs
`are part of the
`7T-system
`
`. .
`
`''
`
`,,
`!).>
`
`pyridine
`
`pyrrole
`
`furan
`
`L_ - - - - - - - - - -1 unshared electron pairs
`(not in 7T-system)
`
`24.5 The configurations of the unshared electron pairs and
`in pyridine, pyrrole, and furan. The orbitals in each
`+ 2-electron 7T-system are shown in grey; 7T-inreractions are shown in
`. Unshared electron pairs not in the 7T-system are shown in white.
`
`i
`
`Because these two effects in furan nearly cancel, furan has a very small dipole mo(cid:173)
`ment. We can see the effect of dipole moment on the relative boiling points of tetrahy(cid:173)
`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 impmtance because they reflect the relative electronegativity of nitrogen.
`
`(24.14)
`
`minor contributors
`
`The aromaticity of some heterocyclic compounds was considered in our discus(cid:173)
`sion of the Htickel 4n + 2 rule (Sec. 15.6D). It is important to understand which
`unshared electron pairs in a heterocyclic compound are part of the 4n + 2 aromatic
`7T-electron system, and which are not. Heteroatoms involved in formal double bonds(cid:173)
`such as the nitrogen of pyridine-contribute one 7T-electron to the six 7T-electron
`aromatic system, just like each of the carbon atoms in the 7T-system. The orbital con(cid:173)
`taining the unshared electron pair of the pyridine nitrogen is perpendicular to the p
`orbitals of the ring and is therefore not involved in 7T-bonding (Fig. 24.5a). An un(cid:173)
`shared electron pair on a heteroatom in a formally allylic position-such as the un-
`
`Page 5 of 7
`
`

`
`1054 Chapter 24: Chemistry of Naphthalene and the Aromatic Heterocycles
`
`TABLE 24.1 Empirical Resonance Energies of
`Some Aromatic Compounds
`
`Compound
`
`benzene
`pyridine
`naphthalene
`
`Resonance energy,
`kcal/mol
`
`34-36
`23-28
`61
`
`furan
`pyrrole
`thiophene
`
`shared pair on the nitrogen of pyrrole-is part of the aromatic 7T-system.
`hydrogen of pyrrole lies in the plane of the ring (Fig. 24.5b). The oxygen of
`24.5c) contributes one unshared electron pair to the aromatic 7T-electron
`the other unshared electron pair occupies a position analogous to the
`pyrrole-in the ring plane, perpendicular to the p orbitals of the ring.
`How much stability does each heterocyclic compound owe to its aro
`ter? In Sec. l5.7C we learned that the empirical resonance enetgy can
`estimate this stability. (Remember that this is the energy a compound
`because of its aromaticity-that is, its aromatic stability.) The empirical
`energies of benzene, naphthalene, and some heterocyclic compounds
`Table 24.1. To the extent that resonance energy is a measure of aromatic
`can see that furan has the least aromatic character of the heterocyclic
`the table.
`
`Problems
`
`7 (a) The dipole moments of pyrrole and pyrrolidine are similar in
`have opposite directions. Explain, indicating the direction of the
`ment in each compound.
`
`0 I
`
`H
`p. = l.80 D
`
`0 I
`
`H
`p. = 1.57 D
`
`(h) Explain why the dipole moments of furan and pyrrole have op
`tions.
`
`8 Each of the following chemical shifts goes \'Vith a hydrogen at carhon-2
`pyridine, pyrrolidine, or pyrrole. Match each chemical shift with the a
`·(cid:173)
`heterocyclic compound, and explain your answer 8 ~-51: 8 6A J: and i'5
`
`C. Basicity and Acidity of the Nitrogen Heterocycles
`
`Basicity Pyridine and quinoline act as ordinary aromatic amine bases: they
`as lxtsic as aniline.
`
`Page 6 of 7
`
`

`
`24.2 Introduction to the Aromatic Heterocycles 1055
`
`-
`
`0 N
`
`+ H3o+ ._..
`
`.,.,.
`
`0~
`7+
`
`H
`pK. = 5.2
`
`(24.15)
`
`(24.16)
`
`Pyridine and quinoline are less basic than aliphatic tertiary amines because of the sf}
`hybridization of their nitrogen unshared electron pairs. (Recall from Sec. 1-4.7 A that
`basicity of an unshared electron pair decreases with increasing :,'-character.)
`Since pyrrole and indole look like amines, it may come as a surprise that the
`nitro gens of these two heterocycles are not basic at all! These compounds are proton(cid:173)
`ated only in strong acid, and protonation occurs on carbon, not nitrogen.
`
`~ ij
`
`i
`I
`I
`
`I
`.
`
`l(-F\+ /H
`f \ /H
`#l.,
`!(_ .. ) + H3o+ ~ ~(~:X .,._....+((':X
`H
`N
`N
`N
`H
`I
`I
`I
`H
`H
`H
`pK. = -4
`
`f \ /Hj
`.,._...., __ X
`N+ H
`I
`H
`
`+H2o
`
`(24.17)
`
`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 aromaticity
`of each compound (Fig. 24.5). Protonation of the pyrrole nitrogen disrupts the aro(cid:173)
`matic six 71'-electron system by taking the nitrogen's unshared pair ''out of circulation."
`
`0 + H3o+ ~ 0
`
`N
`I
`H
`
`/N'{
`H
`H
`not aromatic;
`not observed
`
`+ H20
`
`(24.18)
`
`Furthermore, the positive charge in nitrogen-protonated pyrrole cannot be delocal(cid:173)
`ized by resonance. Although protonation of the carbon of pyrrole (Eq. 24. 17) also
`disrupts the aromatic 71'-electron system. at least the resulting cation is resonance
`stabilized. On the mher hand. protonation of the pyridine unshared electron pair
`occurs easily because this electron pair is 110t part of the 71'-electron system. Hence
`protonation of this electron pair does not destroy aromaticity.
`Imidazole, like pyridine, is basic, and is protonated to give a conjugate acid with
`pi(, = 6.9"i. Imidazole has two nitrogens: one has the elecrronic configuration of pyri(cid:173)
`dine, but the orher is like rhe nitrogen of pyrrole. Protonation of imidazole occurs on
`the pyridine-like nitrogen-~the one whose electron pair is not part of the aromatic
`sextet.
`
`Page 7 of 7