`
`
`
`
`
`SYNGENTA EXHIBIT 1025SYNGENTA EXHIBIT 1025
`
`
`
`Syngenta v. FMC, PGR2020-00028Syngenta v. FMC, PGR2020-00028
`
`SYNGENTA EXHIBIT 1025
`Syngenta v. FMC, PGR2020-00028
`
`

`

`Library of Congress Cataloging in Publication Data
`
`1937-
`Carey, Francis A
`Advanced organic chemistry.
`
`"A Plenum/Rosetta edition."
`Includes bibliographical references and index.
`CONTENTS: pt. A. Structure and mechanisms.-pt.
`1. Chemistry, Organic. I. Sundberg, Richard J., 1938-
`[QD251.2.C36 1977]
`54 7
`ISBN 0-306-25003-9 (pt. A)
`
`B. Reactions and synthesis.
`II. Title.
`
`76-54956
`
`I
`
`First Paperback Printing - June 1977
`Second Paperback Printing - November 1977
`
`A Plenum/Rosetta Edition
`Published by Plenum Publishing Corporation
`227 West 17th Street, New York, N.Y. 10011
`
`© 1977 Plenum Press, New York
`A Division of Plenum Publishing Corporation
`227 West 17th Street, New York, N.Y. 10011
`
`All rights reserved
`
`No part of this book may be reproduced, stored in a retrieval system, or transmitted,
`in any form or by any means, electronic, mechanical, photocopying, microfilming,
`recording, or otherwise, without written permission'from the Publisher
`
`Printed in the United States of America
`
`Pref
`
`This volume
`aimed at de·
`and the mec
`organic che1
`fundamenta
`try, and con:
`to probe d,
`organized o
`the topic of
`Virginia, WE
`undergradu,
`Bythe1
`we hope to
`literature. C
`can supplerr
`structural fe
`effects. A c
`commentaq
`interpretatic
`different dir,
`to make con
`exercised in
`We recomn
`working out
`We ha\
`treatment oJ
`the reader 1
`failing to cri
`
`

`

`18
`
`CHAPTER 1
`CHEMICAL
`BONDING
`AND MOLECULAR
`STRUCTURE
`
`Table 1.9. Coefficients of Wave Functions Calculated for Methyl Cation by the CND0/2
`Approximation a
`
`Orbital
`
`C2s
`
`c2px
`
`C2py
`
`½p,
`
`H
`
`H
`
`H
`
`t/11
`t/12
`t/J3
`t/J4
`t/Js
`t/16
`t/11
`
`0.7915
`0.0000
`0.0000
`0.0000
`-0.6111
`0.0000
`0.0000
`
`0.0000
`0.1431
`0.7466
`0.0000
`0.0000
`0.5625
`0.3251
`
`0.0000
`0.7466
`-0.1431
`0.0000
`0.0000
`-0.3251
`0.5625
`
`0.0000
`0.0000
`0.0000
`1.0000
`0.0000
`0.0000
`0.0000
`
`0.3528
`0.0999
`0.5210
`0.0000
`0.4570
`-0.5374
`-0.3106
`
`0.3528
`0.4012
`-0.3470
`0.0000
`0.4570
`0.5377
`-0.3101
`
`0.3528
`-0.5011
`-0.1740
`0.0000
`0.4570
`-0.0003
`0.6207
`
`a. The orbital energies (eigenvalues) are not given. The lowest-energy orbital is ,{11 ·, the highest-energy orbital, ,{17 .
`
`The coefficients for the AO's that comprise each MO may be related to the
`electron density at each atom by the equation
`
`which gives the electron density at atom r as the sum over all the occupied molecular
`orbitals of the product of the number of electrons in each orbital and the square of the
`coefficient at atom r in each orbital. To illustrate, consider methyl cation (CH3 +), for
`which calculations employing the CNDO/2 approximation may be performed
`readily. If the carbon ls-orbital is omitted, the wave functions for the seven
`molecular orbitals that result from combination of the three hydrogen ls-orbitals
`with carbon 2s, 2Px, 2pY, and 2Pz are computed to have the coefficients shown in
`Table 1.9. 24
`The electron densities are calculated from the coefficients of ,ff 1, i/12 , and i/13 only
`because these are the occupied orbitals for the six-valence-electron system. The
`carbon atom is calculated to have 3.565 electrons (exclusive of those in the ls level),
`and each of the hydrogen atoms is calculated to have 0.812 electron. Since carbon in
`its neutral form has four electrons, its net charge in methyl cation is +0.435
`(4-3.565). Each hydrogen atom has a charge of +0.188 (1-0.812). A sample
`calculation of hydrogen electron density is as follows:
`qH = 2(0.3528) 2 + 2(0.0999) 2 + 2(0.5210)2
`qH= 0.812
`
`Further examination of Table 1.9 reveals that the lowest unoccupied molecular
`orbital is ,ff 4. This orbital is unique among all the orbitals in that it is a pure p-orbital
`localized on carbon, as indicated by the coefficients. The coefficients are zero for
`every AO in i/14 , except for the coefficient of C2p
`, which is 1.
`The construction of qualitative energy-level diagrams may be accomplished
`without recourse to detailed calculations by keeping some basic principles in mind.
`
`2
`
`24. Taken from unpublished output data of calculations reported by H. S. Tremper and D. D. Shillady, J.
`Am. Chem. Soc. 91, 6341 (1969).
`
`These princip
`first diatomic:
`low in energ~
`combine in e
`orbitals, as in
`Thenum
`to the sum of
`bonding coml
`are of like si!
`overlap with ,
`Orbitals
`the species be
`maximumof1
`electrons cot
`qualitative e1
`electron), H2
`reasonable cc
`lear diatomic
`orbitals (two)
`contains two
`orbital. Both
`antibonding ,
`60 kcalfmol,
`103 kcal/mo
`A slight
`lear diatomic
`He ls level
`helium. The
`Exact calcuh
`
`25. H. H. Mich
`
`

`

`158
`CHAPTER 4
`STUDY AND
`DESCRIPTION OF
`ORGANIC
`REACTION
`MECHANISMS
`
`:,i
`(;,,
`
`I.'.·;
`
`i
`!,,,
`1.:-: 11·,
`
`;{r l' ..
`
`4.7. Solvent Effects
`
`Most organic reactions are done in solution, and it is therefore important to
`recognize some of the general ways in which solvent can affect the course and rates of
`reaction. Some of the more common organic solvents can be roughly classified as in
`Table 4.4 on the basis of their structure and dielectric constants. There are important
`differences between protic solvents-solvents that contain relatively mobile protons
`such as those bonded to oxygen, nitrogen, or sulfur-and aprotic solvents. Similarly,
`polar solvents, those that have high dielectric constants, have effects on reaction rates
`I
`different from those of nonpolar solvent media.
`When discussing solvent effects, it is important to distinguish between the
`macroscopic and the microscopic properties of the solvent. Macroscopic properties
`refer to properties of the ,bulk solvent. An important macroscopic property is the
`dielectric constant which is a measure of the ability of the bulk material to
`increase the capacitance of a condenser, relative to a vacuum. In terms of structure,
`the dielectric constant is a function of both the permanent dipole moment of the
`molecule and its polarizability. Polarizability refers to the ease of distortion of the
`molecule's electronic cloud. Dielectric constants increase with dipole moment and
`with polarizability. An important property of solvent molecules with regard to
`organic reaction is the way in which the solvent molecules interact with the changes in
`charge distribution that accompany many reactions. The dielectric constant of a
`solvent has an important effect on its ability to accommodate separation of charge. It
`is not the only factor, however, since, being a macroscopic property, it conveys little
`information about the ability of the solvent molecules to interact with solute
`molecules at close range. These close-range, or microscopic, properties will have a
`pronounced effect on the energy of the reactants and transition states, and thus on
`the energy of activation of reactions.
`
`Table 4.4. Dielectric Constants of Some Common Solvents
`
`Aprotic solvents
`
`Protic solvents
`
`Nonpolar
`
`Hexane
`Carbon
`tetrachloride
`Dioxane
`
`Benzene
`Diethyl ether
`Chloroform
`Tetrahydrofuran
`
`Polar
`
`Pyridine
`Acetone
`
`Hexamethyl
`phosphoramide
`Nitrobenzene
`Nitromethane
`Dimethylformamide
`Dimethyl sulfoxide
`
`12
`21
`
`30
`
`35
`36
`37
`47
`
`1.9
`2.2
`
`2.2
`
`2.3
`4.3
`4.8
`7.6
`
`Acetic acid
`Trifluoroacetic
`acid
`tert-Butanoi
`
`Ammonia
`Ethanol
`Methanol
`Water
`
`6.1
`8.6
`
`12.5
`
`(22)
`24.5
`32.7
`78
`
`Let us cc
`evidence, wb
`determining
`therefore, ref
`bulk dielectri
`
`s
`
`s
`M
`I
`Me-C
`I
`s
`M
`s
`
`to facilitate
`transition st~
`oppositely ch
`by acting' on 1
`the detailed s
`of a number,
`has been me
`solvent, as wl
`other solvent
`
`The Yvalues
`accommodat,
`Yvalues for:
`Solvents
`development
`they do not h:
`
`Ethan
`(% e
`
`100
`80
`50
`20
`
`0
`
`Dielectric constant data are abstracted from the compilation of solvent properties in J. A. Riddick and W. B. Bunger
`(eds.), Organic Solvents, Vol. II of Techniques of Organic Chemistry, Third Edition, Wiley-Interscience, New York,
`1970.
`
`a. From A.H. Fai
`
`b
`
`

`

`Let us consider how solvent might effect the solvolysis oft-butyl chloride. Much
`evidence, which will be discussed in detail in Chapter 5, indicates that the rate(cid:173)
`determining step is ionization of the carbon-chlorine bond. The transition state,
`therefore, reflects some of the charge separation that results from the ionization. The
`bulk dielectric constant may be a poor indicator of the ability of the solvent molecules
`s
`
`159
`SECTION 4.7.
`SOLVENT
`EFFECTS
`
`s
`
`s
`
`s
`
`s
`
`s
`
`CI-
`
`s
`
`s
`
`s
`
`s
`
`s
`
`"'
`
`s
`
`s
`Me
`+/
`s
`Me-C
`Me
`s
`
`s
`
`s
`Me
`8
`8+1
`S Me-c .......... CJ
`I
`Me
`
`s
`
`s
`
`s
`
`s
`
`s
`Me
`I
`Me-C-CI
`I
`s
`Me s
`s
`
`refore important to
`: course and rates of
`1ghly classified as in
`there are important
`,ely mobile protons
`solvents. Similarly,
`:ts on reaction rates
`
`guish between the
`roscopic properties
`,pie property is the
`: bulk material to
`terms of structure,
`ole moment of the
`Jf distortion of the
`lipole moment and
`les with regard to
`with the changes in
`ctric constant of a
`ration of charge. It
`·ty, it conveys little
`teract with solute
`perties will have a
`,tates, and thus on
`
`mts
`
`tic solvents
`
`tic
`
`6.1
`8.6
`
`12.5
`
`(22)
`24.5
`32.7
`78
`
`ddick and W. B. Bunger
`.nterscience, New York,
`
`to facilitate the charge separation in the transition state. The structure of the
`transition state prevents the molecules from actually intervening between the
`oppositely charged centers. Instead, the solvent molecules must stabilize the charge
`by acting' on the periphery of the activated complex. This interaction will depend on
`the detailed structure of the activated complex and the solvent molecule. The ability
`of a number of solvents to stabilize the transition state of t-butyl chloride solvolysis
`has been measured by comparing the rate of ionization relative to a reference
`solvent, as which an 80: 20 ethanol-water mixture has been chosen. The Y value of
`other solvents is defined by the equation
`
`ksolvent = y
`log
`kso% ethanol
`
`The Y values determined in this way are empirical measures of the solvent's ability to
`accommodate formation of the dipolar.solvolysis transition state. Table 4.5 lists the
`Y values for some alcohol-water mixtures and for some other solvent systems.
`Solvents that fall in the nonpolar aprotic class are not effective at stabilizing the
`development of charge separation. These molecules do not contain polar groups, and
`they do not have hydrogen atoms capable of forming hydrogen bonds. Reactions that
`
`Table 4.5. YValues for Some Solvent Systemsa
`
`Ethanol-water
`(% ethanol)
`
`Methanol-water
`(% methanol)
`
`Other solvents
`
`100
`80
`50
`20
`
`0
`
`-2.03
`0.0
`1.65
`3.05
`
`3.49
`
`100
`80
`50
`
`10
`
`-1.09
`0.38
`1.97
`
`3.28
`
`Acetic acid
`Formic acid
`t-Butanol
`90% Acetone-
`water
`90% Dioxane-
`water
`
`-1.64
`2.05
`-3.2
`
`-1.85
`
`-2.03
`
`a. From A.H. Fainberg and S. Winstein, J. Am. Chem. Soc. 78, 2770 (1956).
`
`

`

`160
`CHAPTER 4
`STUDY AND
`DESCRIPTION OF
`ORGANIC
`REACTION
`MECHANISMS
`
`Scheme 4.3. Effect of Solvent Polarity on Reactions of Various Charge Types
`
`A + B+ __. A---B ~ A-B
`
`5-
`8+
`A-B ---J> A---B ---l> A - + B+
`A + B ---l> A---B ---l> A-B
`
`Favored by nonpolar solvent
`
`Favored by polar solvent
`
`Relatively insensitive to
`solvent polarity
`
`Slightly favored by
`polar solvent
`
`Slightly favored by nonpolar
`solvent
`
`Since a solvent
`a change in solven
`formed from compe
`by trial-and-error f
`microscopic solvent
`aprotic solvents, rel:
`. polarity. 23 I~ ~ydro
`bonding. This 1s par
`on oxygen or nitrog
`
`involve charge separation in the transition state therefore usually proceed much
`more slowly in solvents of this class than in protic or highly polar aprotic solvents.
`The reverse is true of reactions in which charge separation is neutralized in the
`transition state. In these reactions, an increase in solvent polarity stabilizes the
`.f
`reactants with respect to the transition state and slows the reaction rate. Arguing
`along these lines, the broad relationships outlined in Scheme 4.3 are deduced.
`I
`The electrostatic solvent effects discussed in the preceding paragraphs are not *
`the only possible modes of interaction of solvent with reactants and transition states.
`1.l
`Specific structural effects may cause either the reactants or transition states to be
`;
`particularly strongly solvated. Figure 4.8 shows how such solvation effects can alter
`f
`
`I ~.
`;l ,.
`•
`
`
`
`-.•.:.!i;,.: .•. •
`
`the potential energy diagram and cause rate variations from solvent to solvent. 1
`
`Unfortunately, no general theory for correlating or predicting such specific solvation
`effects has been developed to date.
`
`Solvent A
`
`Solvent B
`
`Solvent A
`
`Solvent B
`
`Transition state strongly solvated in
`Solvent B, reactivity enhanced in
`Solvent B
`
`Ground state strongly solvated in
`Sol-vent B, reactivity decreased in
`Solvent B
`
`Fig.4.8. Specific solvation effects.
`
`In aprotic solvents, 1
`this type of solvatio
`easily available for r
`because if the solve
`likely to be present
`
`A
`ic
`
`reduced because of
`done against this att
`is therefore reduce<
`nonpolar aprotic s,
`strongly enhanced
`several types of syn
`tions.
`Particularly str
`the study of the "c
`property of specific
`presence of 18-crov
`acts as a reactive rn
`
`In the absence of tl
`unreactive toward ~
`of other salts are al
`
`23. A. J. Parker, 0. Re
`Coetzee and C. D. I
`24. C. L. Liotta and H.
`
`

`

`161
`SECTION 4.7.
`SOLVENT
`EFFECTS
`
`Charge Types
`
`nonpolar solvent
`
`polar solvent
`
`11sensitive to
`}!arity
`
`ired by
`'ent
`
`}red by nonpolar
`
`.lly proceed much
`r aprotic solvents.
`neutralized in the
`rity stabilizes the
`:ion rate. Arguing
`are deduced.
`1aragraphs are not
`d transition states.
`sition states to be
`>n effects can alter
`olvent to solvent.
`1 specific solvation
`
`,olvent B
`
`vated in
`eased in
`
`Since a solvent may affect the rates of two competing reactions in different ways,
`a change in solvent may strongly modify the composition of a product mixture
`formed from competing reaction paths. Many such instances have been encountered
`by trial-and-error procedures in synthetic chemistry. An important example of a
`microscopic solvent effect is the enhanced nucleophilicity of many anions in polar
`aprotic solvents, relative to their nucleophilicity in hydroxylic solvents of comparable
`polarity. 23 In hydroxylic solvents, anions are usually strongly solvated by hydrogen
`bonding. This is particularly true for anions that have a high concentration of charge
`on oxygen or nitrogen atoms:
`
`R-O-H---A---H-O-R
`
`In aprotic solvents, no hydrogen atoms capable of hydrogen bonding are present, and
`this type of solvation cannot occur. As a result, the electrons of the anion are more
`easily available for reaction. The polarity of the aprotic solvent involved is important,
`because if the solvent has a low dielectric constant, dissolved ionic compounds are
`likely to be present as ion pairs or ion aggregates. Reactivity in this case is greatly
`
`ion pair
`
`ion aggregate
`
`reduced because of the strong attractive force exerted by the cation. Work must be
`done against this attractive force if the anion is to act as a nucleophile, and reactivity
`is therefore reduced. Furthermore, most ionic compounds have limited solubility in
`nonpolar aprotic solvents. The realization that nucleophilicity of anions can be
`strongly enhanced in polar aprotic solvents has led to important improvements of
`several types of synthetic processes that involve nucleophilic substitutions or addi(cid:173)
`tions.
`Particularly striking examples of the effect of specific solvation can be cited from
`the study of the "crown ethers." These are macrocyclic polyethers that have the
`property of specifically solvating cations such as Na+ and K+. For example, in the
`presence of 18-crown-6, potassium fluoride is soluble in benzene or acetonitrile and
`acts as a reactive nucleophile:
`
`In the absence of the polyether, potassium fluoride is insoluble in such solvents and
`unreactive toward alkyl halides. Similar enhancement of the reactivity and solubility
`of other salts are also observed in the presence of crown ethers.
`
`Ref. 24
`
`23. A. J. Parker, Q. Rev. Chem. Soc. 16, 163 (1962); C. D. Ritchie, in Solute-Solvent Interactions, J. F.
`Coetzee and C. D. Ritchie (eds.), Marcel Dekker, New York, 1969, Chap. 4.
`24. C. L. Liotta and H.P. Harris, J. Am. Chem. Soc. 96, 2250 (1974).
`
`

`

`162
`CHAPTER 4
`STUDY AND
`DESCRIPTION OF
`ORGANIC
`REACTION
`MECHANISMS
`
`18-crown-6
`
`K + ion specifically solvated
`by crown ether molecule
`
`It should always be borne in mind that solvent effects can modify the energy of
`both the reactants and the transition states. It is the difference in the two salvation
`effects that governs the relative reaction rates. Thus, although it is common to see
`solvent effects discussed solely in terms of reactant salvation or transition-state
`salvation, such discussion is usually an over-simplification. One case that iIIustrates
`this is the hydrolysis of esters by hydroxide ion. The reaction is found to be much
`more rapid in dimethyl sulfoxide-water than in ethanol-water. Reactant salvation
`can be dissected from transition-state salvation by measuring the energy of the
`reactants in the two media. This dissection can be done by calorimetric measure(cid:173)
`ment of the heat of solution of the reactants. The data in Fig. 4.9 compare the
`energies of the reactants and transition states for ethyl acetate and hydroxide ion in
`aqueous ethanol versus aqueous dimethyl sulfoxide. It can be seen that both the
`reactants and the transition state are more strongly solvated in the ethanol-water
`medium. The difference in reaction rate, however, comes from the fact that this
`difference in salvation energies is greater for the small hydroxide ion than for the
`larger anionic species present at the transition state.
`0
`0 8
`11
`:1
`-OH + CH3COC2H 5 ~ H 3C-9-oc2Hs ----l> product
`H08 -
`
`-
`
`10.0 kcal/mo!
`
`Transition state
`
`AH"= 10.9
`kcal/mo!
`
`AH"= 14.9
`kcal/mo!
`
`AH of transfer of
`reactants= 14.0 kcal/mo!
`
`Ethanol-water
`
`Dimethyl sulfoxide-water
`
`Fig. 4.9. Reactant and transition-state salvation in the hydrolysis of ethyl acetate. [From
`P. Haberfield, J. Friedman, and M. F. Pinkston,]. Am. Chem. Soc. 94, 71 (1972).]
`
`4.8. Basic Me
`Hammon
`
`Use of two(cid:173)
`important gener
`reactions in whi,
`rather similar. If
`paths, it is impo
`path to dominat
`Product cor
`the system. Wht
`thermodynamic
`competing rates,
`Let us cons
`transition states
`formation of A'
`sufficiently large
`it follows that tht
`relative stabilitie
`Case 1, then, de:
`kinetic control.
`In Case 2, th
`formation of B' f
`kinetic or thermo
`that energy AG!,
`AG!, and A Gt, ai
`the major prodw
`attainable energ)
`mixture will then
`
`A'
`
`A
`
`+--·
`Case
`
`

`

`208
`CHAPTER 5
`NUCLEOPHILIC
`SUBSTITUTION
`
`Table 5.3. Nudeophilic Constants of Various
`Nudeophilesa
`
`Nucleophile
`
`ncH31
`
`pKa of
`conjugate acid
`
`CH3OH
`NO;-
`F-
`CH3CO;:
`Cl-
`(CH3)zS
`NH3
`N3
`C6Hs0-
`Br-
`CH3O-
`HO-
`NH2OH
`NH2NH2
`(CH3CH2hN
`cw
`(CH3CH2hAs
`C
`HO2
`(CH3CH2hP
`C6HsS-
`C6HsSe-
`(C6H5hSn-
`
`0.0
`1.5
`2.7
`4.3
`4.4
`5.3
`5.5
`5.8
`5.8
`5.8
`6.3
`6.5
`6.6
`6.6
`6.7
`6.7
`7.1
`7.4
`7.8
`8.7
`9.9
`10.7
`11.5
`
`-1.7
`-1.3
`3.45
`4.8
`-5.7
`
`9.25
`4.74
`9.89
`-7.7
`15.7
`15.7
`5.8
`7.9
`10.70
`9.3
`
`-10.7
`
`8.69
`6.5
`
`a. Taken from R. G. Pearson and J. Songstad, J. Am. Chem. Soc. 89, 1827
`(1967); R. G. Pearson, H. Sobel, and J. Songstad,J. Am. Chem. Soc. 90,319
`(1968); P. L. Bock and G. M. Whitesides,]. Am. Chem. Soc. 96, 2826 (1974).
`
`order of nucleophilicity, CH30- > C6H50- > CH3C02 > N03 parallels the order of
`Br0nsted basicity.
`Nucleophilicity usually decreases in going across a row in the periodic table in
`what is most simply ascribable to an electronegativity effect. Thus, HO-> F-;
`(CH3CH2) 3P>(CH3)zS; and C6H 5S->Cl-. Nucleophilicity usually increases in
`going down a column, as evidenced by r > Br - >CI-> F- and C6HsSe - > C6HsS- >
`C6H 50-. There are exceptions, however, of which the order (CH3CH2hP>
`(CH3CH2) 3As > (CH3CH2) 3N is an example. While decreasing electronegativity acts
`to increase the nucleophilicity of heavier atoms in a particular group, it is generally
`accepted that the greater polarizability of the heavier atoms is the more important
`factor.
`An interesting observation is that nucleophiles in which the attacking atom is
`directly bonded to an atom possessing a Ione pair exhibit anomalously high nuc(cid:173)
`leophilicities. We see tha1 H02 is more nucleophilic than HO- (nrn31 = 7.8 versus
`6.5). The enhanced nucleophilicity of such species is called the alpha effect, and is
`apparent in neutral nucleophiles as well. Both hydrazine and hydroxylamine are
`more nucleophilic than ammonia, although each is a weaker Br0nsted base.
`
`c' C
`
`Various exp
`the ground state
`which decrease i
`state is stabilize,
`reasoning, the pn
`
`for which a Ione
`
`The alpha effect r
`it is likely that be
`contribute to the
`The nucleop
`Most of our quali
`from studies mad<
`to strong solvatio
`tion reactions car
`comparable react
`to be poorly nucl<
`to studies in dipol
`salts of alkali me
`concentrations of
`A significant
`polyethers in cata
`crown-6, the strw
`coordinate metal i
`solvent; equally ir
`solvated anion be!
`species, sometim<
`
`51. J. 0. Edwards and
`52. J. D. Aubort and l
`
`

`

`Table 5.9. Rate Constants for Nucleophi.lic Substitution in Primary Alkyl Substratesa
`
`Reaction
`
`X=H-
`
`XCH2Br+LiCI,
`acetone
`XCH2Br+ Bu3P,
`acetone
`XCH2Br+NaOCH3 ,
`methanol
`XCH2OTs, acetic acid
`
`600
`
`26,000
`
`8140
`
`0.052
`
`CH3-
`
`9.9
`
`154
`
`906
`
`0.044
`
`a. From M. Charton, J. Am. Chem. Soc. 97, 3694 (1975).
`
`0.00026
`
`6.4
`
`64
`
`335
`
`1.5
`
`4.9
`
`67
`
`0.018
`
`0.0042
`
`215
`SECTION 5.7.
`STERIC AND OTHER
`SUBSTITUENT
`EFFECTS
`
`isms would differ in
`ization mechanism
`ving-group ability
`e rate-determining
`ton the variation of
`mction of substrate
`ences in reactivity
`:1ry and secondary
`
`oordination to an
`that under normal
`1is base. It has been
`
`the reverse process
`ctivation energy of
`n alcohol improves
`i a leaving group as
`converted to alkyl
`The leaving-group
`s, and it is common
`f alkyl halides.
`m diazonium ions.
`liphatic or aromatic
`
`Aryldiazonium salts are more stable than alkyldiazonium salts, which usually react
`by substitution or elimination under the conditions of their generation. Marked
`differences are often observed in the pattern of reactivity exhibited by diazonium salt
`decomposition compared with that seen in solvolysis reactions of the corresponding
`alkyl halides or arenesulfonates. 61
`
`5. 7. Sterk and Other Substituent Effects on Substitution and Ionization
`Rates
`
`Examples of effects of substrate structure on the rates of nucleophilic substitu(cid:173)
`tion reactions have appeared in the preceding sections of this chapter. Additionally,
`some special effects will be covered in detail in succeeding sections. This section will
`emphasize the role steric effects can play in nucleophilic substitution reactions.
`Reactions with good nucleophiles in solvents of low ionizing power are sensitive
`to the degree of substitution at the carbon atom undergoing substitution. Reactions
`of this type most closely approach the direct-displacement limit, and are retarded by
`steric crowding in the transition state. The relative rates of reaction of alkyl chlorides
`with iodide ion in acetone are methyl, 93; ethyl, 1.0; and isopropyl, 0.0076. 62 This
`rate relationship is an example of a case where this crowding effect is dominant. More
`generally, a statistical analysis of rate data for eighteen sets of nucleophilic substitu(cid:173)
`tion reactions of substrates of the type XCH2 Y, where Y is a leaving group and Xis H
`or alkyl, indicated that the steric effect of X was the most important factor. 63 Table
`5.9 records some of the data bearing on this point.
`In weakly nucleophilic media of high dielectric constant, ionization efficiency
`becomes the dominant factor in determining reactivity. The relative rates of
`
`61. See: C. J. Collins,Acc. Chem. Res. 6,315 (1971); A. Streitwieser, Jr.,J. Org. Chem. 22,861 (1957).
`62. J.B. Conant and R. E. Hussey, J. Am. Chem. Soc. 47,476 (1925).
`63. M. Charton, J. Am. Chem. Soc. 97, 3694 (1975).
`
`

`

`216
`CHAPTER 5
`NUCLEOPHILIC
`SUBSTITUTION
`
`formolysis of alkyl bromides at l00°C are: methyl, 0.58; ethyl, 1.00; isopropyl, 26.1;
`and tert-butyl, about 108
`64 The effect of substituting a methyl group for a hydrogen
`.
`substituent is sensitive to the extent of nucleophilic participation in the transition
`state. A large CHJ/H rate ratio is expected if solvent participation is small in the
`H-substituted compound. If substantial nucleophilic participation is present, the
`ratio will decrease, because the favorable electronic effect of the methyl group will be
`reduced by a steric factor opposing nucleophilic participation. The relative rate of
`acetolysis of tert-butyl bromide to isopropyl bromide at 25°C is 103 7
`, while that of
`2-methyl-2-adamantyl bromide to 2-adamantyl bromide is 108·1:
`
`Ref. 65
`
`The reason for the differing response to methyl substitution is that acetolysis of
`isop!opyl bromide is solvent-assisted. Comparable solvent participation in the
`ionization of 2-adamantyl bromide is hindered by the hydrogens indicated in the
`structural drawing.
`Steric effects of another kind become important in highly branched substrates,
`in which ionization is facilitated by relief of steric crowding in going from the
`tetrahedral ground state to the transition state for ionization. 66 The relative hy(cid:173)
`drolysis rates in 80% aqueous acetone of tert-butyl p-nitrobenzoate and 2,3,3-
`trimethyl-2-butyl p-nitrobenzoate are 1: 4.4:
`
`R- tert-butyl
`k,el R- CH3
`, 4.4
`
`This effect has been called B-strain (back-strain), and in this example provides a
`modest rate enhancement resulting from relief of ground-state strain. As the size of
`the groups is increased, the acceleration caused by steric effects increases substan(cid:173)
`tially. When all the three carbinyl substituents are tert-buty!, for example, solvolysis
`occurs at a rate 13,500 times faster than the tert-butyl systems. 67 Large B-strain
`effects are observed in rigid systems such as
`the 2-alkyl-2-adamantyl p(cid:173)
`nitrobenzoates. Table 5 .10 records pertinent relative rate data. The repulsive van
`der Waals interaction between the substituent and the syn-axial hydrogens is
`relieved as the hybridization of C(2) goes from sp 3 to sp 2
`• As the alkyl group becomes
`
`64. L. C. Bateman and E. D. Hughes, J. Chem. Soc., 1187 (1937); 945 (1940).
`65. J. L. Fry,J. M. Harris, R. C. Bingham, andP. von R. Schleyer,J. Am. Chem. Soc. 92, 2540 (1970).
`66. H. C. Brown, Science 103, 385 (1946); H. C. Brown, Boranes in Organic Chemistry, Cornell
`University Press, Ithaca, N. Y., 1972, Chap. VIII; E. N. Peters and H. C. Brown, J. Am. Chem. Soc.
`97, 2892 (1975),
`67. P. D. Bartlett and T. T. Tidwell, J. Am. Chem. Soc. 90, 4421 (1968).
`
`more sterically de
`transition-state ene
`One feature of
`form strained prod
`products in prefere1
`mon. 2-Methyl-2-a,
`elimination and 18~
`acetone. Eliminati,
`adamantyl p-nitro
`adamantyl p-nitrob
`
`Although steric
`zation are of greate
`nucleophilic substit
`recognized and of
`arylmethyl and ally!
`easy to understand ·
`rapidly in such syste
`nucieophilic substit
`readily, but the rea
`reactive than ethyl c
`
`

`

`); isopropyl, 26.1;
`JP for a hydrogen
`1 in the transition
`on is small in the
`ill is present, the
`:thyl group will be
`re relative rate of
`3
`7
`, while that of
`)
`·
`
`Ref. 65
`
`that acetolysis of
`·ticipation in the
`, indicated in the
`
`nched substrates,
`1 going from the
`The relative hy(cid:173)
`zoate and 2,3,3-
`
`1mple provides a
`tin. As the size of
`1creases substan(cid:173)
`ample, solvolysis
`0 Large B-strain
`2-adamantyl p(cid:173)
`he repulsive van
`ial hydrogens is
`yl group becomes
`
`92, 2540 (1970).
`'.: Chemistry, Cornell
`n, J. Am. Chem. Soc.
`
`Talble 5.10. Relative Hydrolysis Rates of
`2-Alkyl-2-adamantyl p-Nitrobenzoatesa
`
`ifOPNE
`
`R
`
`217
`SECTION 5.7.
`STERIC AND OTHER
`SUBSTITUENT
`EFFECTS
`
`R
`
`CHr
`CH3CH2-
`(CH3hCCHr
`(CH3}iCH(cid:173)
`(CH3hC-
`
`2.0
`15.4
`20.0
`67.0
`4.5X 105
`
`a. From J. L. Fry, E. M. Engler, and P. von R. Schleyer, J.
`Am. Chem. Soc. 94, 4628 (1972).
`b. Relative to tert-butyl p-nitrobenzoate = 1.
`
`more sterically demanding, the ground-state energy increases more than the
`transition-state energy.
`One feature of the reactions of these strained substrates is their reluctance to
`form strained products. The cationic intermediates usually escape to elimination
`products in preference to substitution products. Rearrangement reactions are com(cid:173)
`mon. 2-Methyl-2-adamantyl p-nitrobenzoate gives 82% methyleneadamantane by
`elimination and 18% 2-methyl-2-adamantanol by substitution on hydrolysis in 80%
`acetone. Elimination accounts for 95% of the product from 2-neopentyl-2-
`adamantyl p-nitrobenzoate. The major product (83%) from 2-tert-butyl-2-
`adamantyl p-nitrobenzoate is the rearranged alkene 6:
`
`Although steric effects and substituent effects leading to carbonium ion stabili(cid:173)
`zation are of greatest importance in governing the mechanism and relative rate of
`nucleophilic substitution processes, there are other substituent effects that are
`recognized and of importance. We have mentioned earlier in this chapter that
`arylmethyl and allylic cations are stabilized by electron delocalization. It is therefore
`easy to understand why substitution reactions of the ionization type proceed more
`rapidly in such systems than in simple alkyl systems. It has also been observed that
`nucleophilic substitutions of the direct displacement type also take place more
`readily, but the reason for this is not apparent. Ally! chloride is 33 times more
`reactive than ethyl chloride toward iodide ion in acetone, and benzyl chloride is 93
`
`