Aromatic Substituent Constants
`
`JournaI of Medicinai Chemlstri 197.? \b/ 16 .Yo 11 1207
`
`“Aromatic” Substituent Constants for Structure-Activity Correlations?
`
`Corwin Hansch,* Albert Leo, Stefan H. Unger, Ki Hwan Kim, Donald Xikaitani, and Eric J. Lien
`Department of C h e m i s t y , Pomona College, Claremont, California 91 711 Receiced J u n e 18, 1973
`
`Aromatic substituent constants (lipophilic T , electronic um and u,>. and steric MR, molar refractivity) have been
`collected for 236 substituents including 128 7r values and 191 values for which both u,,, and cr,] were found. Swain
`and Lupton’s 3 and cR values could then be calculated for these 191 substituents by a corrected procedure. The mu-
`tual correlation of u,,, and g,] is high, r = 0.903. while 5 and C are essentially orthogonal.
`
`Interest in the use of substituent constants for correlat-
`ing structure with reactivity continues to grow rapidly in
`both simple organic1 as well as complex biochemical2 and
`biomedicinalsa-d systems. The use of cr constants (Ham-
`mett and Taft) for the electronic and E, constants
`(Taft3e) for the steric effects of substituents has greatly
`facilitated understanding of organic reaction mechan-
`isms.1.3e.4 The hydrophobic parameters5 a and log P have
`bridged the gap between simple organic and biochemical-
`biomedicinal systems. To further advance the extrather-
`modynamic approach4b to quantitative structure-activity
`relationships (QSAR),3a-d we have made a search of the
`literature to assemble as many substituents as possible for
`which both um and uu have been determined. These ap-
`pear in Table I together with measured T values and other
`parameters calculated as described below.
`There are two reasons for focusing on these two particu-
`lar electronic parameters6 instead of any of the others.
`First, far more of these constants are available than others
`such as uI or uR.7 Second, it is possible, using only om and
`up! to factor the electronic effect into resonance and non-
`resonance components.6 Since Taft and Lewis7 first ex-
`plored factoring of this kind, it has become increasingly
`evident that it can lead to greater insight into substituent
`effects. Although there are a variety of ways in which such
`factoring can be accomplished,6-8s$ the general approach of
`Swain and Lupton6 has the advantage that 3 and (R can
`be calculated directly from crm and up, avoiding nongener-
`a1 procedures.8.f A further improvement by way of an op-
`timization-orthonormalization
`procedure will be pub-
`lished shortly.$ This modification has the advantage of
`depending upon a large amount of data instead of an “ar-
`bitrarily” selected model reaction(s); it contains only a
`single general chemical constraint and it guarantees com-
`pletely independent (orthogonal) and equiscalar (normal)
`substituent vectors. Actually, 5 and CR are remarkably
`orthogonal, as will be discussed below, and therefore they
`largely avoid the common pitfall of multicollinearity (even
`though they are neither “optimum” nor precisely orthogo-
`nal).
`To provide a measure of hydrophobic character, Table I
`lists the known5b values of T from the benzene solute sys-
`tem partitioning in the octanol-water soluent system and
`also includes many new x values not previously reported.
`T constants have previously been measured using a variety
`of solute systems.§ The most common “parent” solutes
`tThis work was supported by Grant CA 11110 from the National Insti-
`tutes of Health and in part by Contract DRR-70-4115 from the National
`Institutes of Health.
`:C. G. Swain, S. H. Unger, P. Strong, and N. R. Rosenquist, unpub-
`lished results.
`§To avoid confusion in use of the term “system” in partitioning studies,
`the following symbolism will be followed in this and subsequent papers
`from this laboratory. (11 K or log P is followed by a dash and the formula for
`the substituent or the solute, respectively. For li values, the substituent
`formula can be followed by a slash (/) and then the solute name or formula.
`(21 The solvent system is given in parentheses following the solute, but only
`the organic phase need be specified. If no solvent is specified, it is assumed
`to be octanol-water. For example, a-4-Cl/phenol (oleyl alcohol) = 0.82
`refers to the K value for the chloro substituent in the para position from the
`phenol solute system measured in oleyl alcohol-water.
`
`(besides benzene) on which the substituents are placed
`are phenol, phenoxyacetic acid, benzoic acid, aniline. and
`nitrobenzene. The variation from system to system can
`often be predicted with acceptable precision.5a and it is
`generally not so great that it precludes using the s con-
`stants from benzene to serve in the design of new drugs
`and enzyme substrates where the variable substituent is
`attached to any aromatic ring. The s-/benzene values are
`much more independent of electronic contributions than.
`say, a-/nitrobenzene and are thus more likely to represent
`a true “lipophilicity” for aromatic substituents. Where
`the attachment is at an aliphatic site, the substituent a
`constant from benzene requires a correction for electronic
`effects and possibly for “folding” over the ring.5b Additiv-
`ity of both P and u on benzene rings is considered below.
`The most widely used parameter for steric substituent
`effects in organic reaction mechanism studies is Es.3e This
`parameter is useful for studying intramolecular steric ef-
`fects, particularly in reactions where the substituent is
`near the reaction center. However, since E , constants
`have not been determined for the majority of substituents
`listed in Table I and since biochemical-biomedical “ste-
`ric” requirements are often (but not always) of the “bulk”
`type, we have sought another measure, albeit approxi-
`mate, of the general “steric” bulk. Fortunately, there are
`two parameters which are readily available for each sub-
`stituent: molar refraction (MR) and molecular weight
`(MW). Van der Waals molar volumes as calculated by
`Bondis might also have been used but. for the full range
`of substituents listed in Table I, a great number of ap-
`proximations and assumptions would have been necessary.
`MR values have been used previously in some biological
`QSAR.lO For liquids, the MR can be calculated (in units
`of volume) from the Lorentz-Lorentz relation=
`- 1)/d(n2 + 2)
`(cm3/mol) ( I )
`MR = ~
`~
`(
`1
`2
`~
`
`where MW = molecular weight, n = index of refraction
`(normally at 20”, Na D line), and d = density (normally
`at 20”).
`The tolerance by enzymes and receptors for the “bulki-
`ness” of the substrates and drugs to which they are ex-
`posed is a problem of great concernll in biomedicinal-bio-
`chemical studies. We believe that MR and/or M W may
`be crude but useful measures of “bulk.” W e uish to em-
`phasize, howecer, that we consider these parameters as
`only a possible interim solution. M R contains an electron-
`ic contribution (it is directly proportional to the polarira-
`bility); therefore, its use in multiple regression analysis
`must be ciezoed with caution. The MR values in Table I
`were included partly for the purpose of the cluster analy-
`sis which appears in the following paper.12 In this they are
`somewhat less critical than in a multiple regression.
`Methods
`1. Hydrophobic Parameters. Log P values have been
`
`determined as previously d e ~ c r i b e d . ~ a In general, at least
`
`=References to MR are found in Table I, footnote d
`
`Mylan Exhibit 1024, Page 1
`
`

`
`N=191 R4.903 5 ~ 0 . 1 7 Um =-O.ll (0.03)+1.2310.OB)r up
`
`/
`
`,,/
`
`/”
`
`R I’
`
`.I ‘-a.m
`
`-11.2
`
`- 0 . a
`
`U.GY
`
`0.32
`
`u. 611
`
`vm
`
`u. w
`
`1.16
`
`I . YV
`
`d 2. m
`
`1.77
`
`Figure 1. Plot of oln ~ ‘ 6 . b y , for 191 substituents
`
`four determinations of P have been made a t varying con-
`centrations. Where P is a function of concentration, we
`have extrapolated to infinite dilution. We have used the
`value of 2.13 for log P-benzene. BoCek and Tichj.** have
`obtained a value of 2.15. In a few instances, as noted,
`r-X/benzenec was not available, and a constant from an-
`other solute system was given. Ionic substituents, such as
`- C O z - and -?jMes+, are so hydrophilic that, when at-
`tached to benzene, the resulting log P is so low that it is
`quite difficult to measure. In such cases, the more
`lipophilic biphenyl solute system was used.
`2. Electronic Parameters. un, and gP values were
`taken from our larger (unpublished) collection of substitu-
`ent constantstt and represent both primary and secon-
`dary values of varying quality. We have attempted to se-
`lect the “best” values available for each substituent, using
`updated values and discarding inconsistent values. How-
`ever, we urge that the original sources be consulted be-
`cause of the variety of methods represented.
`We have completely repeated Swain and Lupton’s pro-
`cedure for obtaining 5 and @ since the factor p = 1.65 was
`omitted from the calculation of u’ (ionization of 4-X-bicy-
`clooctanecarboxylic acids in 50 wt % EtOH, Set 5 ) 6 with
`the effect that their 5 values are out of scale w i t h a . Fur-
`thermore, our selected um and up do not always agree
`with those of Swain and Lupton. We have consistently
`rounded to two decimal places, and our 5 and (R are self-
`consistent with the url, and up in Table I. Thus
`
`**M. Tich? and K. BoEek, private communication.
`ttPomona College Medicinal Chemistry Project, Claremont, Calif
`91711.
`
`5 = 1.369 (i0.186)
`0.009 (i0.038)
`
`- 0.373 (h0.142) C J ~ -
`
`S
`1-
`iI
`14 0.9915 0.0417 (2)
`
`The figures in parentheses are 95% confidence limits; the
`overall F statistic if F2.11 = 318.77 (Fz,ll. a = ~ . 0 0 5 = 8.91).
`All the coefficients are evaluated from 14 data points of
`Baker, et al 13 (corrected for p = 1.65), but all 5 are cal-
`culated from eq 2 . Then
`@==oa,-cYr7
`
`(3 1
`CY = 0.921 under the assumption6 that
`which gives
`R(XMe3t) = 0.0 ( u p = 0.82, 5 = 0.89). Independent eval-
`uation of new substituent constants has confirmed the
`general validity of this assumption.8,; Results given below
`further show that 5 and 6l are remarkably orthogonal.
`considering the relative simplicity of the assumptions.
`3. Steric Parameters. There are various systems for
`calculating molar refractivity, but the atom-group-struc-
`ture constants of Vogel and the bond values of Vogel and
`others= are the ones most commonly used. The atom-
`group-structure system of Vogel could be applied to the
`greatest number of substituent structures of Table I, and
`so it was chosen for the sake of consistency. However, ex-
`altations between aliphatic and aromatic values can be
`rather large (as much as lo%), and for substituents con-
`taining unsaturation or a lone electron pair which could
`interact with the benzene ring, and for which Vogel did
`not list separate aromatic values, we have used Ingold’s
`special values. We have ignored the slight variation
`
`Mylan Exhibit 1024, Page 2
`
`

`
`Aromatic Substituent Constants
`
`Journal ofhfedicinal Chemistry, 1973, Vol. 16, No. 11 1209
`
`Table I. “Aromatic” Substituent Constants
`
`No.
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`26
`27
`28
`29
`30
`31
`32
`33
`34
`
`35
`36
`37
`38
`39
`40
`
`?Th
`-0.55
`0.86
`
`0.88
`-0.57
`-4.36W
`-0.65
`-0.32
`0.79
`0.17
`
`-1.49
`-0.38
`-1.87
`0.56
`- 1.03
`-1.04
`0.02
`
`0.40
`
`-0.57
`0.11
`
`0.82
`-0.55
`-0.01
`-0.72
`-1.27
`-1.68
`
`1.02
`
`-0.17j
`
`b m
`~ -0.01
`0.39
`0.28
`0.32
`0.43
`0.56
`-0.10
`0.35
`0.37
`0.12
`0.11
`0.10
`0.28
`0.22
`
`UP
`0.12
`0.23
`0.29
`0.33
`0.54
`0.66
`0 .oo
`0.42
`0.45
`0.14
`0.12
`0.11
`0.36
`0.10
`
`Y
`-0.07
`0.44
`0.27
`0.31
`0.38
`0.51
`-0.15
`0.31
`0.33
`0.10
`0.10
`0.09
`0.24
`0.25
`
`-0.07
`0 .oo
`
`-0.17
`0.00
`
`-0.04
`0 .oo
`
`0.81
`0.23
`0.15
`0.31
`0.01
`0.26
`
`-0.02
`0.50
`0.45
`-0.07
`0.36
`0.07
`0.34
`-0.15
`0.52
`
`0.19
`0.33
`0.51
`0.53
`0.30
`0.27
`
`0.80
`0.19
`0.10
`0.27
`0.21
`0.33
`
`0.07
`0.32
`0.33
`
`0.34
`
`0.27
`-0.05
`0.45
`
`0.19
`0.21
`0.36
`0.30
`0.28
`0.22
`
`0.81
`0.21
`0.12
`0.29
`0.16
`0.32
`
`0.05
`0.38
`0.37
`
`0.35
`
`0.30
`-0.07
`0.48
`
`0.20
`0.25
`0.41
`0.37
`0.29
`0.24
`
`0.16
`
`0.24
`
`MWe
`44.8
`79.9
`251.7
`118.4
`69 .O
`26 .O
`44 .O
`29 .O
`45 .O
`93.9
`49.5
`140.9
`44.0
`44 .O
`60 .O
`15 .O
`31 .O
`30.1
`97 .O
`116 .O
`25 .O
`115.1
`147.1
`40 .O
`72 .O
`27.1 *1U1
`43.1 *V1
`59.0 * v o 1
`59.0 *1VQ
`58.1 *VM1
`58.1 *1VZ
`74.1 *YUS&M1
`29.1 *2
`143.2 *?
`
`at
`MRd
`0.18 11.04Ah
`-0.17
`8.88B
`0.04 28.81
`0.05 20.12
`0.19
`5.02
`0.19
`6.33B
`0.13
`6.05BC
`0.13 6.88B
`0.15
`6.93B
`0.05 13.39
`0.03 10.49
`0.03 18.60
`0.14
`9.81B
`-0.13 10.28B
`11 .22B
`5.65
`7.19
`9.09
`11.17B
`0.08 10.19
`0.05
`9.55B
`0.06 17.59
`0.06 17.51%
`-0.18 10.11
`-0.05 16.42B
`
`-0.13
`0.00
`
`-0.08
`10.99B
`0.20 11.18B
`0.15 12.87B
`11.88
`0.05 14.57B
`14.41
`0.09 22.33
`-0.10 10.30
`0.10
`
`0.01
`0.14
`0.18 14.13B
`0.25 13.44
`0.05 15.18
`0.07 15.57B
`
`Wiswesser line
`notation1
`*BQQ
`*E
`*XEEE
`*XGGG
`*XFFF
`*CN
`* v o
`*VH
`*VQ
`*1E
`*lG
`*11
`* v z
`*lUNQ
`*VMQ
`*1
`*1Q
`*1z
`*VXFFF
`*XFFOX*FF(C,D) 9
`*lUU1
`10
`*1SXFFF
`11
`*lSWXFFF
`11
`*1CN
`1
`*1UlNW -T
`12
`
`Ref
`o m r p g
`1
`1
`2
`2
`3
`3
`3
`3
`2
`2
`2
`2
`2
`2
`5
`4
`2
`2
`1
`1
`1
`1
`1
`1
`4
`6
`7
`7
`
`2
`8
`
`5
`2
`2
`
`14
`
`14
`2
`16
`
`2
`8
`
`9
`10
`11
`11
`4
`12
`
`5
`2
`13
`8
`14
`15
`14
`2
`16
`
`17
`17
`18
`19
`19
`3
`
`0.17
`
`0.15
`
`0.03 15.57B
`
`3
`
`3
`
`0.26
`
`-0.07
`
`Functions
`B (OH) 2
`Br
`CBr3
`cch
`CF3
`CN coo -
`CHO
`COOH
`CHtBr
`CHzC1
`C H J
`CONHI
`CH=NOH
`C=O(NHOH)
`CH3
`CHiOH
`CHtNH,
`CEO (C Fa)
`3,4- (CFzOCFI)
`C=CH
`CHISCF3
`CH2SOzCF3
`CHQCN
`CH=CHNO,
`(trans)
`CH=CH?
`COCHI
`COzCH3
`CHICOOH
`C=O(NHCHs)
`CH?CONH?
`C=S(NHCH3)
`CZHB
`1-(1,2-BioHiaC~H)
`a-carboranyl
`3-Barenyl
`1-Neobarenyl
`C E C C F ~
`CF(CFI)?
`C (OH) (CF3)2
`CH=CHCFI
`(trans)
`41
`CH=CHCFa
`(cis)
`42 CH=CHCN
`43
`CzCCH3
`44
`CH=CHCHO
`45
`CH=CHCOOH
`46
`CHzCH=CHz
`47
`C yclopropyl
`48
`CHCOCHa
`49
`CO?C?H;
`50
`CH?OC=O(CHs)
`51
`CHgCHgCOzH
`52
`3,4- (CH&H,CH?)
`53
`CHzCH(NH3+)-
`coo -
`1.55
`CaH,
`1.53
`CH(CHa)?
`-0.15m
`CH?N(CH3)?
`C F ~ C F ~ C F Z C F ~
`2-T hienyl
`1 . 6 1
`3,4-(CH=
`1.32
`CHCH=CH)
`CH=CHCOCHs
`C yclobutyl
`
`0 .oo
`1.10
`
`-0.69
`0.51
`-0.17
`-0.29
`1.20
`-3.56‘
`
`54
`55
`56
`57
`58
`59
`60
`61
`
`-0.06i
`
`1.39X
`
`64 C(CH:j),
`65 CHsSi(CH&
`66 4-Pyridyl
`67 CH=CHCOICIH:,
`68 Cyclopentyl
`
`1.98
`
`0.32
`0.861
`2.14X
`
`17
`143.2
`*?
`17
`143.2
`*?
`93 .O *lUUlXFFF
`18
`169 .O *XFXFFFXFFF 19
`167.0 *XQXFFFXFFF 19
`95 .O * l U l X F F F -T
`3
`95 .O *lUlXFFF -C
`52.1 *lUlCN
`39.1 *1uu2
`*1U1VH
`55.1
`*lUlVQ
`71.1
`*2u1
`41.1
`* AL3TJ
`41 . I
`*1v1
`57.1
`* v 0 2
`73.1
`*1ov1
`73.1
`*2VQ
`73.1
`*3*(C,D)
`42.1
`*1YZVQ
`88.1
`
`2
`
`22
`4
`
`20
`21
`20
`22
`
`23
`
`0.17
`0.09
`0.13
`0.90
`
`0.27
`-0.15
`
`0.24
`0.14
`
`-0.07
`
`-0.21
`
`-0.03
`
`0.37
`
`-0.03
`-0.26
`
`0.45
`0.05
`-0.07
`-0.26
`
`0.33
`
`-0.02
`-0.27
`
`16.23B
`14.14B
`-0.12 16.88B
`1.04 17.91Bk
`14.49
`13.53
`15.06
`0.15 17.47B
`16.48
`16.52
`-0.05
`-0.01 13.94
`
`-0.19
`
`-0.07
`-0.07
`
`0.47
`0.09
`0.04
`
`0.21
`
`-0.48
`-0.08
`-0.10
`-0.16
`
`0.19
`
`-0.13
`-0.15
`0.01
`0.52
`0.05
`0.04
`
`-0.01
`-0.15
`-0.48
`-0.16
`-0.20
`-0.21
`
`0.03
`-
`0.02
`
`-0.06
`-0.05
`
`0.44
`0.10
`0.03
`
`0.28
`
`-0.49
`-0.06
`-0.07
`-0.15
`
`0.24
`
`-0.08
`-0.10
`
`14.96
`14.98
`18.74
`0.11 17.65
`0.04 24.04An
`0.01 17.47A0
`
`-0.27
`
`21.10B
`17.88
`-0.03 18.59
`-0.11 19.59
`-0.13
`19.62
`-0.07
`29.61D
`23 .03Ae
`-0.19 27.21B
`22.02
`
`43.1 *3
`43.1 *Y
`58.1 * l N l & l
`219 .O */XFF/ 4F
`83.1 * BT5SJ
`52.1 R A* B*(C,D)
`
`* l U l V l
`69.1
`* AL4TJ
`55.1
`*4*(C,D)
`56.1
`*4
`57.1
`*X
`57.1
`*l-SI-1&1&1
`87.2
`* DT6NJ
`78.1
`*1UlVO2
`99.1
`6 9 . 1 * AL5TJ
`
`5
`24
`
`19
`26
`2
`
`20
`
`4
`5
`2
`2
`
`20
`
`20
`21
`20
`8
`
`23
`
`2
`15
`22
`4
`
`4
`2
`25
`19
`26
`2
`
`20
`27
`4
`4
`2
`2
`
`20
`27
`
`Mylan Exhibit 1024, Page 3
`
`

`
`1210 Journai ofMedmnal Chemlstn. 1973, Val 16, No I 1
`
`Hansch, et a1
`
`Table I (Continued)
`
`No.
`Functiow
`69 CiHi,
`70
`(CH?)3N (CH,) 1
`71 CsCl
`72 CeF,
`73 CsH2[2,4,6-
`(NO?)il
`74 C6Hi
`
`T*
`
`0.60
`
`6 1 "
`
`-0.08
`
`0.25
`0.34
`0.26
`
`Ul)
`-0.15
`- 0 , 1 3
`0.24
`0.41
`0.30
`
`7 c
`-0.06
`
`0.24
`0.30
`0.24
`
`M R '
`1%
`-0.09 24.25
`28.04
`0.02 49.53B
`0.13 23.98B
`0.08 42.21B
`
`1.96
`
`0.06
`
`-0.01
`
`0.08
`
`-0.08 25.36"
`
`76 Cyclohexyl
`77
`(CH?)rN(CH3)3+
`
`2.51X
`-4.15
`
`0.15
`
`-0.22
`0.02
`
`24.80
`
`26.69
`
`0.30
`
`0.33
`
`0.28
`
`0.07 32.74
`
`MWe
`71.2
`86.2
`249.3
`167.1
`212.1
`
`77.1
`
`81.2
`
`83.2
`101.2
`
`118.1
`
`Wiswesser line
`notation '
`
`*5
`*3N1&1
`*R-/G 5
`*R-/F 5
`*R BNW DNW
`FNW
`*R
`* AL35TJ
`* AL6TJ
`*3K
`* CT56 BN DOJ
`
`Ref
`d p "
`-
`5
`25
`29
`29
`1
`
`gri,
`5
`
`29
`29
`1
`
`2
`
`2
`27
`
`27
`25
`
`30
`
`30
`
`78
`
`
`'
`T
`2-Benzoxazolyl
`79 _t.yJ
`2-B enzthiazolyl
`80 C=O(CaH:)
`81 CH=NCsH$
`82 CHlCsH5
`83 CH(OH)C6H,
`
`2.13
`
`0.27
`
`0.29
`
`0.25
`
`0.06 38.88DiJ
`
`134.2 * C T 5 6 B N DSJ
`
`30
`
`30
`
`1.05
`-0.29
`2.01
`0.54
`
`0.34
`0.35
`-0.08
`
`2.66
`
`0.14
`0.03
`
`0.15
`
`0.43
`0.42
`-0.09
`-0.03
`
`0.01
`0.16
`-0.07
`-0.12
`0.05
`
`0.30
`0.31
`-0.08
`
`0.12
`0.06
`
`0.18
`
`0.16 30.33B
`0.13 3 3 . 0 1 ~ 7 1
`-0.01 30.01
`31.52
`29.44
`0.05 33.21B
`-0.12 34.17B
`34.65
`-0.11 45.68B
`
`105.1 *VR
`104.1 *lUNR
`91.1 *lR
`107.1 *YQR
`95.2 * AL36TJ
`101.1 *lUUlR
`103.1 *lUlR
`105.2 *2R
`176.2 *lIJlVR DNW
`
`0.05
`-0.18
`
`0.22
`-0.15
`
`-0.15 40.25B
`- 0.04 48.24AQ
`
`31
`33
`1
`34
`27
`1
`35
`36
`20
`
`31
`32
`1
`
`1
`35
`
`20
`
`20
`37
`
`85 CsCCsH,
`86 CH=CHCsH,
`87 CHQCHQCGH;
`88 CH=CHCOC,Hd-
`(4-NO2)
`89 CH=CHCOCsHj
`90 Ferrocenyl
`
`0.951
`2.46
`
`0.18
`-0.15
`
`91 Adamantyl
`
`3.30Y
`
`-0.12
`
`-0.13
`
`-0.12
`
`-0.02 40.63Ar
`
`131.2 *lUlVR
`* AL50J 0-FE--
`185.0
`OL50J
`135.3 * BL66 B6 A B-
`C 1B ITJ
`
`38
`
`0.17
`
`0.21
`
`0.15
`
`0.08 5 9 . 0 8 D ~ ~ 193.2 * C T 5 6 B N D N J 30
`BR
`
`l-Phenyl-2-
`benzimidazolvl
`
`F
`GeBr:$
`GeC1,
`GeFa
`H
`HgCHJ
`I
`IO
`IO?
`NO
`NO2
`N z N f
`N N N
`NH:!
`NHOH
`NHr--
`NHNH,
`NHS02NHSO.r
`NH?
`5-C1-1-tetrazolyl
`
`N-CClr
`N -C=O
`N-C=S
`5-Azido-l-
`tetrazolyl
`NHCN
`1-Tetrazolyl
`5-OH-1-tetrazolyi
`F. SH-1-tetrazolyl
`
`93
`94
`95
`96
`97
`98
`99
`100
`101
`102
`103
`104
`105
`106
`107
`10s
`109
`110
`111
`112
`
`113
`
`114
`115
`116
`117
`
`118
`119
`120
`121
`
`0.71
`0.14
`
`0 .oo
`1.12
`-3.74
`-3.46
`-0.12
`-0.28
`
`0.46
`- 1.23
`-1.34
`
`-0.88
`-2.11a
`
`-0.65
`
`0.41
`
`1.15
`
`- 1.04
`
`0.36
`0.37
`0.34
`0.66
`0.71
`0.85
`0 .oo
`0.43
`0.35
`
`0.68
`
`0.71
`1.76
`0.27
`-0.16
`-0.04
`0.86
`-0.02
`
`0.56
`0.23
`0.06
`0.73
`0.79
`0.97
`0.00
`0.10
`0 . 1 8
`
`0.78
`0.12
`0.78
`1.91
`0.15
`-0.66
`-0.34
`0.60
`-0.55
`
`0.60
`
`0.21
`0.27
`0.48
`0.54
`
`0.21
`0.52
`0.39
`0.45
`
`0.61
`
`0.13
`0.19
`0.38
`0.54
`
`0.06
`0.50
`0.33
`0.45
`
`0.27
`0.41
`0.43
`0.62
`0.67
`0.79
`0.00
`0.54
`0.40
`
`0.31
`-0.15
`-0.34
`0.16
`0.17
`0.24
`0 .oo
`-0.40
`-0.19
`
`0.63
`
`0.20
`
`0.16
`0.36
`-0.13
`-0.68
`-0.40
`-0.27
`-0.71
`
`211.3
`60.37B
`35.4
`6.03B
`19 .o
`0.92B
`312.3
`36.35D
`178.9
`25.85D
`129.6
`6.95D
`1 .o
`1.03
`215.6
`19.43D
`126.9
`13.94B
`142 9
`39.06C'
`63.51CD. 158.9
`5 2
`30.0
`7.36'
`46 . O
`28.0
`42 . O
`16 . O
`32 . O
`17 . O
`31 . O
`174.2
`
`10 2 B
`5.42B
`7.22
`
`8.44
`28.40'
`
`0.07 23. 16Di,
`
`103.5
`
`-0.08 18.35D
`96.9
`-0.08
`8.82D
`42 . O
`-0.09
`17.24D
`58.1
`0.05 26 .85CDr 110.1
`
`-0.18 10.14
`41 .O
`0.02 18.33D"
`69.1
`--0.04 19.77D"
`8 5 . 1
`0.05 26.06D3( 101.1
`
`0.67
`1.69
`0.30
`0.02
`0.06
`0.94
`0.17
`
`0.58
`
`0.23
`0.29
`0.51
`0.53
`
`0.26
`0.52
`0.40
`0.44
`
`20
`37
`
`39
`
`30
`
`34
`2
`2
`40
`40
`40
`22
`41
`2
`
`1
`4
`2
`42
`43
`2
`4
`44
`4
`
`13
`2
`2
`40
`40
`40
`22
`41
`2
`
`1
`
`2
`42
`43
`2
`4
`44
`4
`
`*VOYR&R
`*G
`*F
`*-GE-EEE
`*-GE-GGG
`*-GE-FFF
`*H
`*-HG-l
`*I
`*IO
`*IW
`*NO
`*NW
`*NN &J
`*NNN
`*Z
`*MQ
`*Z &H
`*MZ
`"MSWMSZW
`* ATSNNNNJ
`EG
`*NUYGG
`*NCO
`*NCS
`* AT5NNNNJ
`ENNN
`*MCN
`* AT5NNNNJ
`* ATSNNNNJ E$
`* AT5NNNNJ
`ESH
`
`3
`
`3
`
`3
`3
`43
`3
`
`28
`3
`3
`3
`
`3
`3
`43
`3
`
`28
`3
`3
`3
`
`Mylan Exhibit 1024, Page 4
`
`

`
`Aromatic Substituent Constants
`
`Table I (Continued)
`
`JournalofMedicinal Chemistry, J973, Vol. 16, No. J I 1211
`
`No.
`
`Functiona
`
`T b
`
`O m
`
`UP
`
`5c
`
`RC
`
`MRd
`
`MWe
`
`Wiswesser line
`notation1
`
`Ref
`Om
`c * g
`
`0.30
`
`0.19
`
`0.33
`
`-0.11
`
`101.1
`
`*M- ETSNNNSJ
`
`28 28
`
`123 NHCHO
`124 NHCONH?
`125 NHCSNHz
`126 NHCHa
`127 NHSOqCHI
`128 N(CF3)s
`129 NHCOCFX
`
`-0.98
`-1.30
`-1.40
`-0.47
`-1.18
`
`0.08
`
`0.19
`-0.03
`0.22
`-0.30
`0.20
`0.40
`0.30
`
`0.00
`-0.24
`0.16
`-0.84
`0.03
`0.53
`0.12
`
`0.25
`0.04
`0.23
`-0.11
`0.25
`0.34
`0.36
`
`-0.23 10.31
`-0.28
`13.72
`-0.05 22.19
`-0.74 10.33
`-0.20 18.17'
`0.22 14.28
`-0.21 14.30
`
`0.63
`
`0.64
`
`0.61
`
`0.07 49.17Dm
`
`131
`132
`133
`134
`135
`136
`137
`138
`139
`140
`141
`142
`143
`144
`145
`146
`147
`148
`149
`150
`151
`
`-0.97
`
`0 .08"'
`0.18
`-1.51
`0.46
`-0.47
`0.17
`
`-5.96W
`
`1.45u
`1 .69
`1.37
`0.45
`-0.29
`0.49
`
`0.17
`0.21
`0.24
`-0.24
`-0.15
`
`-0.03
`0.00
`0.12
`-0.61
`-0.83
`
`0.23
`0.28
`0.27
`-0.11
`0.10
`
`-0.25
`-0.26
`-0.13
`-0.51
`-0.92
`
`0.07
`0.04
`0.30
`0.88
`0.11
`-0.10
`-0.34
`0.32
`-0.12
`0.16
`-0.08
`0.02
`0.27
`
`-0.15
`-0.26
`0.07
`0.82
`-0.10
`
`-0.51
`0.39
`-0.40
`0.01
`-0.55
`-0.19
`0.31
`
`0.14
`0.14
`0.38
`0.89
`0.18
`
`-0.28
`0.28
`-0.02
`0.21
`0.09
`0.09
`0.24
`
`-0.28
`-0.39
`-0.28
`0 .oo
`-0.26
`
`-0.25
`0.13
`-0.38
`-0.18
`-0.63
`-0.27
`0.08
`
`19.77
`14.93
`23.40
`14.98
`15.55
`31 .22'
`20.88D
`19.58
`21.18
`23.19
`31.66
`
`24.25
`25.82
`24.26
`31.31
`30.04
`37 .88'
`33.01D
`34.64
`37.45
`
`44.0
`59.1
`75.1
`30.1
`94.1
`152 .O
`112 .o
`201.2
`
`*MVH
`*MVZ
`*MYZUS
`*M1
`*MSW1
`*NXFFFXFFF
`*MVXFFF
`* AT5NNNNJ
`ESS-
`ET5MNNNJ
`
`92.5
`58.1
`74.1
`44.1
`44.1
`172.2
`72.1
`72.1
`88.1
`87.1
`103.2
`59.1
`86.1
`102.1
`72.15
`105.1
`92.1
`156.2
`104.1
`120.1
`135.2
`
`*MVlG
`*MV1
`*MYUS
`*M2
`*Nl&l
`*NSWl&&SWl
`*NUNN1&1
`*MV2
`*MV02
`*MVM2
`*MY US&M 2
`*K
`*MVY
`*MlV02
`*M4
`*NUNR
`*MR
`*MSWR
`*NUlR
`*MVR
`*NUNR BQ E l
`
`
`
`
`
`
`
`
`
`
`
`
`
`43 43
`43 43
`28 28
`4
`2
`43 43
`45 45
`43 43
`
`3
`
`3
`
`43 43
`2
`2
`14 14
`4
`6
`46
`2
`
`43 43
`14 14
`14 14
`2
`2
`43 43
`47
`6
`4
`13 13
`48 48
`43 43
`43 43
`43 43
`43 43
`
`NHCOCHzCl
`NHCOCHI
`NHCSCHs
`NHCzHj
`N(CH3)z
`N(SOzCH3)z
`N=NN (CH3)2
`NHCOCzHj
`NHC02CzHj
`NHCONHCzHj
`NHCSNHCzH:
`N(CH,)C
`NHCOCH (CH3)z
`NHCH?COzC?Hs
`NHC4Hg
`N=NC sH j
`NHCaH,
`NHSOzCsHj
`N=CHCsHj
`NHCOCsH,
`N=NC sH3-
`(2-OH) (5-CH3)
`N=CHCsHa-
`
`152
`
`154 N(C6Hj)z - '
`155 0 -
`156 OH
`157 3,4-(OCFzO)
`158 OCF3
`159 OCHF?
`160 OCONHz
`161 3,4-(OCH,O)
`162 OCH,
`164 OCFzCHFCl
`165 OCOCH,
`166 OCH2COOH
`167 OEt
`168 OPO(OCH3)z
`169 OCH(CH3)Z
`170 OC3H7
`171 OCiHo
`172 OCjHii
`173 OCsHj
`174 OSOzCaH:
`175 0-8-glucose
`
`176 OCOC6Hj
`177 POCI,
`178 PCl,
`179 POF,
`180 PFZ
`181 PSClZ
`182 POZH-
`183 PHz
`184 P(Cl)N(CHS),
`185 PO(CH3)t
`
`- 3.87W
`-0.67
`
`1.04
`
`- 1.05
`-0.05
`-0.02
`-0.88
`
`-0.64
`-0.87
`0.38
`
`1.05
`
`2.08
`0.93
`-2.84-
`
`1.46
`
`-0.07
`
`-0.54
`
`0.10
`
`-0.63
`
`39.29D
`
`134.2
`
`*NUlR DO1
`
`0.09
`
`-0.06
`
`0.14
`
`-0.19
`
`41.03
`
`150.2
`
`*MVR DO1
`
`0.00
`-0.47
`0.12
`0.36
`0.38
`0.31
`
`-0.16
`0.12
`0.39
`0.35
`0.39
`
`0.10
`
`0.10
`0.10
`0.10
`0.10
`0.25
`0.36
`
`0.21
`0.80
`0.53
`0.81
`0.26
`0.73
`0.20
`0.05
`0.38
`0.42
`
`-0.22
`-0.81
`-0.37
`0.36
`0.35
`0.18
`
`-0.16
`-0.27
`0.36
`0.28
`0.31
`-0.33
`-0.24
`0.04
`-0.45
`-0.25
`-0.32
`-0.34
`-0.03
`0.33
`
`0.07
`-0.35
`0.29
`0.35
`0.38
`0.35
`
`-0.17
`0.26
`0.39
`0.37
`0.41
`
`-0.29
`-0.49
`-0.64
`0.04
`0 .oo
`-0.14
`0 .oo
`-0.51
`0 .oo
`-0.06
`-0.07
`
`0.22
`
`-0.44
`
`0.30
`0.22
`0.25
`0.25
`0.34
`0.36
`
`-0.72
`-0.45
`-0.55
`-0.57
`-0.35
`0 .oo
`
`0.13
`0.43
`0.61
`0.89
`0.61
`0.39
`0.26
`
`0.56
`
`0.23
`0.93
`0.49
`0.77
`0.12
`0.84
`0.17
`
`0.30
`
`-0.08
`-0.42
`0.16
`0.18
`0.50
`-0.39
`0.11
`
`0.28
`
`54.96
`
`2.85B
`8.95B
`7.86B
`7.86B
`11 .28B
`8.96B
`7.87B
`16.99
`17.30B
`12.47B
`13.99B
`12 .47B
`22 .02B
`17 .06B
`17 ,06B
`21 .66B
`26.26B
`27 .68B
`36.70'
`36.53D
`
`32 .33B
`20.16D
`21 .42D
`9.58D
`11.02D
`28 .29D
`
`12.19D
`27.01D
`19.93D
`
`168.2
`16 .O
`17 . O
`82 .O
`85 . O
`57 .O
`60 . O
`46 . O
`31 .O
`95.1
`133.5
`59 . O
`75 .O
`45.1
`125 . O
`59.1
`59.1
`73.1
`87.2
`93.1
`157.2
`179 .O
`
`121.1
`117.9
`101.9
`85 .O
`69 .O
`133.9
`80 .O
`33 . O
`110.5
`77 .o
`
`*NR&R
`*O
`*Q
`*OXFFO*(C,D)
`*OXFFF
`*OYFF
`* o v z
`*010*(C,D)
`*01
`* o s w 1
`*OXFFY GF
`* o v 1
`*OlVQ
`*02
`*OPO&O1&01
`*OY
`*03
`'04
`*05
`*OR
`*OSWR
`*0- BT6OTJ
`
`*PO&GG
`*PGG
`*PO&FF
`*PFF
`*PS&GG
`*PWQ
`*PHH
`*PGN1&1
`*PO&1&1
`
`43 43
`
`43 43
`
`49 50
`44 44
`2
`2
`9
`9
`45 45
`51 51
`
`2
`
`22 22
`2
`2
`43 43
`51 51
`2
`2
`52
`2
`53
`2
`2
`2
`2
`2
`2
`2
`2
`4
`2
`43 43
`
`43 43
`54 53
`54 41
`41 41
`41 41
`54 53
`2
`2
`54
`41 41
`54
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Mylan Exhibit 1024, Page 5
`
`

`
`__Ref
`Flit r,
`55
`.i 5
`54
`41
`5 3
`56
`
`Nli.
`186
`187
`188
`189
`190
`191
`192
`193
`194
`195
`196
`
`I97
`
`198
`199
`200
`2 01
`202
`203
`204
`203
`2 06
`207
`208
`209
`210
`211
`21 2
`213
`21 4
`21 5
`216
`21 7
`218
`219
`220
`221
`322
`223
`224
`22.5
`226
`
`Function,'
`
`-,,
`
`0 70
`
`0 05%
`1 23
`
`--4 76iV
`0 39
`-1 82
`1 65
`
`0 ,ir5
`1 44
`0 41
`
`- 1 58
`-1 63
`0 61
`0 10
`1 07
`
`0 27
`2 32
`
`c
`
`0 42
`0 O?
`
`0 35
`0 65
`0 42
`0 56
`
`0 09
`0 38
`0 33
`
`( I 40
`
`0 20
`0 35
`0 38
`0 11
`0 29
`0 80
`0 61
`- 0 02
`0 05
`0 25
`0 46
`
`0 63
`0 79
`0 40
`0 41
`0 33
`0 54
`0 75
`0 52
`0 60
`0 1<5
`0 3s
`0 39
`0 18
`I 00
`(J 61
`
`0 iii
`
`0 37
`-0 08
`
`0 52
`
`rT
`0 53
`u 31
`0 33
`0 60
`
`0 44
`
`0 50
`
`0 32
`
`\ j
`
`M I Z '
`0 19 21 87D
`0 39 21 19D
`32 42D
`0 12 31 16D
`39 49D"
`40 75D
`47 6 2 D '
`40 99D
`36 14D
`0 20 40 46D
`41 68D
`
`MWe
`109 .0
`61 1
`121.1
`137.1
`177.5
`161 . .i
`193.6
`143 .5
`127.1
`165.2
`157.1
`
`Wiswesser line
`notation
`"P0&01&01
`* P l & l
`+PO2 &02
`*P0&02&02
`"PO&GR C F
`^PGR C F
`"PS&GR C F
`'"PGR
`*PHR C F
`"P0&03&03
`*POl&R C F
`
`39 37D
`
`157.1
`
`*PO&l&R C F
`
`0 49
`0 53
`0 19
`0 47
`0 91
`0 68
`-0 05
`0 09
`0 15
`0 57
`
`0 29
`0 31
`0 07
`0 21
`0 75
`0 57
`-0 02
`0 03
`0 28
`0 41
`
`0 69
`0 93
`0 50
`0 52
`0 37
`0 58
`0 86
`0 49
`0 72
`0 00
`0 47
`0 44
`0 03
`0 90
`0 70
`0 le
`0 70
`
`0 60
`0 73
`0 35
`0 36
`0 30
`0 51
`0 70
`0 52
`0 54
`0 20
`0 34
`0 36
`0 23
`1 02
`0 56
`
`0 62
`
`40 63D'
`0 23 47 81D
`0 24 59 29D
`0 12 60 55D
`0 27 67 42D
`8 65
`0 22
`0 15
`9 89A
`-0 03
`0 07
`9 22B
`- 0 11
`0 19 12 28
`28 34B
`0 14 13 07
`0 26 12 86
`0 18 13 81B
`0 19 13 40
`0 09 13 81B
`0 11 13 28
`0 22 13 08
`0 01 13 70
`0 22 13 49
`- 0 18 13 82B
`0 16 18 408
`0 11 18 42R
`-0 18 18 42R
`-0 04
`0 18 33 20
`34 29B
`
`0 13
`
`141.1
`161.2
`201.2
`185.2
`217.2
`8 3 . 1
`127.1
`6 4 . 1
`80.1
`33.1
`8 0 . 1
`150.4
`117.1
`133.1
`101.1
`38 .1
`8 3 . 1
`9 9 . 1
`115.1
`6 3 . 1
`79 .I
`47.1
`133.1
`7 5 . 1
`6 1 . 1
`6 2 . 1
`141.2
`109.2
`216.3
`
`*Pl&R C F
`*P0&4&4
`-PO&R&R
`*PR&R
`*PS&R&R
`"SWF
`'"SFFFFF
`"SW
`'SWO
`'SEI
`"SZW
`^SXGGG
`'SO&XFFF
`*SWXFFF
`WXFFF
`"SCN
`"SYFF
`"SO&YFF
`YSWYFF
`Y30% 1
`*SWI
`"S 1
`xSXFFY FF
`"SVI
`'S2
`"Sl&l
`*SWR
`*SN.
`"Sl&UNSWR D1
`
`56
`54
`54
`54
`
`5 4
`55
`54
`
`<5 4
`
`54
`55
`57
`57
`5 7
`58
`59
`60
`2
`2
`9
`
`1
`
`18
`61
`61
`6
`1
`62
`1
`
`2
`2
`61
`2
`9 ..
`>
`5
`
`63
`
`0 74
`
`2 59
`
`0 32
`0 61
`0 10
`0 48
`0 48
`0 54
`-0 04
`0 00
`
`0 38
`0 66
`0 00
`0 57
`0 56
`0 69
`-0 07
`-0 01
`
`0 29
`0 58
`0 13
`0 44
`0 44
`0 47
`-0 04
`- 0 01
`
`0 12 16 32D
`0 13 16 82D
`-0 12 17 03D
`0 17 32 76D
`0 16 23 85D
`7 62D
`0 25
`-0 04 24 96D
`-0 01 43 64D
`
`148 . 0
`105 .o
`94 . O
`267.8
`134.4
`8 5 . 1
`73.2
`147.4
`
`0 02
`
`- - 0 01
`
`-0 0.3
`
`0 02 62 32D
`
`221.6
`
`0 01
`
`- 0 13
`
`0 . 1 1 80.99D
`
`295 7
`
`-2 I
`6,' c
`228
`229
`230
`231
`23%
`233
`234
`
`235
`
`236
`
`~
`
`'-SE-XFFF
`'-SE-CN
`*-SE-l
`'-SI-EEE
`'-SI-GGG
`--SI-FFF
`*-SI-l&l&l
`*-SI-l&l&O-SI-
`1&1&1
`"-SI-l& O-SI-
`1&1&12
`'-SI- O-SI-
`- 0 09
`1&1&13
`-_
`first,
`' Function begins with attachment atom, sorted alphabetically on attachment atom and within each such grouping:
`if' no (1 o r 11, then alphabetically on remainder; second, if no C, then on H and alphabetically on remainder; third, C then
`I i then allJhabetically on remainder. l2 A11 T values from partition coefficients measured in this laboratory using octanol-
`watci' solvent system and substituted benzene solutes unless footnoted to give other sources or suffixed to give other solute
`systcms: W --- from substituted biphenyl solutes; X = from substituted phenoxyacetic acid solutes; Y = calculated from
`0 1 I deiiv:iLive: Z = from substituted toluene solutes.
`Calculated from u,,, and u,, given in this table according to the pro-
`c.t-durr (iutlined in the text. d Molar refraction using A. I. Vogel's [ J . Chem. Soc., 1833 (1948) ] atom, group, or structural Ru
`lyell(,w l i n d values unless suffixed: A = calculated [usually from index of refraction, density, and molecular weight from
`I'firentz 1,orentz formula (eq I ) ] using Vogel's (1948) values for corrections; B = atom, group, or structural H, ( = R c red
`values from Ingold ("Structure and Mechanism in Organic Chemistry," 2nd ed, Cornel1 University Press, Ithaca, N. Y.,
`line
`1969. 1 1 1 ~ 142 1.52). Note: Table 10.1 "alcohol" and "ether" values inverted; C = approximate; D = bond values [including
`1JlJnd t o ( ' 1Jf substrate) from A. I. Vogel, W. T. Cresswell, G. €3. Jeffery, and J. Leicester, J . Chem. soc., 514 (19.521, and
`cswrlier i.ct:'c.iences cit,ed therein (general); A. I. Vogel, W. T. Cresswell, and J. Leicester, J . Phys. Chem., 58, 174 (1954) (Sn,
`Si, (if,. and fIg bonds); A. A. Foxton, (2. H. Jeffery, and A. I. Vogel, J . Chem. SOC. A , 249 (1966) (P bonds); R. G. Gillis, Rev.
`l'unj A p p / . C'hcm., 10, 21 (1960) (bonds to C, H, 0, and self), updated by P. M. Christopher and T. L. Patterson, Aust. J .
`( ' h ~ m . . 21, 2:173 f 19683, and earlier references cited therein; C. Stijlzer and A. Simon, Chem. Ber., 96, 1335 (1963) (P bonds to
`I,', C I . N ; 11. Sayre, J . Amer. Chem. Soc., 80, 5438 (1958) (P bonds to S). From "Handbook of Chemistry and Physics,"
`531.~1 ed, Chemical Rubber Publishing Co., Cleveland, Ohio, 1972. The WLN follow as closely as possible the rules in "The
`
`53
`
`5 5
`
`55
`57
`57
`57
`58
`59
`60
`2
`2
`2
`
`18
`61
`61
`2
`1
`62
`1
`2
`2
`2
`61
`2
`2
`2
`5
`36
`63
`
`64
`4
`2
`40
`40
`41
`2
`65
`
`64
`48
`2
`40
`40
`41
`2
`63
`
`65
`
`65
`
`65
`
`65
`
`Mylan Exhibit 1024, Page 6
`
`

`
`Aromatic Substituent Constants
`
`Journal ofMedicinal Chemistr?, 2973, Vol 16, No 11 1213
`
`Wiswesser Line-Formula Chemical Notation,” E. C. Smith, Ed., McGraw-Hill, New York, N. Y., 1968, with these additions.
`(1) The WLN begins a t the point of attachment: (a) if the substituent group becomes part of an aromatic fused ring system,
`the substituent is cited as a closed ring and the attachment locants (for the substituent ring) are marked with asterisks. The
`notation is followed by a parentheses showing attachment locants on the parent ring; (b) if the substituent completes a
`single saturated ring on an aromatic ring it is treated as a linear chain with a two-point attachment; (c) the WLN for a car-
`bocyclic or heterocyclic ring as a substituent begins with a space and then a locant showing the attachment point on the sub-
`stituent ring. (2) Methyl contractions are made on “X,” “Y,” and “K” symbols but not on rings. (3) Multipliers are used
`according to normal rules. (4) The # symbol denotes a saturated alkyl chain of undetermined length. (5) If a “?” begins the
`notation, the structure is not definable by WLN. The following refrences refer to um and up, respectively: (1) 0. Exner,
`Collect. Czech. Chem. Commun., 31, 65 (1966); (2) D. H. McDaniel and H. C. Brown, J . Org. Chem., 23, 420 (1958); (3) W. A.
`Sheppard, Trans. N . Y. Acad. Sci., [11] 29, 700 (1967); (4) H. H. Jaff6, Chem. Rev., 53, 191 (1953); (5) M. Charton, J . Org.
`Chem., 30, 552 (1965); (6) M. Charton, ibid., 28, 3121 (1963); (7) P. Cecchi, Ric. Sci., 28, 2526 (1958); (8) P. Zuman, “Sub-
`stituent Effects in Organic Polarography,” Plenum Press, New York, N. Y., 1967, p 76; (9) L. M. Yagupol’skii and L. N.
`Yagupol’skaya, Dokl. Chem., 134, 1207 (1960); (10) J. A. Landgrebe and R. H. Rynbrandt, J. Org. Chem., 31, 2585 (1966);
`(11) V. V. Orda, L. M. Yagupol’skii, V. F. Bystrov, and A. U. Stepanyants, J. Gen. Chem. USSR, 35, 1631 (1965); (12) R.
`Stewart and L. G. Walker, Can. J. Chem., 35, 1561 (1957); (13) W. F. Little, C. N. Reilley, J. D. Johnson, K. N. Lynn, and
`A. P. Sanders, J. Amer. Chem. SOC., 86, 1376 (1964); (14) T. Nishiguchi and Y. Iwakura, J. Org. Chem., 35, 1591 (1970);
`(15) 0. Exner and J. Jon&, Collect. Czech. Chem. Commun., 27, 2296 (1962); (16) M. F. Hawthorne, T. E. Berry, and P. A.
`Wegner, J. Amer. Chem. SOC., 87, 4746 (1965); (17) L. I. Zakharkin, V. N. Kalinin, and I. P. Shepilov, Dokl. Chem., 174, 484
`(1967); (18) V. F. Bystrov, L. M. Yagupol’skii, A. U. Stepanyants, and Yu. A. Fialkov, ibid., 153, 1019 (1963); (19) W. A.
`Sheppard, J. Amer. Chem. SOC., 87, 2410 (1965); (20) G. B. Ellam and C. D. Johnson, J . Or