CHAPTER
`
`VI
`
`Cluster Analysis and
`the Design of Congener Sets
`
`VI-1 POSSIBILITIES OF MOLECULAR
`MODIFICATION
`
`As the study of structure-activity relationships develops
`and especially as work in the biomedicinal chemical, field
`gains momentum, the need to deal with many more vari-
`ables becomes pressing. From an economic standpoint,
`the probelm of ruling out
`irrelevant parameters and
`focusing on .the relevant ones early in a structure-
`activity study is one of extreme importance. This pro-
`blem is both crucial and complex and deserves much
`more systematic attention than has been customarily
`allotted to it in the past.
`.
`'
`It has been pointed out‘
`that the number of deriva-
`tives that can be made from a set of N substituents
`
`where m is the number of nonsymmetric positions on
`the parent compound is Nm; for example, if one were
`making derivatives of quinoline using the 166 well-char-
`
`r/Y.‘I
`.\ /.
`/I
`
`if we made only one-billionth of the possibilities, it
`would amount to one million molecules; yet relatively
`few dmg modification programs make as many as a
`thousand derivatives.
`
`A general formula for calculating the possibilities is
`
`k . __"_l___
`k!(n — k)!
`
`X
`
`In this expression, X is the number of substituents to be
`considered, n is the total number of nonsymrnetric
`positions on the parent molecule, andk is the number of
`substituents to be placed on the parent compound at
`one time. With this formula we can consider simpler and
`more varied cases. For example, using only 100 substitu-
`ents from the 2000 of Appendix I and considering only
`three out of the seven possible positions on quinoline
`leads to 35,000,000 analogs. With 100 substituents and
`only two positions, one still has to face 210,000 possibil-
`ities. Even considering only 20 substituents, two at a,
`time, means 8400 possibilities. No wonder that “me
`too” drugs are always being developed.
`
`acterized substituents of Table VI-l in all possible com-
`binations, this would amount to 1667 or approximately
`3.5 X 10” molecules. Of course, 166 is a small fraction
`of the almost 2000 substituents in Appendix I. What
`constitutes a reasonable sample of 1015 congeners? Even
`48
`
`VI-2 THE COLLINEARITY PROBLEM
`
`Since the cost of modifying a parent structure is so great
`and since the possibilities are so enormous, one wants to
`
`AURO - EXHIBIT 1018
`
`

`
`Table Vl-1 Well-Characterized0 Aromatic Substituentsb
`
`Br
`C1
`F
`S02F
`SF5
`I
`I02
`NO
`N02
`NNN
`H
`OH
`SH
`B(OHh
`NH2
`NHOH
`S02 NH2
`NHNH2
`5 -Cl-1-Tetrazo1y 1
`N=CC12
`CF3
`OCF3
`S02CF3
`SCF3
`CN
`NCS
`SCN
`co2-
`1-Tetrazolyl
`NHCN
`CHO
`C02H
`CH2 Br
`CH2C1
`CH2I
`NHCHO
`CONH2
`CH=NOH
`CH3
`NHCONH2
`NHC=S(NH2 )
`OCH3
`CH20H
`SOCH3
`S02CH3
`OS02CH3
`SCH3
`SeCH3
`NHCH3
`NHS0 2CH3
`CF2CF3
`c=cH
`NHCOCF3
`CH2CN
`
`1r
`
`0.86
`0.71
`0.14
`0.05
`1.23
`1.12
`-3.46
`-1.20
`-0.28
`0.46
`0.00
`-0.67
`0.39
`-0.55
`-1.23
`-1.34
`-1.82
`-0.88
`-0.65
`0.41
`0.88
`1.04
`0.55
`1.44
`-0.57
`1.15
`0.41
`-4.36
`-1.04
`-0.26
`-0.65
`-0.32
`0.79
`0.17
`1.50
`-0.98
`-1.49
`-0.38
`0.56
`-1.30
`-1.40
`-0.02
`-1.03
`-1.58
`-1.63
`-0.88
`0.61
`0.74
`-0.47
`-1.18
`1.68
`0.40
`0.08
`-0.57
`
`H-
`Accpt
`
`H-
`Donor
`
`MR
`
`[¥
`
`<R
`
`am
`
`ap
`
`0
`0
`0
`1
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`1
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`1
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`1
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`0
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`
`1
`0
`0
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`
`1
`0
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`1
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`0
`
`0
`1
`0
`0
`0
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`0
`1
`
`0
`0
`1
`0
`
`8.88
`6.03
`0.92
`8.65
`9.89
`13.94
`63.51
`5.20
`7.36
`10.20
`1.03
`2.85
`9.22
`11.04
`5.42
`7.22
`12.28
`8.44
`23.16
`18.35
`5.02
`7.86
`12.86
`13.81
`6.33
`17.24
`13.40
`6.05
`18.33
`10.14
`6.88
`6.93
`13.39
`10.49
`18.60
`10.31
`9.81
`10.28
`5.65
`13.72
`22.19
`7.87
`7.19
`13.70
`13.49
`16.99
`13.82
`17.03
`10.33
`I8.17
`9.23
`9.55
`14.30
`10.11
`
`0.44
`0.41
`0.43
`0.75
`0.57
`0.40
`0.63
`0.50
`0.67
`0.30
`0.00
`0.29
`0.28
`-0.07
`0.02
`0.06
`0.41
`0.17
`0.58
`0.23
`0.38
`0.38
`0.73
`0.35
`0.51
`0.51
`0.36
`-0.15
`0.52
`0.26
`0.31
`0.33
`0.10
`0.10
`0.09
`0.25
`0.24
`0.25
`-0.04
`0.04
`0.23
`0.26
`0.00
`0.52
`0.54
`0.39
`0.20
`0.13
`-0.1I
`0.25
`0.44
`0.19
`0.36
`0.21
`
`-0.17
`-0.15
`-0.34
`0.22
`0.15
`-0.19
`0.20
`0.45
`0.16
`-0.13
`0.00
`-0.64
`-0.11
`0.18
`-0.68
`-0.40
`0.19
`-0.71
`0.07
`-0.08
`0.19
`0.00
`0.26
`0.18
`0.19
`-0.09
`0.19
`0.13
`0.02
`-0.18
`0.13
`0.15
`0.05
`0.03
`0.03
`-0.23
`0.14
`-0.13
`-0.13
`-0.28
`-0.05
`-0.51
`0.00
`0.01
`0.22
`0.00
`-0.18
`-0.12
`-0.74
`-0.20
`0.11
`0.05
`-0.21
`-0.18
`
`0.39
`0.37
`0.34
`0.80
`0.61
`0.35
`0.68
`0.62
`0.71
`0.27
`0.00
`0.12
`0.25
`-0.01
`-0.16
`-0.04
`0.46
`-0.02
`0.60
`0.21
`0.43
`0.38
`0.79
`0.40
`0.56
`0.48
`0.41
`-0.10
`0.52
`0.21
`0.35
`0.37
`0.12
`0.11
`0.10
`0.19
`0.28
`0.22
`-0.07
`-0.03
`0.22
`0.12
`0.00
`0.52
`0.60
`0.39
`0.15
`0.10
`-0.30
`0.20
`0.47
`0.21
`0.30
`0.16
`
`0.23
`0.23
`0.06
`0.91
`0.68
`0.18
`0.78
`0.91
`0.78
`0.15
`0.00
`-0.37
`0.15
`0.12
`-0.66
`-0.34
`0.57
`-0.55
`0.61
`0.13
`0.54
`0.35
`0.93
`0.50
`0.66
`0.38
`0.52
`0.00
`0.50
`0.06
`0.42
`0.45
`0.14
`0.12
`0.11
`0.00
`0.36
`0.10
`-0:17
`-0.24
`0.16
`-0.27
`0.00
`0.49
`0.72
`0.36
`0.00
`0.00
`-0.84
`0.03
`0.52
`0.23
`0.12
`0.01
`49
`
`

`
`Table VI-I Well-Characterized0 Aromatic Substituentsb (Continued)
`
`CH=CHN02-(trans)
`CH=CHz
`NHC=O(CH2 Cl)
`COCH3
`SCOCH3
`OCOCH 3
`C02CH3
`NHCOCH3
`NHCOzCH3*
`C=O(NHCH3)
`CH=NOCH3
`NHC=S(CH3)
`CH=NNHC=S(NH2 )
`CH2 CH3
`CH=NNHCONHNH2
`CH2 0CH3
`OCH2 CH3
`SOCzHs *
`SCzHs
`SeC2H5 *
`NHC2H5
`S02 CzH5 *
`N(CH3 )z
`NHSOzC2 Hs*
`P(CH3h
`PO(OCH3h
`C(OH)(CF 3 )z
`CH=CHCN
`Cyclopropy1
`COC2Hs*
`SCOC2 H 5 *
`COzCzHs
`OCOC2 H5 *
`CH 2 CH2 COzH
`NHCOzC2 Hs
`CONHC2 Hs*
`NHCOCzHs *
`CH=NOCzHs*
`NHC=S{C2 Hs)*
`CH(CH3h
`C3Ha
`NHC=S(NHC2 H5 )
`OCH(CH3)2
`OC3 H1
`CH2 0C2H5 *
`SOC3H7*
`S02C3H7*
`SC3H7*
`SeC3H7*
`NHC3H7*
`~HS02C3H7*
`N(CH3h
`Si(CH3h
`CH=C(CNh
`so
`
`1T
`
`0.11
`0.82
`-0.50
`-0.55
`0.10
`-0.64
`-0.01
`-0.97
`-0.37
`-1.27
`0.40
`-0.42
`-0.27
`1.02
`-1.32
`-0.78
`0.38
`-1.04
`1.07
`1.28
`0.08
`-1.09
`0.18
`-0.64
`0.44
`-1.18
`1.28
`-0.17
`1.14
`0.06
`0.64
`0.51
`-0.10
`-0.29
`0.17
`-0.73
`-0.43
`0.94
`0.12
`1.53
`1.55
`-0.71
`0.85
`1.05
`-0.24
`-0.50
`-0.55
`1.61
`1.82
`0.62
`-0.10
`-5.96
`2.59
`0.05
`
`H-
`Accpt
`
`H-
`Donor
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`1
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`1
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`0
`0
`
`MR
`
`16.42
`10.99
`19.77
`11.18
`18.42
`12.47
`12.87
`14.93
`16.53
`14.57
`14.93
`23.40
`29.92
`10.30
`24.86
`12.07
`12.47
`18.35
`18.42
`21.68
`14.98
`18:14
`15.55
`22.82
`21.19
`21.87
`15.18
`16.23
`13.53
`15.83
`23.07
`17.47
`17.12
`16.52
`21.18
`19.22
`19.58
`19.58
`28.05
`14.96
`14.96
`31.66
`17.06
`17.06
`16.72
`23.00
`22.79
`23.07
`26.33
`19.63
`27.47
`21.20
`24.96
`21.53
`
`~
`
`&t
`
`Om
`
`aP
`
`0.33
`0.07
`0.23
`0.32
`0.36
`0.41
`0.33
`0.28
`0.14
`0.34
`0.39
`0.27
`0.46
`-0.05
`0.23
`0.01
`0.22
`0.52
`0.23
`0.13
`-0.11
`0.54
`0.10
`0.25
`-0.08
`.0.37
`0.28
`0.26
`-0.03
`0.32
`0.36
`0.33
`0.41
`-0.02
`0.14
`0.34
`0.28
`0.39
`0.27
`-0.05
`-0.06
`0.38
`0.30
`0.22
`0.01
`0.52
`0.54
`0 23
`0.13
`-0.11
`0.25
`0.89
`-0.04
`0.58
`
`-0.05
`-0.08
`-0.25
`0.20
`0.11
`-0.07
`0.15
`-0.26
`-0.28
`0.05
`-0.06
`-0.13
`-0.02
`-0.10
`-0.05
`0.02
`-0.44
`0.01
`-0.18
`-0.12
`-0.51
`0.22
`-0.92
`-0.20
`0.39
`0.19
`0.05
`-0.07
`-0.19
`0.20
`0.11
`0.15
`-0.07
`-0.05
`-0.28
`0.05
`-0.26
`-0.06
`-0.13
`-0.10
`-0.08
`-0.28
`-0.72
`-0.45
`0.02
`0.01
`0.22
`-0.18
`-0.12
`-0.51
`-0.20
`0.00
`-0.04
`0.30
`
`0.32
`0.05
`0.17
`0.38
`0.39
`0.39
`0.37
`0.21
`0.07
`0.35
`0.37
`0.24
`0.45
`-0.07
`0.22
`0.02
`0.10
`0.52
`0.18
`0.10
`-0.24
`0.60
`-0.15
`0.20
`0.03
`0.42
`0.29
`0.24
`-0.07
`0.38
`0.39
`0.37
`0.39
`-0.03
`0.07
`0.35
`0.21
`0.37
`0.24
`-0.07
`-0.07
`0.30
`0.10
`0.10
`0.02
`0.52
`0.60
`0.15
`0.10
`-0.24
`0.20
`0.88
`-0.04
`0.66
`
`0.26
`-0.02
`-0.03
`0.50
`0.44
`0.31
`0.45
`0.00
`-0.15
`0.36
`0.30
`0.12
`0.40
`-0.15
`0.16
`0.03
`-0.24
`0.49
`0.03
`0.00
`-0.61
`0.72
`-0.83
`0.03
`0.31
`0.53
`0.30
`0.17
`-0.21
`0.50
`0.44
`0.45
`0.31
`-0.07
`-0.15
`0.36
`0.00
`0.30
`0.12
`-0.15
`-0.13
`0.07
`-0.45
`-0.25
`0.03
`0.49
`0.72
`0.00
`0.00
`-0.61
`0.03
`0.82
`-0.07
`0.84
`
`~--.......
`
`

`
`Table VI-I Well-Characterized0 Aromatic Substituentsb (Continued)
`
`I-Pyrryl
`2-Thienyl
`3-Thienyl
`CH=CHCOCH3
`CH =CH C02 CH3 *
`COC3H7*
`SCOC3H1*
`OCOC3H7*
`C02C3H1*
`(CH2hC02H*
`CONHC3H7*
`NHCOC3H7*
`NHC=OCH(CH3h
`NHC02C3H7*
`CH=NOC3H7*
`NHC=S(C3H1)*
`C4H9
`C(CH3h
`OC4H9
`CH20C3H7*
`N(C2Hsh,
`NHC4H9*
`P(C2H5 ) 2 *
`PO(OC2H5 h*
`CH2 Si( CH3 )3
`CH=CHCOC2Hs *
`CH=CHC02 C2H5
`CH=NOC4H9*
`CsHu *
`CH20C4H9*
`C6Hs
`N=NC6H5
`OC6 H 5
`S02C6 H5
`OS02C6 }15
`NHC6 H5
`NHS02 C6 H5
`2,5-di-Me-1-pyrry1
`CH=CHCOC3H1*
`CH=CHC02 C3H7 *
`Cyclohexy1
`2-Benzthiazo1y1
`COC6 Hs
`C0 2 C6 H5
`OCOC6 H5
`N=CHC6 H5
`CH=N4Hs
`NHCOC6 H5
`CH2C6 H 5
`CH20C6 H5
`c=cc6 Hs
`CH=NNHCOC6 H 5
`CH2Si(C2H5 h*
`CH=CHC6 H5-( trans)
`
`7r
`
`0.95
`1.6 I
`1.8 I
`-0.06
`0.32
`0.53
`I .18
`0.44
`1.07
`0.25
`-O.I9
`0.1 I
`-O.I8
`0.7I
`1.48
`0.66
`2.13
`1.98
`1.55
`0.30
`1.18
`1.16
`1.52
`-0.10
`2.00
`0.48
`0.86
`2.02
`2.67
`0.84
`1.96
`1.69
`2.08
`0.27
`0.93
`1.37
`0.45
`1.95
`1.02
`I.40
`2.5 I
`2.13
`1.05
`1.46
`1.46
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`-0.29
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`1.66
`2.65
`0.43
`3.26
`2.68
`
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`21.85
`24.04
`24.04
`21.10
`22.56
`20.48
`27.72
`21.77
`22.17
`21.17
`23.87
`24.23
`24.23
`25.83
`24.23
`32.70
`19.61
`19.62
`21.66
`21.37
`24.85
`24.26
`30.49
`31.16
`29.61
`25.75
`27.21
`28.88
`24.26
`26.02
`25.36
`31.3I
`27.68
`33.20
`36.70
`30.04
`37.88
`31.15
`30.40
`31.86
`26.69
`38.88
`30.33
`32.31
`32.33
`33.01
`33.01
`34.64
`30.01
`32.19
`33.21
`42.37
`43.56
`34.I7
`
`0.50
`0.10
`0.04
`0.28
`0.24
`0.32
`0.36
`0.41
`0.33
`-0.02
`0.34
`0.28
`0. I8
`0.14
`0.39
`0.27
`-0.06
`-0.07
`0.25
`O.OI
`0.01
`-0.28
`-0.08
`0.37
`-O.I5
`0.28
`0.24
`0.39
`-0.06
`0.01
`0.08
`0.28
`0.34
`0.56
`0.36
`-0.02
`0.2I
`0.52
`0.28
`0.24
`-0.13
`0.25
`0.30
`0.33
`0.23
`0.09
`0.31
`0.09
`-0.08
`0.02
`0.12
`0.33
`-0 15
`0.06
`
`-0.09
`0.04
`-0.06
`-0.27
`-0.19
`0.20
`0.11
`-0.07
`0.15
`-0.05
`-0.05
`-0.26
`-0.26
`-0.28
`-0.06
`-0.13
`-0.11
`-0.13
`-0.55
`0.02
`-0.91
`-0.25
`0.39
`0.19
`-0.07
`-0.27
`-0.19
`-0.06
`-0.08
`0.02
`-0.08
`0.13
`-0.35
`0.18
`0.00
`-0.38
`-0.18
`-O.IO
`-·o.27
`-O.I9
`-0.10
`0.06
`0.16
`0.13
`-0.08
`-0.63
`0.13
`-0.27
`-O.OI
`0.02
`0.05
`0.20
`-0.07
`-O.I2
`
`0.47
`0.09
`0.03
`0.21
`0.19
`0.38
`0.39
`0.39
`0.37
`-0.03
`0.35
`0.21
`0.1 I
`0.07
`0.37
`0.24
`-0.08
`-0.10
`0.10
`0.02
`-0.23
`-0.34
`0.03
`0.42
`-0.16
`0.21
`0.19
`0.37
`-0.08
`0.02
`0.06
`0.32
`0.25
`0.61
`0.36
`-0.12
`0.16
`0.49
`0.21
`O.I9
`-0.15
`0.27
`0.34
`0.37
`0.21
`-0.08
`0.35
`0.02
`-0.08
`0.03
`O.I4
`0.39
`-0.16
`0.03
`
`0.37
`0.05
`-0.02
`-O.OI
`0.03
`0.50
`0.44
`0.31
`0.45
`-0.07
`0.36
`0.00
`-0.10
`-0.15
`0.30
`0.12
`-0.16
`-0.20
`-0.32
`0.03
`-0.90
`-0.51
`0.31
`0.53
`-0.21
`-0.01
`0.03
`0.30
`-0.16
`0.03
`-0.01
`0.39
`-0.03
`0.70
`0.33
`-0.40
`0.01
`0.38
`·-0.01
`0.03
`-0.22
`0.29
`0.43
`0.44
`0.13
`-0.55
`0.42
`-0.19
`-0.09
`0.04
`O.I6
`0.5I
`-0.2I
`-0.07
`51
`
`'
`
`'j
`I
`
`:I
`t
`
`I
`
`

`
`Table Vl-1 Well-Characterized0 Aromatic Substituentsb (Continued)
`
`CH=CHCOC 6 H5
`Ferrocenyl
`N(C6Hsh
`P=O(C6Hs)z
`
`11'
`
`0.95
`2.46
`3.61
`0.70
`
`H-
`Accpt
`
`H-
`Donor
`
`MR
`
`/¥
`
`~
`
`Om
`
`ap
`
`l
`0
`1
`
`0
`0
`0
`0
`
`40.25
`48.24
`54.96
`59.29
`
`0.22
`-0.15
`0.07
`0.3I
`
`-0.15
`-0.04
`-0.29
`0.24
`
`0.18
`-O.I5
`0.00
`0.38
`
`0.05
`-O.I8
`-0.22
`0.53
`
`4 By well-characterized, we mean that the set of eight constants is known for each substituent; we do not mean to
`imply that all of the constants are of the highest accuracy.
`bSubstituents are ordered first by number of C, then by number of H, and the remaining elements alphabetically.
`
`TableVI-2 Well-Characterized0 Aliphatic Substituents
`
`Br
`Cl
`F
`
`N02
`H
`OH
`SH
`NH2
`CBr3
`CCI3
`CF3
`CN
`SCN
`C02
`C02H
`CH2 Br
`CH2 C1
`CH21
`CONH2
`CH=NOH
`CH3
`NHCONH2
`OCH3
`CH20H
`SOCH3
`OS02CH3
`SCH3
`NHCH3
`CF2CF3
`G==CH
`CH2CN
`CH=CHN02 -trans
`CH=CH2
`COCH3
`OCOCH3
`COzCH3
`NHCOCH3
`C=O(NHCH3)
`
`52
`
`Fr
`
`0.20
`0.06
`-0.38
`0.59
`-1.16
`0.23
`-1.64
`-0.23
`-1.54
`2.03
`1.61
`0.29
`-1.27
`-0.48
`-5.19
`-1.11
`0.74
`0.60
`1.13
`-2.18
`-1.02
`0.77
`-2.90
`-1.54
`-1.10
`-2.24
`-1.34
`-0.02
`-1.38
`1.34
`0.01
`-0.73
`-0.63
`0.88
`-1.13
`-0.72
`-0.72
`-1.94
`-1.94
`
`H-Accpt
`
`H-Donor
`
`0
`0
`0
`0
`1
`0
`l
`0
`I
`0
`0
`0
`I
`
`1
`1
`0
`0
`0
`1
`
`0
`1
`1
`1
`1
`1
`0
`1
`0
`0
`
`0
`I
`1
`
`0
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`1
`0
`0
`0
`1
`1
`0
`1
`0
`1
`0
`0
`0
`l
`0
`1
`0
`0
`0
`0
`0
`0
`1
`
`MR
`
`8.80
`5.93
`1.05
`13.76
`6.71
`1.03
`2.55
`8.76
`4.37
`28.8I
`20.12
`5.02
`5.39
`13.40
`5.15
`6.03
`13.39
`10.49
`18.60
`9.81
`I0.28
`5.65
`13.72
`7.33
`7.19
`13.70
`16.99
`13.33
`9.11
`9.23
`8.25
`10.11
`16.42
`9.79
`10.29
`11.85
`11.85
`13.71
`13.39
`
`f¥
`
`0.44
`0.41
`0.43
`0.40
`0.67
`0.00
`0.29
`0.28
`0.02
`0.27
`0.31
`0.38
`0.51
`0.36
`-0.15
`0.33
`0.10
`0.10
`0.09
`0.24
`0.25
`-0.04
`0.04
`0.26
`0.00
`0.52
`0.39
`0.20
`-0.11
`0.44
`0.19
`0.21
`0.33
`0.07
`0.32
`0.41
`0.33
`0.28
`0.34
`
`L-----------------------........... -.FT._-.-.~, •. ,.r_. .• R.r•=·•"•zn•··~•·•,•••·•·•rr•·rl·'l~'l=i·"l'i·•·~llllllllllllllllllllllllllllllllllll
`
`

`
`Table VI-2 Well-Characterized0 Aliphatic Substituents (Continued)
`
`CH2CH3
`OCH2CH3
`CH20CH3
`SOC2H5 *
`SC2Hs
`CH2Si(CH3h
`NHC2H5
`N(CH3h
`CH=CHCN
`Cyclopropy1
`COC2H5 *
`C02C2Hs
`OCOC2Hs*
`EtC02H
`NHC02C2Hs
`CONHC2H 5 *
`NHCOC 2 Hs*
`CH(CH3h
`C3H7
`OCH(CH3h
`OC3H1
`CH20C2Hs*
`SOC3H1*
`SC3H7*
`NHC3H7 *
`Si(CH3h
`2-Thieny1
`3-Thienyl
`CH=CHCOCH3
`CH=CHC02CH3 *
`COC3H1*
`OCOC3H 7*
`C02C3H7*
`(CH2)3C02H*
`NHCOC3H 7 *
`CONHC3H7*
`C4H9
`CCCH3h
`OC4H9
`CH20C3H1*
`NHC4H9*
`N(C2Hsh
`CH=CHCOC2Hs*
`CH=CHC02C2Hs
`CsHu *
`CH20C4 H9*
`C6Hs
`OC6 H 5
`S02C6 H 5
`NHC6H5
`2-Benzthiazolyl
`CH=CHCOC3H 7*
`CH=CHC02C3H1*
`COC6 H5
`C02C6 H 5
`
`Fr
`
`1.43
`-0.51
`-0.23
`-1.70
`0.52
`3.62
`-0.84
`-0.64
`-0.74
`1.49
`-0.59
`-O.I8
`-O.I8
`-0.03
`-1.40
`-1.40
`-1.40
`(84
`1.97
`-0.10
`0.03
`0.03
`-1.16
`1.06
`-0.30
`2.96
`1.58
`1.58
`-0.13
`0.28
`-0.05
`0.36
`0.36
`0.5I
`-0.86
`-0.86
`2.51
`2.22
`0.57
`0.57
`0.24
`0.16
`0.41
`0.82
`3.10
`1.11
`1.90
`1.22
`-0.39
`0.75
`1. 78
`0.95
`1.36
`0.69
`0.60
`
`H-Accpt
`
`H-Donor
`
`0
`
`0
`0
`1
`
`1
`0
`
`1
`I
`I
`1
`0
`0
`
`I
`0
`
`0
`0
`0
`1
`1
`1
`1
`1
`1
`1
`1
`0
`0
`
`1
`1
`1
`1
`0
`1
`0
`1
`
`0
`0
`0
`0
`0
`0
`1
`0
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`I
`1
`1
`0
`0
`0
`0
`1
`0
`0
`0
`0
`0
`0
`0
`0
`I
`0
`0
`0
`0
`0
`
`MR
`
`10.30
`11.93
`12.07
`18.35
`17.93
`29.61
`13.76
`14.14
`15.33
`13.53
`14.65
`16.76
`I7.12
`16.52
`19.96
`18.04
`18.36
`. 14.96
`14.96
`16.52
`16.52
`I6.72
`23.00
`22.58
`18.41
`24.96
`24.04
`24.04
`19.92
`21.85
`I9.30
`21.77
`21.46
`2l.l7
`23.01
`22.69
`19.61
`19.62
`21.12
`21.37
`23.06
`23.44
`24.57
`26.03
`24.26
`26.02
`25.36
`27.02
`33.20
`28.50
`38.88
`29.22
`26.50
`29.96
`31.60
`
`[¥
`
`-0.05
`0.22
`0.01
`0.52
`0.23
`-0.15
`-0.11
`0.10
`0.26
`-0.03
`0.32
`0.33
`0.41
`-0.02
`0.14
`0.34
`0.28
`-0.05
`-0.06
`0.30
`0.22
`0.01
`0.52
`0.23
`-O.Il
`-0.04
`0.10
`0.04
`0.28
`0.24
`0.32
`0.41
`0.33
`-0.02
`0.28
`0.34
`-0.06
`-0.07
`0.25
`0.01
`-0.28
`0.01
`0.28
`0.24
`-0.06
`0.01
`0.08
`0.34
`0.56
`-0.02
`0.25
`0.28
`0.24
`0.30
`0.33
`53
`
`

`
`54
`
`Cluster Analysis and the Design of Congener Sets
`
`Table VI-2 Well-Characterized0 Aliphatic Substituents (Continued)
`
`Fr
`
`1.22
`-0.03
`2.44
`1. 7I
`4.82
`2.72
`1.81
`2.43
`2.43
`
`OCOC6 Hs
`NHCOC6H5
`CH2C6Hs
`CH20C6Hs
`CH2Si(C2Hsh*
`CH=CHC6H5-(trans)
`CH=CHCOC6 H5
`Ferrocenyl
`N(C6Hsh
`
`0 See footnote a, Table Vl-1.
`
`H-Accpt
`
`H-Donor
`
`0
`I
`0
`0
`I
`0
`
`0
`1
`0
`0
`0
`0
`0
`0
`0
`
`MR
`
`32.33
`34.28
`30.01
`31.77
`43.56
`32.97
`39.05
`48.24
`53.55
`
`§
`
`0.23
`0.09
`-0.08
`0.02
`-0.15
`0.06
`0.22
`-0.15
`0.07
`
`gain the maximum amount of information possible from
`each derivative that is to be tested in some standard
`system. This means that at any given point in time, one
`wants to consider all of the known variables that cause
`change in activity of the parent molecule when a sub(cid:173)
`stituent change is made. For quantitative work, we are
`limited to those variables that can be defined in numer(cid:173)
`ical terms. Four such parameters, 1T, MR, :Y and 61, are
`well characterized and have been shown to be relevant in
`many biomedicinal QSAR. The problem of selecting a
`set of substituents that would be independent with re(cid:173)
`spect to these four variables is illustrated in Tables Vl-3
`and VI-4?
`
`Table VI-3 Two Sets of Substituents for Compound
`Modification
`
`Set A
`
`Set B
`
`CH3
`N02
`COCH3
`c=cH
`SCH3
`
`NHC6 H5
`OCH2CH2CH3
`S02CH2CH2CH3
`I
`CH2Cl
`
`CH3
`CF3
`F
`CN
`N0 2
`
`CH2CH3
`NHCOCH3
`CONH2
`S02NH2
`0CF3
`
`Table VI-4 Squared Correlation Matrices for Substitu(cid:173)
`ents of Table Vl-3°
`
`Set A
`
`Set B
`
`1T
`
`6i
`
`$
`
`MR
`
`1T
`
`IR
`
`§
`
`MR
`
`1T
`iR
`§
`MR
`
`0.94 0.30 0.32
`1T
`iR
`0.32 0.38
`1
`1
`0.09 §
`MR
`
`0.09 0.08 0.26
`0.15 0.03
`1
`0.03
`1
`
`0 The figures are r2 for the correlation between variables.
`
`From an inspection of these two sets, even knowing
`the values of 1T, 9", iR, and MR, it is not possible to
`decide which is the better set as fat as independence
`among the four variables is concerned. However, it can
`easily be done by formulating the correlation matrices
`for the two sets of substituents as in Table Vl-4. One
`sees immediately from the correlation matrix that 1T and
`6i are almost completely collinear in Set A; either of
`these two vectors would give almost the same result in
`a correlation equation. Hence, one cannot be sure
`whether the correct variable is 1T or 6i or if indeed both
`variables are involved. All of the other variables except
`!¥ and MR show significant collinearity. Selecting data
`Set A would mean that one would have to make more
`derivatives if either 1T or iR turned up in the correlation
`equation to resolve their relative importance. Only 1T and
`MR show significant collinearity in data Set B, and this
`is not serious for most purposes. Although 10 substitu(cid:173)
`ents would not be enough to work in a system where
`four variables are influencing a given process, they do
`illustrate the collinearity problem.
`Since only a tiny fraction of the almost infinite num(cid:173)
`ber of possibilities can be studied in drug modification,
`we cannot afford redundancy. Testing two congeners
`that have essentially the same physicochemical pro(cid:173)
`perties is most likely to be less valuable than testing two
`with different properties. One often sees sets of con(cid:173)
`geners in the literature where all of the normal alkyl
`groups from methyl to decyl have been made and tested.
`While this may give one useful information on optimum
`lipophilicity, it also may not. The variables 1T andMR for
`such substituents are prefectly collinear so that hydro(cid:173)
`phobicity and bulk tolerance effects cannot be resolved
`with such a set of congeners. Of course, such a data set
`would reveal nothing about the electronic effect of
`sub sti tuen ts.
`
`

`
`Vl-3 Cluster Analysis
`
`55
`
`....._
`
`.--L
`
`..___
`
`L
`
`L...-
`
`"' u·
`c:
`"' .~
`-o
`c:
`0
`·;::;
`"' E
`~
`;;;
`E
`<(
`
`I
`
`l
`
`..--
`
`L...
`
`l
`
`r-L-
`
`A B C DE FG HI
`
`* *** * **
`J KUM N OP Q~ S TU ~W X YZ AA
`Substituents
`Figure VI-1
`
`. .
`
`VI-3 CLUSTER ANALYSIS
`
`The problem of selecting a set of substituents with in(cid:173)
`dependence among several parameters has concerned
`medicinal chemists for some time. Meyer and Hemme
`pointed out in 1935 that one could not gain information
`about the relative role of physicochemical properties of
`narcotics from the study of sets of homologous series.
`The alkyl groups are completely collinear with respect to
`many parameters.
`Craig4 first emphasized the importance of plotting rr vs
`a to obtain a set of substituents with minimal collinear(cid:173)
`ity and, at the same time, good coverage of substituent
`space. Wooton et al. 5 have developed a sophisticated
`algorithm for substituent selection.
`Hierarchical clustering can greatly assist in the proper
`selection of substituents from the ever-growing number
`available. Most computer centers have available the
`UCLA biomed BMDP2M, BMDP1M, or the Xerox Data
`Systems CLUSANL programs. The clustering in this
`chapter has been done with the Xerox program.
`
`In this program, the parameters x' can be placed on
`the same scale via eq VI-1. X in this expression is the
`mean value of a given parameter and Si is the standard
`
`(VI-1)
`
`deviation. This equation defines the deviation of each
`point from the group average X; in units of the standard
`deviation. If we have N substituents, each with K para(cid:173)
`meters, then the Euclidian distance between them is
`given by
`
`K
`-
`. f l2% - -
`dij- [ ~ (Xik - Ajk) ]
`l, 1 - 1' 2 ... N (VI-2)
`k=l
`
`In hierarchical clustering, all interpoint distances in K
`space are calculated via eq VI-2, and the two closest
`points are clustered into a pseudo point (see Figure
`VI-I). In Figure Vl-l,R and S are the two points closest
`to each other; the pseudo point is formed from these
`
`

`
`56
`
`two and is then clustered with T; this group of three is
`then clustered withP and Q. Note that His so isolated in
`data space that it does not enter a cluster until the
`penultimate group. At the bottom of the graph all points
`are distinct units in data space; at the top, all have been
`forced into a single cluster.
`The composition of the clusters that one obtains
`depends entirely on the parameters that are used in eq
`VI-2 to obtain the dij- If one uses parameters not pertin(cid:173)
`ent to the data set for which substituents are being
`selected, this will not result in a well-balanced group of
`congeners on which to base the QSAR. For this reason,
`in the case of substituents for use in an aromatic system
`we have clustered only on rr, f#", (i{,MR, and H-bonding;
`these are established variables that can be shown to be
`reasonably independent. The parameters Om and ap have
`been shown to be strongly related? This can be seen
`from the correlation matrix of Table VI-9 for all 166
`aromatic substituents.
`If steric effects are involved, it is assumed thatMR will
`the steric properties of substituents. 1
`approximate
`Since at the present time we do not have a set of hydro(cid:173)
`gen-bonding parameters, we have assigned hydrogen
`bond acceptors a value of 1, hydrogen bond donors a
`value of 1 (at present there are no substituents acting
`only as donors), and other substituents a value of 0. We
`believe that the inclusion of hydrogen bonding gives
`better balanced sets of clusters.
`The aliphatic constants of Table VI-2 have been
`clustered on the same variables (Table VI-6), except that
`(R has not been included. These constants refer to
`systems where resonance is not present.
`The 166 "aromatic" substituents of Table VI-1 have
`been forced into three sets of clusters containing 20, 10,
`and 5 su bstituents, respectively. Note that in the· "20"
`set the clusters vary in size from 2 to 16 members. Those
`substituents closest to each other in six-dimensional
`space are forced into clusters; hence, when choosing a
`set of substituents, one should, insofar as possible, select
`one substituent from each cluster. Some substituents
`turn out to be rather strange from the point of view of
`synthesis, metabolic stability, or chemical reactivity; for
`this reason, one may need to take two substituents from
`the same cluster.
`When one forces 166 substituents into 20 clusters, it
`means of necessity that the substituents in a particular
`set may not appear similar from the traditional view(cid:173)
`point of organic chemistry. For example, in the "5"
`cluster set of Table VI-5 we find H and cyclopropyl to(cid:173)
`gether. If, instead of forcing 166 substituents into five
`clusters, we had compressed them to a lesser degree into
`60, then a single cluster with Hand Me would result; the
`
`Cluster Analysis and the Design of Congener Sets
`
`similarity is obviously much closer. At the "60" cluster
`level, 15 substituents are so far removed from the others
`in data space that they "cluster" alone [e.g., F, 10 2 ,
`C02 -, N(CH3hl.
`One does not assume by selecting one substituent
`from each group that a set of substituents perfectly
`orthogonal with respect to each vector will be obtained.
`The next imperative step is to form a correlation matrix
`as in Table VI-4. The collinearity between two variables
`will often be unacceptably high; a plot of the values of
`one variable against the other helps one choose new sub(cid:173)
`stituents to break up this feature.
`For example, a chemist selects a substituent from each
`cluster in the "1 0" cluster set of aromatic substituents
`+
`giving the following groups: Br, N02 , N(CH 3)3, OH,
`S02 NH2 , OCF 3 , NCS, NHCOC 6H5 , OCH 3 , C4H9 • The
`correlation matrix is given in Table VI-7. This is not a
`satisfactory set because of the high collinearity between
`nand:¥ and between H-acceptor and MR.
`Discussing this set with medicinal chemists brings out a
`number of further objections. The N0 2 group is so read(cid:173)
`ily reduced in biological systems that it would be more
`appropriate to substitute it with CN from the same
`cluster. The N{CH 3) 3 group bears a charge. It is well
`known from studies in physical organic chemistry that
`charged substituents behave poorly when mixed in sets
`of neutral groups. In the initial phases of study, one
`would not expect the charged group to behave in the
`same fashion as neutral substituents. Several such groups
`could be introduced later via an indicator variable. The
`only other substituent in this cluster is 102 , which is not
`selected because little is known of its behavior in
`+
`biologic systems. N(CH 3 )3 is replaced with H from the
`first and largest cluster. The NCS group is so highly
`active chemically that it might not behave as a true
`congener and is replaced with OC 6H5 • The new set is
`then: Br, H, CN, OH, S0 2NH2, OCF 3 , OC 6H5 ,
`NHCOC 6 H5 , OCH3 , C4 H9 . This affords the correlation
`matrix ofTable VI-8.
`Table Vl-8 shows that although there is still some
`collinearity between certain variables, it has been re(cid:173)
`duced to a reasonable level. Also, the new set of sub(cid:173)
`stituents contains a good spread in values of the various
`parameters: rr (-1.82 to 2.13), :¥(-0.06 to 0.44, tR
`(-0.64 to 0.19), and MR (0.10 to 3.46).
`The hydrogen bonding parameters are of course the
`most poorly defined. Nevertheless, inspection of the
`clustering of the aromatic substituents at the 10 set level
`shows that they do cluster hydrogen-bonding groups
`well. Most of the nonhydrogen bonders are clustered
`into groups 1 and 8. The acceptors fall into clusters 2, 6,
`and 7. The substituents that are both donors and
`
`

`
`Table VI-Sa Aromatic Constants-Twenty Ouster Sets
`
`10 members= Br
`SH
`2 17 members= S02F
`S02 CH3
`CH=C(CN)z
`OS02 CH3
`3 16 members= H
`c=cH
`N=CC1z
`Se(C2 H5 )*
`3 members= OH
`4
`5 4 members= B(OH)2
`6 8 members= NH(OH)
`, NHCHO
`7 5 members= S0 2(NH2 )
`8 16 members= OCF3
`CH=CHCN
`COCH 3
`COzC3H1*
`9 15 members= NCS
`CH=NOC4H9*
`CH=CHCOzCzHs
`10 15 members= CH2 I
`N=NC6H5
`Cyclohexy1
`11 21 members= NHC=S(NH2 )
`NHC=O(CH2CI)
`NHC0 2C2 H5
`NHCOC3H7*
`CH=NNHCOC6H5
`8 members= OCH3
`N(CH3)z
`5 members= NHCH3
`13
`5 members= CH2 0CH3
`14
`2 members= P(CH3) 2
`15
`16 10 members= SCOC3 H7*
`2-Benzthiazolyl
`3 members= CH2 Si(CzHsh*
`17
`18 3 single-
`I
`member= 10 2
`groups
`20
`
`12
`
`C1
`SF 5
`N0 2
`5-C1-1-tetrazo1yl
`PO(OCH3h
`OCOCH 3
`CH3
`CH2CH3
`SCH3
`
`NH2
`CH 2 0H
`NHCONH2
`NHS02 CH3
`CON Hz
`CH2 CN
`SCN
`SCOCH3
`
`I
`CF3
`SOz(CF3)
`SOC3 H7*
`1-Tetrazoly1
`
`CH2 Br
`Cyclopropyl
`Se(CH3 )
`
`NHNH2
`EtC0 2 H
`NHCN
`NHCOCH3
`C=O(NHCH3)
`CH=CHN0 2 (tr)
`COzCH3
`C0 2C2H5
`
`Pyrryl
`2,5-di-Me-Pyrry1*
`CH=CHCOC 3 H1*
`2-Thieny1
`L=CC6Hs
`CH2 Si(CH3h
`CH=NNHCONHNH2
`NHCOCzH 5*
`NHC=OCH(CH3)2
`8(0H)(CF3h
`
`CH=NOC2 H5 *
`CH=CHCOCH3
`CH=CHCOzC3H1*
`Se(C3H7)*
`CH=CHC6H5 (tr)
`CH2 C6H5
`CH=NNHC=S(NH 2 )
`NHC=S(CH3)
`NHCOzC 3H1*
`NHC=S(C3}f?)*
`
`OCHzCH3
`N(CzH 5 )z
`NH(C2 H5 )
`CH2 0CzH5 *
`P(CzHsh*
`COC6 H5
`PO(OCzHsh*
`Ferrocenyl
`
`C0 2-
`
`OCH(CH3h*
`N=CHC 6 H5
`NHC 3 H7*
`CH2 0C3H1*
`
`COzC6Hs
`CH=NC6H5
`N(C6Hs h
`
`+
`N(CH3))
`
`NNN
`SCF3
`NO
`SOzCzHs*
`SOCzH5 *
`
`CH=CH2
`HC(CH3)z
`S(CzHs)
`
`(CHzhCOzH*
`CH=NOH
`
`CONBC2 H5 *
`CH=NOCH3
`COCzH5 *
`COC3H7*
`
`OCOC3H7*
`CH=CHC02CH3*
`OCOC6H5
`3-Thienyl
`Si(CH3h
`C4H9 ·
`CONHC3H7*
`NHSOzC2Hs *
`NHC=S(C2 Hs)*
`NHSOzC6Hs
`
`OC3H7
`
`NHC4H9*
`CH20C4H9*
`
`OS0 2C6Hs
`S02 C6H5
`
`F
`CF 2CF3
`CN
`S02C3 H1*
`SOCH3
`
`CH2 C1
`C3H7
`SC3H7*
`
`NHCOCF1
`
`C02H
`OCOC2Hs*
`CHO
`SCOC 2H5 *
`
`CH=NOC3H7*
`CH=CHCOCzHs *
`OC6H5 .
`C6Hs
`CsHn *
`C(CH3h
`NHC=S(NHC2Hs)
`NHC0 2 CH3*
`NHS0 2C3H7*
`NHCOC6Hs
`
`OC4H9 *
`
`NHC 6 H5
`CHzOC6Hs
`
`CH=CHCOC6Hs
`P=O(C6Hsh
`
`(.h
`
`"--
`
`

`
`Vo
`00
`
`Table VI-Sb Aromatic Constants-Ten Cluster Sets
`
`26 members= Br
`SH
`H
`c==cH
`N=CCh
`Se(C2 Hs)*
`2 17 members= S02F
`S02CH3
`CH=C(CN)z
`OSOzCH3
`3 2 members= 102
`4 8 members= OH
`NHC3H7*
`5 18 members= B(OH)z
`NHCONH2
`NHS02 CH3
`CONHC2Hs*
`6 21 members= OCF 3
`CH=CHCN
`COCH3
`C02C3H7*
`CH2 0C 6 H5
`7 25 members= NCS
`CH=NOC4H9*
`CH=CHC02C2Hs
`SCOC3H7*
`2-Benzthiazo1yl
`8 20 members= CH21
`N=NC6Hs
`Cyclohexyl
`P(CH3)2
`9 21 members= NHC=S(NH2)
`NHC=O(CHzCl)
`NHCOzC2Hs
`NHCOC3H7*
`CH=NNHCOC6H5
`10 8 members= OCH3
`N(CH3h
`
`C1
`SF5
`CH3
`CH2 CH3
`SCH3
`
`N0 2
`5-Cl-1·tetrazoly1
`PO(OCH3h
`<;?COCH3
`N(CH3h
`NH2
`NHC4H9"'
`CH20H
`NHCN
`NHCOCH3
`C02H
`CH2CN
`SCN
`SCOCH3
`CHzOCH3
`
`I
`CF3.
`CH2Br
`Cyclopropyl
`Se(CH3)
`
`SOz(CF3)
`SOC3H7*
`l-Tetrazoly1
`
`NHNH2
`NHC6Hs
`EtC0 2 H
`CH=NOH
`S02(NHz)
`C02-
`CH=CHN02 .(tr)
`COzCH3
`C02C2 Hs
`CH20CzHs*
`
`Pyrry1
`2,5-di-Me-Pyrryl *
`CH=CHCOC3H7*
`COC6H5
`PO(OCzHsh*
`2-Thienyl
`c=cc6 Hs
`CH 2 Si(CH3h
`P(CzHsh*
`CH=NNHCONHNH2
`NHCOC2Hs*
`NHG=OCH(CH3)z
`C(OH)(CF3h
`
`CH=NOC2 Hs*
`CH=CHOCH3
`CH=CHC02C3H7*
`COzC6Hs
`CH=NC6 Hs
`Se(C3H7)*
`CH=CHC6Hs (tr)
`CH2C6Hs
`CH2Si(CzHsh*
`CN=NNHC=S(NH2 )
`NHC=S(CH3)
`NHC02C3H7*
`NHC=S(C3H7)*
`
`NNN
`SCF3
`CH=CH2
`CH(CH3)2
`SCC2Hs)
`
`NO
`S02 C2Hs*
`SOC2Hs*
`
`F
`CF2CF3
`CH2C1
`C3H7
`SC3H7*
`
`CN
`S02C3H7*
`SOCH3
`
`NHCH3
`
`NH(CzHs)
`
`(CHzhC02H*
`NHCOCF3
`CONH2
`
`CH=NOCH3
`COC2H5 *
`COC3H7*
`CHzOC3H7
`
`OCOC3H7*
`CH=CHOz CH3 *
`OCOC6 Hs
`OS0 2 C6 H5
`S02 C6H5
`3-Thienyl
`Si(CH3h
`C4H9
`Ferrocenyl
`CONHC3H7*
`NHSO.ZC2Hs*
`NHC=S(C2 Hs)*
`NHS02C6Hs
`
`NH(OH)
`NHCHO
`C=O(NHCH3)
`
`OCOCzHs*
`CHO
`SCOC2 Hs*
`CH20C4H9*
`
`CH=NOC3H7*
`CH=CHCOC2 Hs *
`OC6H5
`CH=CHCOC6 Hs
`P=O(C6Hsh
`C6Hs
`CsHu *
`C(CH3h
`N(C6Hsh
`NHC=S(NHC2 Hs)
`NHC02CH3*
`NHSOzC3H7*
`NHCOC 6 Hs
`
`OCHzCH3
`N(CzHs)2
`
`OCH(CH3)z*
`N=CHC6Hs
`
`OC3H7
`
`OC4H9*
`
`

`
`Table VI-Se Aromatic Constants-Five Cluster Sets
`
`26 members= Br
`SH
`H
`c=CH
`N=CCl2
`Se(C2Hs)*
`2 65 members= S02 F
`S02CH3
`CH=C(CNh
`OS02CH3
`CH=NOCH3
`COC2Hs*
`COC3H7*
`CH20C3H7*
`NCS
`CH=NOC4H9*
`CH=CHC02C2Hs
`SCOC3H1*
`2-Benzthiazolyl
`3 16 members= OH
`NHC3H7*
`OCH(CH3h*
`N=CHC6Hs
`4 39 members= B(OHh
`NHCONH2
`NHS02CH3
`CONHC2Hs*
`CH=NNHC=S(NH2)
`NHC=S(CH3)
`NHC02C3H7*
`NHC=S(C3H7 )*
`5 20 members= CH2I
`N=NC6Hs
`Cyclohexyl
`P(CH3h
`
`Cl
`SFs
`CH3
`CH2CH3
`SCH3
`
`N02
`5-Cl-1-Tetrazolyl
`PO(OCH3h
`OCOCH3
`OCOC2H5 *
`CHO
`SCOC2Hs *
`CH20C4H9*
`Pyrryl
`2,5-di-Me-Pyrryl *
`CH=CHCOC3H1*
`COC6Hs
`PO(OC2Hsh*
`NH2
`NHC4H9*
`OC3H7
`
`CH20H
`NHCN
`NHCOCH3
`C02H
`CONHC3H7*
`NHS02C2Hs*
`NHC==;;;S(C2Hs )*
`NHS02C6Hs
`2-Thienyl
`c=cc6Hs
`CH2Si(CH3h
`P(C2Hsh *
`
`I
`CF3
`CH2Br
`Cyclopropyl
`Se(CH3)
`
`S02(CF3)
`SOC 3 H1*
`1-Tetrazolyl
`OCF3
`CH=CHCN
`COCH3
`C02C3H7*
`CH20C6Hs
`CH=NOC2H5 *
`CH=CHCOCH3
`CH=CHC02C3H1*
`C02C6Hs
`CH=NC6H5
`NHNH2
`NHC6Hs
`OC4H9 *
`
`EtC02H
`CH=NOH
`S02(NH2)
`co2-
`NHC=S(NHC2H5 )
`NHC02CH3*
`NHS02C3H7*
`NHCOC6Hs
`Se(C3H7)*
`CH=CHC6H5 (tr)
`CH2C6Hs
`CH2Si(C2Hs h *
`
`NNN
`SCF3
`CH=CH2
`CH(CH3h
`S(C2Hs)
`
`NO
`S02C2Hs *
`SOC 2 H5 *
`CH2CN
`SCN
`SCOCH3
`CH20CH3
`102
`OCOC3H7*
`CH=CHC02CH3 *
`OCOC6Hs
`OS02C6Hs
`S02C6Hs
`NHCH3
`OCH3
`N(CH3)2
`
`(CH2hC02H*
`NHCOCF3
`CONH2
`NHC=S(NH2)
`NHC=O( CH2 Cl)
`NHC02C2Hs
`NHCOC3H7*
`CH=NNHCOC6Hs
`3-Thienyl
`Si(CH3h
`C4H9
`Ferrocenyl
`
`F
`CF2CF3
`CH2Cl
`C3H7
`SC3H1*
`
`CN
`S02C3H7*
`SOCH3
`CH=CHN02 (tr)
`C02CH3
`co2~Hs
`<;H20C2Hs *
`N(CH3h
`CH=NOC3H1*
`CH=CHCOC2Hs *
`OC6Hs
`CH=CHCOC6Hs
`P=O(C6Hsh
`NH(C2Hs)
`OCH2CH3
`N(C2Hsh
`
`NH(OH)
`NIICHO
`C=O(NHCH3)
`CH=NNHCONHNH2
`NHCOC2Hs*
`NHC=OCH(CH3h
`C(OH)(CF3h
`
`C6Hs
`CsHll *
`C(CH3h
`N(C6Hsh
`
`Vt
`1.0
`
`

`
`"' 0
`
`Table VI-6a Aliphatic Constants-Twenty Cluster Sets
`
`4
`
`6 members= Br
`CF2 CF3
`2 5 members::;: N0 2
`3 6 members= H
`SCH3
`6 members= OH
`C=O(NHCH3)
`5 2 me