Derivados porfirínicos com potencial aplicação em terapia fotodinâmica. Alterações...

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Ni

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Ni

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19 R = OH

20 R = NH₂

21 R = F

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23 R = NH2

24 R = F POCl3/ DMF

CH3PPh3Br / B ase / THF

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AcOH / CHCl3

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(33)

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Ni Ni

(34)

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N N

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OH

OH OH

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CH3PPh3Br / NaH

THF 78% N

N N

N

OAc

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AcO Ni

O

N

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N

OAc

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AcO Ni

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47 48

K2CO3

MeOH 98% N

N N

N

OAc

OAc OAc

AcO Ni

N

N N

N

OH

OH OH

HO Ni

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(38)

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Ni(OAc)2.H2O

AcOH / CHCl3

93% Ni N N N N OMe OMe OMe MeO O 39 Ni

POCl3/ DMF

CHCl3 47% N N N N OMe OMe OMe MeO 40 CH3PPh3Br / NaH

THF 35%

Ni

# * =Y ;m

0 N N N N OH OH OH HO N NH N HN OH OH OH HO 19 41

Ni(OAc)2.H2O

MeOH / CHCl3

99% Ni N N N N OAc OAc OAc AcO 45

Ac2O / Et3N / DMAP

Py 83% Ni N N N N OAc OAc OAc AcO 46 Ni O 47

CH3PPh3Br / NaH

THF 78% N N N N OAc OAc OAc AcO Ni 48

K2CO3

MeOH 98% N N N N OH OH OH HO Ni

POCl3/ DMF

CH3Cl3

75%

(39)

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R

R I) tolueno, refluxo

II) adição MeOH

Ni Ni

47) R =p-PhOAc

O O

O

49) R =p-PhOAc

CO2H CO2Me

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(40)

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37

400 500 600 700

0,0 0,5 1,0

A

b

s

o

rb

â

n

c

ia

λ_(nm)

Composto 47

Reação de Diels-Alder Após Adição de Metanol

& 3/2 @ $ 98

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V3 BX 0 >

A 1 0 $ B > A

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N

CO2H

N N

O O

O H

H

47) R = OAc

O O

O metanol

N MeO₂C

50) R = OAc MeO2C

H

H MeOH

CO2H

> ?

(41)

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51 52

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N

N N

N R

R

R R

N

N N

N R

R

R R

DMAD (26)

tolueno

Ni Ni

CO2Me

N

N N

N R

R

R Ni

CO2Me

0 $4 B

H ? 1 - @

1 2 $4 '

(42)

' $!

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A 1

400 500 600 700

0.0 0.2 0.4 0.6 0.8 1.0

A

b

s

o

rb

â

n

c

ia

λ_(nm)

Composto 47

Reação de Diels-Alder Após tentativa de purificação

& */2 @ 0 = %>%+ 1

$ A >

$ 1 2 A

%>%+ ' ? @

1

(43)

' $!

0 *

Ha

N

CO2Me

N H

47) R = OAc

N MeO2C

54) R = OAc

MeO2C

CO2Me

N MeO₂C

55) R = OAc CO2Me

DMAD

53) R = OAc

Hb

Ha

Hb

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(44)

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NH N

HN

CO2Me

i) O O

O

refluxo, 18h _N

NH N

HN

CO2Me

O O O H H N HN N NH

CO2Me CO2Me

O O

O H H

+

ii) MeOH, refluxo

N

NH N

HN

CO2Me

HO2C

MeO2C H

H

N HN N

NH

CO2Me CO2Me

H H

+ MeO2C

HO2C

7 56 57

58 59

tolueno,

A B

%>%+ V3 HX

$ O Vn[Z6 X1

300 400 500 600 700 800 0.0 0.2 0.4 0.6 0.8 1.0 A b s o rb a n c ia

λ (nm)

Composto 7

300 400 500 600 700 800 0.0 0.2 0.4 0.6 0.8 1.0

668 nm (Abs 0,29)

669 nm (Abs 0,27)

A b s o rb â n c ia

λ_(nm)

(Composto 58) (Composto 59)

(45)

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h V 3 IX $ ' V=/5X

3 1;Y

400 600

0.0 0.5 1.0

295

402

668

Composto 58

280 320 360

295

λ (nm)

A

b

s

o

rb

â

n

c

ia

λ (nm) 400 600

0.0 0.5

294

403

668 Composto 59

280 320 360

294

λ (nm)

A

b

so

rb

â

n

ci

a

λ (nm)

& 1/ $ A h B 2 211

? ? B

$ 3 V2 X 2 21 B

V @ ++X1 0 ' @ ;Y _'

2 R V∆₂ ₂_{1 =6}Y_{X < V-}₆_{1 1 2} _o _X

2 R 3 : ∆₂₂ _R _$ ₃ _A

h : -6 R V NX: R $ V X 2 o R 3

B 1

2 3 V2 X ?

$ 91

' 1 % 2 2 21 ' @ 1;Y

" ∆∆∆∆ _: _"λλλλ

; < _{6 [=} _{6 6Z} _{5; 8}

2 6 =Y 6 5; Z= 7

(46)

' $!

43

2 2 21 B G :

$ O 1 2 3

2 21 G & k @ l ?

0 1 F

B ! $

(47)

( (

(48)

( (

45

3 - =

=

2 G $4 $ ?

' G @ V= =

X;[ ₂ _> _V

n56mX;Z W V;6 > 96mX1;7

, > d Vn;YmX;8 $ ,1 ? ?

OA G $ @ 1 H $

G & $

G 1

( $4 G

$ ? A $4

A OA 1 2 $ ?

A ? B G

A 1 $

? 3 G 1 - G ? '

$

G $ G $ A

3 1

F @ > V)* ) X O

G $ >2 B 1 2

B $ > ?

G $ % 1

F ?

B ? ? G

$ :

? ! G $4 1

$ G G V ' X

> $ O $

G $4 V $4 ' 98 99X1

$ * +` G V*X p 897 76 VY66 X: V >

(49)

( (

D @ ? $ G

V X @A $ 1 2 > ?

$4 '

$ 1

$ $ >2 >

? & A @

?

$4 > ! B @ 1 2 @

? ? +`

G V*X ' A B $

>2 ? > 1

? B

@ O B

1 k W l >

G B $4 B :

$ @ A $

(50)

47

(51)

* -

>

• _/ ₃ _G _@ _V=_QX _;66

966 Y66 (QB H , K `";66 , K `"966 , K

`"Y66 1 / ? V X

@ V X $ V0( X B

" V R

• _{1 R} _R _R _{? R ?} _? _{R ?} ₁

R 1 1 R 1 1 1 R

1 1 1 1 R 1 1 1 1 R 1

R 1 1 R 1 1 1 R 1?

R ? 1 1?R ? 1 R 1 1 R

? R ? ?1? R ? ? R

1X V,X Q B VQBX h @

B 1

• _/ ₃ _G =; _{ZY =66} _=5Y

(QB H , K `";66 , K `"966 , K `"Y66

1 - $ B " G *

=; _T=_{QU "} ₀ _Q

- 0"=;Y " - @ W B 0

• ₂ _A _$ _V=_{Q "} =; _{X V (F"5 X} _B

H , K `"Y66 $

1 B G =_Q"=_{Q / J}_,_" =_Q"=; _Q( =_Q"=; _{Q(, 1}

• ₂ _V _X _B _B _"

[6 ( Kj_{1 2} _$4 _B

B 76"5;6 566"966 @ 2 / j₁

• _$4 ₃ _B _Q _@

(52)

49

• _A _G _B _{02 +} _{0 58[6 "}

02>0#2 0@ 2 W 5=661

• _/ _' ₃ _B _B

! Y66 N [[= 1

• ₂ _A _%>%+ _B _H _Q ₂ _{W 79Y5}

79Y;1

• ₂ _A _{( >- +>0/} _B _?

( 0/ V, K X - + 1 V 2

" + > X

• _/

G 196

• _% _? _> _$4 _!

(53)

* , - 0 6% 64 7 ? 47

NiCO_3(s) AcOH Ni(OAc)₂.H₂O_(s)

96%

/- A ? VY 66 :

95 = X A G $ G Qn91 F

?f ? 76\ !

' Vn=66\ X 1

( /Z 77 V96 9 X→_8[m

(54)

51

* - @ A> 0 6++7

N

N N

N

OMe

OMe OMe

MeO N

NH N

HN

OMe

OMe OMe

MeO

37 38

Ni(OAc)₂.H₂O

AcOH / CHCl₃ 93%

Ni

/ $ .* V=8Z Y : 6 5Z X F V/2 X51Q5/

V966 : 5 6Y X 2 /Q V;6 X $ ' 9

@ 1 2 G $ V @ X > ( /Q V56 X

@ 1 / ! 5

$4 VY X ( /Q 1 .

V [6\ X 1

( /=8Y V6 5Y X→_8;m

(B%-,_? _V

(55)

H2TPP(OMe)4

Technique UV-Visible Spectral RegionUV-Vis-NIR Spectrum Range190.0000 - 1100.0000 nm Points Count 911 Data Spacing 1.0000 nm

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) -0.05 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 A b s o rb a n c e 4 2 2 .0 0 4 5 4 .0 0 5 1 8 .0 0 5 5 6 .0 0 5 9 4 .0 0 6 5 5 .0 0 6 8 8 .0 0

& ,,/- %>%+ .* Q ;1

NiTPP(OMe)4

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 A b s o rb a n c e 5 3 0 .0 0 4 1 9 .0 0

& , /- %>%+ . Q ;1

(56)

53

* . - @ A> 0 ++

N

N N

N

OMe

OMe OMe

MeO

O

N

N N

N

OMe

OMe OMe

MeO

38 39

POCl3/ DMF

CHCl3

47%

Ni Ni

/ / ' % $ / ;

V; [ : ;8 Y X ( V; : ;8 X H 1 / '

$ ;6 1

-V6\ X > . V==6 : 6 =9 X

Q ;V76 X $ ' 9 @ 1 2 !

V @ X > $

F /2 Q V Qn8>=6X > 3

? ' Q ;V; ' ;6 X1 2 3

F 5 /9 ! 1 /

A > B

Q ;*@ ' V7*5 " 8*= " =6*6X ? .1 1

( /Y9 V[[ q X→_9Zm

(B%-,_? _V

(57)

NiTPP(OMe)4

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 A b s o rb a n c e 5 3 0 .0 0 4 1 9 .0 0

& , /- %>%+ . Q ;1

NiTPP(OMe)4CHO

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 A b s o rb a n c e 4 3 1 .0 0 5 4 1 .0 0 5 8 5 .0 0

& ,./- %>%+ .1 Q ;1

(58)

55

* ) - @ A> 0 ++

N

N N

N

OMe

OMe OMe

MeO N

N N

N

OMe

OMe OMe

MeO

39 40

CH3PPh3Br / NaH

THF 35%

Ni Ni

O

/ - 5Y 2 V X

Q; @;, 87m V556 : 6 [6 X 0Q VY X > =6

' $ ;6 1 - F Q 8Ym

V=[ : 6 [; X ' > ;6 '

$ = Y @ G $ $ 1

2 .1 ! VY6 : [= q X '

56 V @ X1 2 $ ! $ Q5 5V=6 X

A 1 2 ' A 3

F 5 /9 ! 1 /

A > B Q5 5*@ '

V[*9X ? ) 1

( /=Z Z V5= [ q X→_;Ym

(B%-,_? _V

(59)

NiTPP(OMe)4CHO

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 A b s o rb a n c e 4 3 1 .0 0 5 4 1 .0 0 5 8 5 .0 0

& ,./- %>%+ .1 Q ;1

NiTPP(OMe)4CH=CH2

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00 A b s o rb a n c e 4 2 6 .0 0 5 3 7 .0 0

& ,)/- %>%+ ) Q ;1

(60)

57

* 2 - @ ; A> 0 ++

N

N N

N

OH

OH OH

HO N

NH N

HN

OH

OH OH

HO

19 41

Ni(OAc)2.H2O

MeOH / CHCl3

99%

Ni

/ 2 $ ,1 V=6 : =9 Z q X Q ; V=6 X

$ $ F V/2 X51Q5/ V=6 : Y= q X ( /Q V7 X

' 5 1 2 G $ V @ X

!

A > B Q5 5*( /Q V7*5X1 2

? ), A 1

( /=6 [ V=9 Y q X→88m

(B%-,_? _V

;/ 966 (QBXδV X* Z == V 7Q1 MR QBX: Z Z[ V 7Q MR QBX: 7 Z6 V 7QX1 (B%-,.₌_V

;/ =66 (QBXδV X* ==9 7 V QX: =56 9 V X: =;5 Z V QX: =;; 9 V X: =;[ 6 V QX: =99 [ V X: =Y7 [ V X1 B"@ "+@ 4 * 99Q58F9F /9g V(QXg Z;Y =Y;Z:

(61)

H2TPP(OH)4

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 A b s o rb a n c e 4 1 8 .0 0 5 1 6 .0 0 5 5 5 .0 0 5 9 2 .0 0 6 5 0 .0 0

& ,2/- %>%+ ,1 ( /Q1

NiTPP(OH)4

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 A b s o rb a n c e 4 1 5 .0 0 5 2 7 .0 0

& ,3/- %>%+ ), Q ;1

(62)

59

* 3 - @ A> 0 ++

N

N N

N

OAc

OAc OAc

AcO N

N N

N

OH

OH OH

HO

41 45

Ac2O / Et3N / DMAP

Py 83%

Ni Ni

/- H 6\ 2 5/

V=6; Y q : ==[ : = 68 X -;F V=Y; q : === : = =6 X1 - >

), V=;Y : 6 =7 X V5 6 X O ?

(2 1 2 $ 6\ ;6

=5 @ 1 2 $

$ $ F ' $ Q ; V; ' 56 X1 2 3

F 5 /9 ! 1 /

A > B

Q5 5*( /Q V8*=X1 2 ? )2

A 1

( /=;7 9 V6 =Y; X→_7;m

(B%-,_? _V

; 966 (QBX δ V X* 5 9[ V =5QX: Z == V 7Q1 MR 7 ;QBX: Z Z[ V 7Q MR 7 ;QBX: 7 ZZ V 7QX1 (B%-,.₌ _V

; =66 (QBX δ V X* 5= ; V Q;X: ==7 = V X: =56 6 V QX: =;5 ; V QX: =;9 Y V QX: =;7 [ V X: =95 Z V X: =Y6 [ V X: =[8 Y V R/ G X1 B"@ "+@

(63)

NiTPP(OH)4

& ,3/- %>%+ ), Q ;1

NiTPP(OAc)4

& ,*/- %>%+ )2 Q ;1

(64)

61

* * - @ A> 0 ++

N

N N

N

OAc

OAc OAc

AcO N

N N

N

OAc

OAc OAc

AcO

45 46

POCl3/ DMF

CH3Cl3

75%

Ni Ni

O

/ / ' % $ / ;

V= 6 : =6 Z X ( V= 5 : =Y1Y X H 1 / '

$ ;6 1

-V6\ X > )2V=;7 9 : 6 =Y; X

Q ; V=6 X $ ' =5 @ 1 2 !

V @ X > $

F /2 Q V Q 8>=6X > 3

? ' Q ;V; ' ;6 X1 2 3 F 5 /9

! 1 /

A > B Q5 5*- /2 V8*=X1

( /=6[ 8 V6 ==Y X→_ZYm

(B%-,_? _V

; ;66 (QBXδV X* 5 99 V ;QX: 5 9[ V 8QX: Z 9Y V 7QX: Z 8Z V 7QX: 7 Z; V [QX: 8 ;6 V =QX: 8 ;= V =QX1 (B%-,.₌ _V

; ZY Y (QBX δ V X* 5= ; V Q;X: =56 ; V QX: =56 Z V X: =;9 9 V QX: =;9 Y V QX: =;9 Z V QX: =;Z [ V X1 B"@ "+@ 4 *

(65)

NiTPP(OAc)4

& ,*/- %>%+ )2 Q ;1

NiTPP(OAc)4CHO

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 A b s o rb a n c e 4 3 1 .0 0 5 4 3 .0 0 5 8 4 .0 0

& , /- %>%+ )3 Q ;1

(66)

63

* - @ A> 0 ++

46 47

CH3PPh3Br / NaH

THF 78% N

N N

N

OAc

OAc OAc

AcO Ni

O

N

N N

N

OAc

OAc OAc

AcO Ni

H

/ - 5Y 2 V X

Q; @;, 8Zm V5=6 6 YZ X 0Q VZ X > =6

' $ ;6 1 - F Q 8Ym

V=9 6 YY X ' > ;6 '

$ = Y @ G $ $ 1

2 )3 ! VY5 9 : Y[ 5 q X '

Y V @ X1 2 $ ! $ Q5 5 V=6

X A 1 2 ' A 3

F 5 /9 ! 1 /

A > B

Q5 5*@ ' *- /2 V9*;*;X ? )* 1

( /5Y 6 V5[ 8 q X→_97m

(B%-,_? _V

; ;66 (QBXδV X* 5 9Y V =5QX: Y 67 V =Q ,8R= ZQB ,9R== 6QBX: Y Z9

V =Q ,8R= ZQB ,9R=Z =QBX: [ ;Y V =Q ,8R== 6QB ,9R=Z =QBX: Z ;8 V 7QX: Z 85 V

7QX: 7 Z5 V ZQX1 (B%-,.₌ _V

; ZY Y (QBX δ V X* 5= ; V Q;X: ==Y 9 V Q5X: =56 = V QX: =;5 [ V QX: =;9 Y V QX: =Y6 [ V X: =[8 Y V R/ G X1 B"@ "+@ 4 * Y9Q;8F9F /7g

(67)

NiTPP(OAc)4CHO

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 A b s o rb a n c e 4 3 1 .0 0 5 4 3 .0 0 5 8 4 .0 0

& , /- %>%+ )3 Q ;1

NiTPP(OAc)4CH=CH2

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) -0.05 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 A b s o rb a n c e 4 2 2 .0 0 5 3 7 .0 0

& ,1/- %>%+ )* Q ;1

(68)

65

* 1 - @ ; A> 0 ++

47 48

K2CO3

MeOH 98% N

N N

N

OAc

OAc OAc

AcO Ni

N

N N

N

OH

OH OH

HO Ni

H

/ - )* VZ Y : 7 = X $

L5 /; ( /Q V5 X 1 2 !

=6 > ? @

h V X1 / A ' Q ;

A 1 F ) 1

( /[ 6 VZ 8 q X→_87m

(B%-,_? _V

;/ Y66 (QBX δ V X* Y ;5 V =Q ,8R= 9QB ,9R=6 YQBX: Y [9 V =Q ,8R= 9QB ,9R=[ ZQBX: [ ;5 V =Q ,8R=6 YQB ,9R=[ ZQBX: Z 6Y V 7QX: Z YZ V 7QX: 7 Y[

V ZQX1(B%-,.₌ _V

; =5Y (QBXδV X* [9 5 V > Q5X: ==9 = V > Q5X: ==9 5 V QX: ==9 Z V QX: =;5 9 V QX: =;[ Y V QX1B"@ "+@ 4 * 9[Q;=F9F /9g V(QXg Z[= =[8;:

(69)

NiTPP(OAc)4CH=CH2

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) -0.05 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 A b s o rb a n c e 4 2 2 .0 0 5 3 7 .0 0

& ,1/- %>%+ )* Q ;1

NiTPP(OH)4CH=CH2

Technique UV-Visible Spectral RegionUV-Vis-NIR Spectrum Range190.0000 - 1100.0000 nm Points Count 911

Data Spacing 1.0000 nm

800 750 700 650 600 550 500 450 400 350 300 Wavelength (nm) 0.00 0.05 0.10 0.15 0.20 0.25 0.30 0.35 0.40 0.45 0.50 0.55 0.60 0.65 0.70 0.75 0.80 0.85 0.90 0.95 1.00 A b s o rb a n c e 5 3 5 .0 0 4 2 1 .0 0

& /- %>%+ ) ( /Q1

(70)

)*

67

(71)

)*

-

(B%

F $ (F =_Q =;

@ 1 0 G $

G $ / J Q( Q(, 1 0 B

(72)

)* 69 = . 8 .0 0 0 0 7 .9 6 0 7 8 .0 2 1 5 8 .9 6 9 4 3 .3 8 8 5 In te g ra l 8 .7 5 9 6 8 .7 4 7 0 7 .9 3 0 0 7 .9 0 8 5 7 .8 9 6 5 7 .8 7 6 9 7 .2 2 4 1 7 .2 0 2 0 4 .0 4 8 3 3 .4 9 2 7 (ppm) 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

(73)

)*

' .1 ! .

= D? + & B =

6?87

= 7 ZY 7Q ,R Y 6

5

;

9

Y Z 86 7Q

[ Z 56 7Q

Z

7

9 6Y

; 98

8Q

;Q

N

N N

N

O

O O

O Ni

1

1 1

1

2

2 2

2

2 2 2

3

3 3 3

4

4 5

5

5 5

5

5 5 6

6

6 6

7 7

8

(74)

)* 71 = .1 0 .9 9 9 6 0 .9 9 0 6 5 .9 9 9 3 8 .0 3 8 7 8 .0 0 2 0 8 .9 8 0 9 3 .1 2 8 0 9 .3 1 3 9 9 .2 9 3 7 8 .7 2 2 3 8 .7 1 7 9 7 .8 9 2 7 7 .2 0 7 1 7 .2 0 1 4 4 .0 3 7 0 4 .0 2 0 5 (ppm) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5

(75)

)*

' )1 ! .11

= D? + & B

= 7 Z5 [Q

5

;

9

Y Z 78 7Q

[ Z 56 7Q

Z

7

9 69

9 65

8Q

;Q

8 8i 8 ;= V8iX =Q

=6 8 58 =Q

N

N N

N

O

O O

O Ni

9' 9

1

1 1

1

2

2 2

2

2 2 2

3

3 3 3

4

4 5

5

5 5

5

5 5 6

6

6 6

7 7

8

8 8

O

(76)

)* 73 = ) 0 .9 9 7 9 5 .9 9 5 4 8 .0 0 4 7 8 .0 0 0 0 1 .0 0 0 1 1 .0 0 3 1 0 .9 9 7 7 1 1 .9 3 8 8 .7 1 5 0 8 .7 0 5 4 8 .6 8 6 9 8 .6 8 1 4 7 .9 0 9 8 7 .8 8 7 8 7 .8 8 4 4 7 .7 6 6 2 7 .7 3 7 4 7 .2 1 3 2 7 .1 8 9 1 7 .1 8 5 0 7 .1 7 4 7 7 .1 4 5 9 6 .4 4 9 2 6 .4 1 3 5 6 .3 9 2 2 6 .3 5 5 8 5 .7 7 3 2 5 .7 6 6 3 5 .7 1 5 4 5 .7 0 9 3 5 .0 6 3 4 5 .0 5 7 3 5 .0 2 7 7 5 .0 2 1 5 4 .0 3 8 4 4 .0 3 2 2 (ppm) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0

(77)

)*

' 21 ! ) 1

= D? + & B =

6?87

= 7 Z6 [Q

5

;

9

Y Z 75 7Q

[ Z =7 7Q

Z

7

9 6;

9 69

;Q

8Q

8 8i 7 Z7 V8iX =Q

=6 [ 96 =Q ,8R8C D M ,9R8D 9

==

==i

Y 69

Y Z9

=Q

,8R8 I M ,9R8C D

,8R8 I M ,9R8D 9

N

N N

N

O

O O

O Ni

9' 9

1

1 1

1

2

2 2

2

2 2 2

3

3 3 3

4

4 5

5

5 5

5

5 5 6

6

6 6

7 7

8

8 8

10

(78)

)*

75

= ),

8

.0

0

8

.0

9

5

6

8

.0

4

0

8

In

te

g

ra

l

8

.6

9

2

7

.7

6

9

2

7

.7

4

8

1

7

.1

1

6

2

7

.0

9

5

2

(ppm)

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0

(79)

)*

(B%,._{= E},_?F

1 5 8 .6 2 3 5 1 4 4 .5 9 2 3 1 3 5 .9 5 1 0 1 3 3 .4 1 2 5 1 3 2 .7 0 6 9 1 2 0 .3 6 3 3 1 1 4 .7 9 1 5 (ppm) 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170

(B%,._{= 6} _{@,.27 G}

1 3 5 .9 5 1 0 1 3 2 .7 0 6 9 1 1 4 .7 9 1 5 (ppm) 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170

(80)

)*

77

' 3/ ! ),1

= D= D? + & B =

6?87

= =;5 Z 7 Z6 7Q

5 =99 [

; =56 9

9 =;; 9

Y =;[ 6 Z Z[ 7Q ,8R 7 9

[ ==9 7 Z == 7Q ,8R 7 9

Z =Y7 [

N

N N

N

OH

OH OH

HO Ni

1 1

1 1 1

1 1

1

2

2 2

2

2 2 2

3

3 3 3

4

4 5

5

5 5

5

5 5 6

6

6 6

7 7

(81)

)*

= )2

8

.0

0

8

.1

1

4

7

.9

8

6

3

1

2

.0

0

2

In

teg

ra

l

8

.7

6

5

8

.0

1

4

7

.9

9

0

6

7

.4

2

9

3

7

.4

0

8

5

2

.4

5

6

(82)

)*

79

(B%,._{= E},_?F

1 6 9 .4 9 3 6 1 5 0 .5 9 6 2 1 4 2 .7 0 4 2 1 3 8 .2 5 9 9 1 3 4 .4 9 2 1 1 3 2 .3 0 9 9 1 2 0 .0 5 3 6 1 1 8 .0 7 5 1 2 1 .3 3 3 7 (ppm) -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180

(B%,._{= 6} _{@,.27 G}

1 3 4 .4 8 4 8 1 3 2 .3 0 2 7 1 2 0 .0 4 6 3 2 1 .3 3 3 7 (ppm) -10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170

r >7'8:. N8CC 71# .*.:J * $08:= )2 N.1 .1:J N.19J

(83)

)*

' */ ! )21

= D= D? + & B =

6?87

= =;5 ; 7 ZZ 7Q

5 =95 Z

; ==7 =

9 =;7 [

Y =;9 Y Z Z[ 7Q ,8R 7 9

[ =56 6 Z == 7Q ,8R 7 9

Z =Y6 [

7 =[8 Y

8 5= ; 5 9[ =5Q

N

N N

N

O

O O

O Ni

1 1

1

1 1

1

2 2 2

2

2 2 2

3

3 3 3

4 4

4

4 5

5

5 5

5

5 5 6

6

6 6

7 7

8

8 8

O

O O

9

(84)

)* 81 = )3 0 .9 7 1 9 0 .9 6 6 3 6 .0 0 0 0 7 .9 8 2 2 7 .9 3 0 6 1 1 .9 6 1 In te g ra l 9 .3 0 9 5 9 .2 9 9 4 8 .7 3 4 3 7 .9 9 6 4 7 .4 4 5 0 2 .4 5 7 9 2 .4 4 3 3 (ppm) 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

(85)

)*

(B%,._{= E},_?F

1 3 7 .5 9 8 7 1 3 4 .6 8 9 5 1 3 4 .5 2 9 5 1 3 4 .4 5 6 7 1 2 0 .7 1 8 0 1 2 0 .2 9 6 2 2 1 .3 3 2 4 (ppm) 0 20 40 60 80 100 120 140 160 180 200

(B%,._{= 6} _{@,.27 G}

1 3 4 .6 7 8 5 1 3 4 .5 2 5 8 1 3 4 .4 5 6 7 1 2 0 .2 9 2 5 2 1 .3 3 2 4 (ppm) 0 20 40 60 80 100 120 140 160 180 200

>7'8:. ND= = 71# .*.:J * $08:= )3 N.1 .1:J N.19J

(86)

)*

83

' / ! )31

= D= D? + & B

= =;9 9 7 Z; [Q

5

; =56 Z

9 =;Z [

Y =;9 Z 7 66 7Q

[ =56 ; Z 99 7Q

Z

7

8 5= ; 5 9Y =5Q

=6 =;9 Y 8 ;= =Q

== 8 ;6 =Q

N

N N

N

O

O O

O Ni

1

1 1

1 1 1

2 2 2

2

2 2 2

3

3 3 3

4 4

4

4 5

5

5 5

5

5 5 6

6

6 6

7 7

8

8 8

O

O O

9

9 O 10

(87)

(88)

)*

85

(B%,._{= E},_?F

1 6 9 .4 8 3 5 1 5 0 .6 1 7 4 1 3 4 .4 9 3 1 1 2 0 .1 2 1 7 1 1 5 .3 9 4 2 2 1 .3 3 9 7 (ppm) 0 20 40 60 80 100 120 140 160 180 200

(B%,._{= 6} _{@,.27 G}

1 3 4 .4 8 5 8 1 3 4 .2 0 2 2 1 3 2 .6 1 6 7 1 2 0 .1 1 4 4 1 1 5 .3 8 6 9 2 1 .3 3 9 7 (ppm) 0 20 40 60 80 100 120 140 160 180 200

r >7'8:

. ND= = 71# .*.:J * $08:= )* N.1 .1:J N.19J

(89)

)*

' 1/ ! )*1

= D= D? + & B =

6?87

= =6 =;5 [ 7 Z5 ZQ

5

;

9

Y =;9 Y Z 85 7Q

[ =56 = Z 96 7Q

Z =Y6 [

7 =[8 Y

8 5= ; 5 9Y =5Q

== [ ;Y =Q ,8R== 6QB

,9R=Z =QB

=5 =5i ==Y 9 Y 67 Y Z9 =Q =Q

,8R= ZQB ,9R== 6QB

,8R= ZQB ,9R=Z =QB

(90)

)* 87 = ) 7 .0 4 2 0 8 .0 2 4 8 8 .0 0 0 2 1 .0 0 5 3 1 .0 0 3 1 0 .9 9 8 3 In te g ra l 8 .6 1 8 0 8 .5 6 9 4 8 .5 2 9 1 8 .5 1 9 0 8 .5 0 7 1 7 .6 7 1 5 7 .6 5 6 9 7 .4 9 1 0 7 .4 7 6 4 7 .0 9 7 1 7 .0 8 1 5 7 .0 6 6 8 7 .0 3 3 8 7 .0 1 7 4 6 .3 4 5 8 6 .3 2 6 5 6 .3 1 3 7 6 .2 9 2 6 5 .6 5 4 0 5 .6 1 9 2 5 .3 3 4 3 5 .3 0 7 7 5 .2 9 9 5 (ppm) 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0

(91)

)*

(B%,._{= E},_?F

1 3 6 .5 8 0 7 1 3 6 .4 7 3 9 1 3 5 .7 3 3 6 1 3 5 .4 2 8 4 1 3 2 .6 7 3 6 1 3 2 .4 5 2 3 1 1 4 .7 0 2 3 1 1 4 .6 1 8 3 1 1 4 .2 5 9 7 6 4 .2 3 0 0 (ppm) 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170

(B%,._{= 6} _{@,.27 G}

1 3 5 .8 3 2 5 1 3 5 .7 9 6 1 1 3 5 .4 9 0 0 1 3 2 .4 0 0 2 1 1 4 .7 5 7 4 1 1 4 .6 7 0 0 (ppm) 0 20 40 60 80 100 120 140 160 180 200

r >7'8:

(92)

)*

89

' , / ! ) 1

= D= D? + & B =

6?87

= 7 =;5 9 7 Y[ ZQ

5

;

9

Y =;[ Y Z YZ 7Q

[ ==9 Z Z 6Y 7Q

Z

8 ==9 5 [ ;5 =Q ,8R=6 YQB

,9R=[ ZQB

=6

[9 5

==9 =

Y ;5 V=6X

Y [9 V=6iX

=Q

,8R= 9QB ,9R=6 YQB

,8R= 9QB ,9R=[ ZQB

r A =_Q =; _@A _$

;/ 1 2 $4 V

3 :=X ' =_Q"=; _Q( ₁

N

N N

N

OH

OH OH

HO Ni

1

1 1

1

2

2 2

2

2 2 2

3

3 3 3

4

4 5

5

5 5

5

5 5 6

6

6 6

7 7

H H

(93)

+ , !

(94)

+ , !

-91

1 - (

H

I ' & J

=>M1 ( @: k" ( . 6l: 9s $ N W F d J K =8851

5> Q1 @ k 6 6 1 6 l k$ 6 l

1 @ % 5 2 F d J K =8Z71

;> , 1 . " 6 $ 6 % 1= # , @

@ 56661

9> 1 +1: ( @ 1: Q K F1: ' ( 9= 76=1

Y> -1 1: @ 1$ ,11 =< 9=Y=1

[> X B " 1 #1: % (1 1 , " * * 98 58;1 X

B " 1 #1: % (1 1 , " * * 98 9;81 X

M B 21: ( M 6 $ * < ;1 X ` 1"J1 6

$ 1 *9< =;1 X M B 21: ( M1: 6 $ 1 * < 761 X

21: , 21 6 $ 1 3 : 56Y1 X L1 ( M1 N A 1

(1 . . > ( ) 597 ;5=1 @X W (1 1: # 1 1: N 1 M1 , 7

. 1 ) <D ;78Z1 X @ 1 L1: % K 1: 2 %1 #1: K M1:

d 1: # 1: @ @ K 01 L1. 7 . " "

9 =7Z1 OX ( 1 M1: 1 Q1: 0 ,1 N1: N %1 1 1 1

D9 =571 KX 2 Q1: M1 -1 . > (1 ,111 II 5;Z81 X @ 1 . , . ,11)9D9 =66Y1

Z> X , K 1: @ 1 $ ) ,112 :B ;58Y1 X 2 L1 1: ,

(1 1: , 1: F B@ K 21 F1: 21: % (1 21 , . F $ 8

,11 =9[Y1 X L BW 21 F1: W 1 L1: ( @ 1 M1: b@ #1: @ W 01 M1:

@ L1 (1$ ) ,113 :D Z9Z1

7> F K O 1: K +1: 0 K 01. " ,11* 89B ;==78;1

8> N@ K M 1 Q1 N1: Q 1: / (1 J1: , d ,1 L1 , " . ,131 I8

Z97Y1

=6> , 1: N@ 1 1: N >M: , (1 1K , ,1 1 9B8 5ZZ1

==> / Q V=7Z[>=8Y9X L 2 V=865>=8Y7X

(95)

+ , !

-W @ t1 $ * /1 1 Q1: 2 L1 ) " .

,1 <BC 871

=5> 1: 0 @ 21 $ * 0" > A 7 M @ N W u

+ 1 56651 + ,F* 6>9Z6>79Y7=>; V- X1

=;> X 21 (1 #1: 0 G 21 1: F (1 #1 1 (1 1: 21 (1 1: M1 21 1,

. 1 2 DC 5;6[1 X 21 (1 #1: 0 G 21 1: F (1 #1 1 (1 1:

M1 21 1: L /1$ ) 1 2 <B 9Z5;1 X b@ 1: F (1 #1 1

(1 1: 0 G 21 1: 21 (1 1: M1 21 1: (1 1 (1: 21 M1

1 $ ) 2 <B 5=781 X (1 21 1: F (1 #1 1 (1 1: 0 G 21

1: 21 (1 1: M1 21 1" F ( 2 OP ;;51 X 2 1 (1 21: F (1

#1 1 (1 1: 0 G 21 1: 1 21 (1 1: M1 21 1 , . ) ;5;;1 X

M1 21 1: F (1 #1 (1 1: 0 G 21 1 " F ( . POG =6Z1 X ( @ 1:

@ W 01 M1: W L1$ ) 1,111 <C [=Z=1 @X (1 21 1: F

(1 #1 1 (1 1: % (1 #1 Q1: 21 (1 1: M1 21 1$ ) 1 ,113

:D ;Y[81 X ( 21 1: L @ 1 Q1$ ) 1 ,112 :B Z[6;1 OX ( 21 1:

# #1 (1: L K 1 N1: ( 1 21: 1 Q1: K K 1 , 7 . 1,11 ::

=5Y71 KX K %1 1: ( 21 1: @ 1 , . 1 ,1 3 =8 =6891 X

M1 21 1: M K 21 Q1: F (1 #1 1 (1 1: L1 1 F1, . . 1

. ,1 2 ZZ[1 X ( 21 1: K %1 1: @ 1 , . . 1

. ,1 ) =69Z1

=9> 21 1: Q ,1: ( Q1: 21 1: M1 21Q OL ".

' . - 1 56651

=Y> W 1: 1 M1 " ( . 6 K 9 @ 1 L d

2 < @ F d J K 566=1

=[> X M1 " E . O 1 ,133 = 5==1 X M1 2 d . O 1 ,13* B

=[1 X F L1 1: W 1 21: ( 01: % K K #1 " E .

O 1 <8 =[[71 X W -1 M1" E . O 1 <8 =[Y61 X 1:

0 @ 21 $ * %" > A 7 M @ N W u F d

(96)

+ , !

-93

Y8Z1 @X N1 @ .6 > 6 17

/' =8861

=Z> , M1 21$ ,11 <H ;1

=7> K #1: % 0 -1 -1 1 M1: , @ 21 N1 , " . ,12,

D: 9Y6=1

=8> X 2 L1: #1: , K 1: - K N1: K N1: @ 1

, ) " . 1 ,1.) =8< =1 X 2 L1: #1: (1: -1

, ) " . 1,1.) =8< =8Z1 X 2 L1: #1: -1: @ B #1,

) " . 1,1.) =8< 5==1

56> X ( 21 1 M1: 0 21 1: F 1 1: # (1 -1 1: /1 21:

+ J1, K # . ) 8= Z671 X ( 21 1 M1: 21 /1: 0

21 1: F % @ 1 1: 1 1 : /1 21: ( 1 1: + J1: 21 (1

#1: 0 G 21 1: F (1 #1 1 (1 1: M1 21 1, K # . ) 8= 85;1

5=> X Q1 M1 $ ,1*. 9I 7881 X 2 1 1: # >Q 1: M @ 21

N1: @ 21 1 1: N #1 21, . F $ O,1* =[[61

55> 0 G M1 1 1: F (1 #1 1 (1 1: 0 G 21 1: M1 21 1: ( $ 21 1:

+1 F1: 1: % (1 1K 7 . 2 8: ;7Z71

5;> + @ Q1 Q1: @ @ M1 Q1: % Q1: , K Q1) " ,133 BI= =;;1

59> , -1 -1: , 21 L1: N1 (1: W (1 M1: # M1 M1: Q

(1 (1: / 1 1: 1 1 N1, 6 6 B Z671

5Y> @ 1: ( 21 1, " . ,1) DC =7671

5[> + @ Q1 Q1: @ @ M1 Q1: % Q1: , K Q1) " ,133 BI= =;;1

5Z> ( 21 1: ( K @ K 01 %1: @ @K 21 1> , K . ) :C 5[=1

57> M @ 21 N1: / 1, . N.J ,133 Z891

58> # 01 N1: N 1 ( Q 6 =88= 5s 1: . 9 M @

uN W F d J K1

;6> 2 (1 (1: , (1 01$ ) BC 85;Y1

;=> L 1: @ M> 1$ ) ,111 <C Z69;1

;5> X M1 1: @ "( M1: ( 1 , . ,1 * =9 =6Y=1 X

/ L1 01: - $ " K 0

(97)

+ , !

-;;> X / L1 01: F 1 1: # %1 1: + J1: /1 21: F (1 #1 1

(1 1: 0 G 21 1: 21 (1 1: M1 21 1 ? " ( 3 4

' ( . @ + * ++ N K @ t0 3 * + $ 2

( 0 ! 2 $4 ) h t > 1

*1 1 79>7Y1 X / L1 01: F (1 #1 1 (1 1: 0 G 21 1: 21

(1 1: + J1: /1 21: F 1 1: # %1 1: M1 21 1?" 6

" 6 . * ( ( 6 0OP * 6 @1

+ * `++ , W Q W @ W 566Z 0 @ W > Q W1 , K

2 *1 1 Y81 X / L1 01: 21 (1 1: 0 G 21 1: F (1 #1 1

(1 1: F 1 1: # %1 1: /1 21: + J1: M1 21 1 $

V X

;9> X J >Q 1: N O K 01 1: @ 1$ ) ,1 1 :C [=;Y1 X (

21 1: # #1 (1: L K 1 N1: ( 1 21: 1 Q1: K K 1 , 7 .

,11 :: =5Y71 X W 1 L1: M F1: W M1 (1: @ W 01 M1: @ L1 (1

K 7 . ) ,11. : 5[=Y1 X ( +1: W 1 L1: (1 /1:

@ W 01 M1: @ L1 (1 , . F $ 8 ,11) 8[=1 X 21 (1 #1:

/ L1 01: (1 21 1: F (1 #1 1 (1 1: 0 G 21 1: 21 (1 1:

M1 21 1: , 1: ' %1 , . /+* =61=665< O 1566Z667Y51

;Y> @ 1: # @ d #1: Q1>M1: ( >, N1: B N1 M1: @ 1(1 .

. " ,11 9D< 781

;[> @ 1, " . ,1.3 =H [5Y1

;Z> 2 21 1: 1 1: M1 1: # @ M1: 2 M1: L K 1 ,

. ,13* :9 9Z[1

;7> W M1 1: @ +1 1: Q Q1 1: L W 1 1: ( B 21 (1 ,

. ,1 * =9 75Z1

;8> , > d 1 1, . ,113 B8 ;[5;1

96> 1 1: 2 N1 1 1: 1 1 ) 6 . 5

$ /' =8761