Biomimetic Copper-Dioxygen Chemistry - American Chemical Society

6

Mechanistic Bioinorganic Chemistry Downloaded from pubs.acs.org by KTH ROYAL INST OF TECHNOLOGY on 03/01/16. For personal use only.

Biomimetic Copper-Dioxygen Chemistry Reversible O -Binding and Mechanistic Insights into Cu(I)/O -Mediated Arene Hydroxylation and Amide Hydrolysis 2

2

Narasimha N. Murthy and Kenneth D . Karlin

1

Department of Chemistry, Remsen Hall, The Johns Hopkins University, Charles and 34th Streets, Baltimore, M D 21218-2685

Copper(I) complexes that bind dioxygen (O ) reversibly can also effect either the biomimetic hydroxylation of arenes,or the hydro lysis of an unactivated amide such as dimethylformamide (DMF). Several classes of Cu O (i.e., peroxo-dicopper(II)) complexes have been generated; an X-ray structure of a trans μ-1,2 peroxo complex, the kinetics and thermodynamics of formation, and spectroscopic characterizations have been achieved. One dinucleating ligand sys tem affords μ-η :η peroxo dicopper(II) species, subsequently at tacking an arene substrate that is part of the ligand framework; this attack occurs via an electrophilic mechanism, accompanied by an "NIH shift." A different reaction pathway for hydrolysis of DMF occurs when using a dinucleating ligand that permits adjacent co ordination of hydroxide and amide substrate. Possible mechanisms and the biological relevance of hydrolysis reactions mediated by dinuclear metal complexes are discussed. 2

2

2

THE

2

2

COPPER(II) A N D COPPER(I) IONS u n d e r g o f a c i l e r e d o x i n t e r c o n v e r

sions f o r w h i c h t h e s t a n d a r d r e d u c t i o n p o t e n t i a l is h i g h l y d e p e n d e n t o n t h e n a t u r e o f t h e l i g a n d s a n d c o o r d i n a t i o n g e o m e t r i e s o b s e r v e d (1). T h u s , c o p p e r i o n is a u s e f u l e l e c t r o n t r a n s f e r o r o x i d a t i o n c a t a l y s t i n t h e p r e s e n c e o f d i o x y g e n (0 ) ( 2 - 4 ) . T h e s e p r o p e r t i e s h a v e b e e n p u t to a d v a n t a g e 2

b y n a t u r e , w h e r e c o p p e r - c o n t a i n i n g p r o t e i n s (5-11) e x i s t as e l e c t r o n 1

Corresponding author

0065-2393/95/0246-0165/$09.62/0 © 1995 American Chemical Society

166

M E C H A N I S T I C BIOINORGANIC CHEMISTRY

t r a n s f e r agents (JO, I I ) , 0 - c a r r i e r s ( h e m o c y a n i n ( H e ) ) ( T a b l e I ) , o x y genases i n v o l v e d i n O - a t o m i n c o r p o r a t i o n i n t o b i o l o g i c a l substrates ( T a b l e I), oxidases effecting d e h y d r o g e n a t i o n reactions w h i l e r e d u c i n g 0 t o w a t e r (12-14), a n d e v e n n i t r o g e n - o x i d e r e d u c t a s e s (10, 15). M u c h o f o u r o w n effort h a s b e e n c o n c e r n e d w i t h 0 - r e a c t i o n s w i t h s y n t h e t i c copper(I) complexes, w i t h particular interest i n establishing the basic coordination chemistry involved in C u ( I ) / 0 interactions and reactivity p a t t e r n s , i n p a r t i c u l a r C u - 0 ( n = 1,2) r e v e r s i b l e b i n d i n g , s t r u c t u r e , a n d spectroscopy, a n d reactivity o f these o r d e r i v e d species w i t h sub strates (6, 7). I n t h i s c h a p t e r , w e d e s c r i b e a n u m b e r o f t h e s e i n v e s t i gations, b e a r i n g o n models for h e m o c y a n i n a n d c o p p e r monooxygenases s u c h as t y r o s i n a s e . A s a n o u t c o m e o f t h e s e s t u d i e s , w e d i s c o v e r e d a dicopper complex system effecting t h e hydrolysis o f an unactivated amide under m i l d conditions. T h e dicopper complex system m a y b e relevant to reactivity o f an emerging area o f metallobiochemistry, w h i c h involves peptidase or phosphatase h y d r o l y t i c enzymes containing d i - o r trinuclear metal i o n active-site centers. 2

2


2

n

n

2

2

Hemocyanin and Reversible 0 -Binding Compounds 2

in Model

A l t h o u g h t h e r e is a c o n s i d e r a b l e b o d y o f d a t a a n d u n d e r s t a n d i n g o f heme-iron 0 - c a r r i e r s and cytochrome P - 4 5 0 monooxygenases and their m o d e l c o m p o u n d c h e m i s t r y (24-26), m u c h less is k n o w n a b o u t n o n h e m e i r o n (27) a n d c o p p e r p r o t e i n s (5-23) i n v o l v e d i n 0 m e t a b o l i s m ( T a b l e I) (28). M u c h o f t h e a t t e n t i o n i n i n o r g a n i c f u n c t i o n a l m o d e l i n g o f c o p p e r p r o t e i n s i n v o l v e d i n 0 u s e h a s f o c u s e d o n h e m o c y a n i n (5-10, 16, 17), b e c a u s e o f its i n t r i g u i n g d i n u c l e a r c o p p e r c e n t e r that t u r n s f r o m c o l o r l e s s t o i n t e n s e b l u e u p o n c o n v e r s i o n f r o m its d e o x y t o o x y f o r m ( F i g u r e 1). Invertebrate molluscan a n d arthropodal hemocyanins (Hcs) are very large ( M W 4 . 5 - 9 0 Χ 1 0 ) 0 - t r a n s p o r t i n g proteins. T h e y consist o f highly cooperative multisubunits, with molluscan hemocyanins contain i n g 10 o r 2 0 subunits, i n w h i c h t h e functional unit has a m o l e c u l a r w e i g h t ~ 5 5 , 0 0 0 . A r t h r o p o d a l H c s are h e x a m e r s o r m u l t i h e x a m e r s w i t h langer s u b u n i t s ( ~ 7 5 , 0 0 0 ) . A l t h o u g h d i f f e r e n c e s exist b e t w e e n b o t h classes o f p r o t e i n s , a v a r i e t y o f d a t a i n d i c a t e a c l o s e l y r e l a t e d a c t i v e site structure and binding mode. 2

2

2

5

2

R e d u c e d h e m o c y a n i n (i.e., d e o x y - H c ) is c o l o r l e s s , i n d i c a t i v e o f a 3d c o p p e r ( I ) f o r m u l a t i o n . C r y s t a l s t r u c t u r e s o f t w o d e o x y f o r m s a r e n o w a v a i l a b l e , a n d a n i n v e s t i g a t i o n o f t h e h o r s e s h o e c r a b Limulus II p r o t e i n indicates that t h e t w o Cu(I) ions are 4.6 Â apart, each f o u n d i n a t r i g o n a l - p l a n a r c o o r d i n a t i o n e n v i r o n m e n t w i t h C u - N i ~ 2 . 0 À (17). T h e r e is n o b r i d g i n g l i g a n d i n t h i s f o r m , a n d c o o p e r a t i v e effects o f 0 b i n d i n g a r e p r o b a b l y i n i t i a t e d a n d t r a n s m i t t e d as a r e s u l t o f m o v e m e n t 10

H

S

2

2

( n + 1 )

2

x

+ x(0 ")

a

2

2

2

2

2

0

0

nitric oxide synthase

cytochrome P-450 monooxygenases secondary amine monooxygenase

0

hemoglobin myoglobin

Heme Iron

2

0

soluble-methane monooxygenase pteridine-dependent hydroxylases

0

hemerythrin myohemerythrin

Nonheme Iron

Iron and Copper 0 -Carriers and Monooxygenases

X-ray structure is available. References are given for the copper proteins only.

(D = e Donor)

2

Monooxygenases XH + 0 XO + H 0 or X + 0 + D H -*· X O + H 0 + D

n+

Dioxygen Transport xM + 0 3 6 0 n m ) r e v e a l e d d i s t i n c t i v e f e a t u r e s a t t r i b u t a b l e t o i n t e r m e d i a t e s p e c i e s [ C u ( R - X Y L - H ) ( 0 ) ] (7), p o s s e s s i n g a s t r o n g b a n d i n t h e 4 3 5 4 4 0 n m (c - 3 0 0 0 - 5 0 0 0 ) r a n g e . T o i l l u s t r a t e t h e m a g n i t u d e o f t h e k i n e t i c s a n d t h e r m o d y n a m i c p a r a m e t e r s , k = 4 1 0 M " s " a n d k /k- = K = 2 . 9 Χ 1 0 M " at 1 8 3 Κ f o r 6 (R = H ) , w i t h Δ Η ° = - 6 2 ± 1 k j m o l " a n d AS° = 1 9 6 ± 6 J K mol (44). C o r r o b o r a t i v e e x p e r i m e n t a l i n f o r mation comes from bench-top studies of certain of these synthetic a n alogues. T h u s , for t h e R = N 0 , F , a n d C N d e r i v a t i v e s , t h e h y d r o x y l a t i o n p r o c e s s is s l o w e d t o t h e p o i n t t h a t t h e [ C u ( R - X Y L - H ) ( 0 ) ] (7) i n t e r m e d i a t e s a r e s t a b i l i z e d at - 8 0 ° C a n d o b s e r v a b l e b y u s u a l l o w - t e m perature U V - v i s spectroscopic methods. T h e similarity of spectral fea3

3

2

2 +

2

2

2

2 +

2

1

3

7

1

3

3

1

3

1

_ 1

- 1

2

2

2

2 +

6.

175

Biomimetic Copper-Dioxygen Chemistry

M U R T H Y A N D KARLIN


OH

Scheme 4 tures of 7 w i t h [ C u ( N ) ( 0 ) ] (5), a l o n g w i t h t h e i r c l o s e l y r e l a t e d l i g a n d s t r u c t u r e , suggests t h a t t h e s e x y l y l d e r i v a t i v e s also h a v e t h e μ-η :η p e r o x o c o o r d i n a t i o n to t w o C u ( I I ) i o n s , i . e . , S c h e m e 3. 2

n

2 +

2

2

2

T h e k i n e t i c s t u d i e s also i n d i c a t e d t h a t t h e i n i t i a l r e v e r s i b l e 0 b i n d i n g to [ C u ( R - X Y L - X ) ] (6) is f o l l o w e d b y a n i r r e v e r s i b l e h y d r o x y l a t i o n s t e p (k , F i g u r e 4). T h e r e is n o m e a s u r a b l e effect u p o n k w h e n X is d e u t e r i u m . T h i s f i n d i n g is c o n s i s t e n t w i t h e l e c t r o p h i l i c a t t a c k o n t h e a r e n e s u b s t r a t e 7r-system, p r e c l u d i n g r a t e - d e t e r m i n i n g C - H b o n d c l e a v a g e . S u p p o r t i n g t h i s v i e w , w e also find a n i n c r e a s e i n Δ Η * o f t h e h y d r o x y l a t i o n s t e p (k ) w i t h e l e c t r o n - w i t h d r a w i n g a b i l i t y o f R , w h e n s t u d y i n g t h e o x y g e n a t i o n o f c o m p l e x e s [ C u ( R - X Y L - H ) ] (6, R = f - B u , F, H , and N 0 ) . 2

2 +

2

4

4

4

2 +

2

2

T h e n o t i o n of an e l e c t r o p h i l i c attack m e d i a t e d b y the p e r o x o g r o u p i n [ C u ( R - X Y L - H ) ( 0 ) ] (7) is also i n a c c o r d w i t h s t u d i e s o n r e a c t i v i t y c o m p a r i s o n s o f t h r e e classes o f p e r o x o - d i c o p p e r ( I I ) c o m p l e x e s , i n c l u d i n g [{(TMPA)Cu} (0 )] (3) a n d [ C u ( N ) ( 0 ) ] (5, η = 4) ( F i g u r e 5) (48). W e f o u n d that the μ-τ? :?? -0 -) g r o u p i n [ C u ( N ) ( 0 ) ] (5) b e h a v e s as a nonbasic or e l e c t r o p h i l i c p e r o x o l i g a n d , i n contrast to the basic or n u c l e o p h i l i c b e h a v i o r o f t h e p e r o x o g r o u p i n 3, w h i c h possesses " e n d o n " coordination. F o r example, in reactions w i t h H , C 0 , and P P h , 2

2 +

2

2

2

2 +

2

2

2

2

2

n

2

2 +

2

4

2 +

2

+

2

3

176


Basic/Nucleophilic Peroxide PPh

(a)

H

(b)

O2

+

+ 2

n

co

2

1

2

n

2

2

{L Cu 0 CO} n

PhOH.

(e)

2

{L Cu 0 C(0)R} n

(d)

LCu(I)-PPh3 complex

{L Cu (OOH)} - S ^ - H 0 n

RC(Q)+

(c) Mechanistic Bioinorganic Chemistry Downloaded from pubs.acs.org by KTH ROYAL INST OF TECHNOLOGY on 03/01/16. For personal use only.

3

2

PhO"

n

—

2

+

{LnCu

2

{L„Cu2 C03} U

(OOH)}

Non-Basic/Electrophilic Peroxide '

'

(a)

C u ^ C u

P

P

h

»

3

^ {NnCu (PPh ) } + OPPh 2

(b) — — — » -

No reaction

(c)

No reaction

R C

(

Q )

3

2

3

• N reaction

(d) (e)

>

+

I

0

PhOH^

p

h

0

.

+

Cu(II) Complex(es) radical coupling products

Figure 5. Summary of reactivity comparisons of end-on vs. side-on bound peroxo-dicopper(II) complexes (48). [Cu (N )(0 )] (5) d o e s n o t r e a d i l y p r o t o n a t e , i t is u n r e a c t i v e t o w a r d C 0 and it slowly oxygenates P P h , whereas 3 r e a d i l y gives H 0 , carbonates, o r liberates 0 , respectively. A rather important mechanistic insight comes from experiments usi n g [ C u ( R - X Y L - M e ) ] (6, X = M e ) , i n w h i c h a m e t h y l g r o u p was p l a c e d at t h e 2 - p o s i t i o n o f t h e l i g a n d (45). I n s t e a d o f c a u s i n g m e t h y l h y d r o x ylation or b l o c k i n g r i n g attack, 2 - h y d r o x y l a t i o n occurs a n d t h e m e t h y l g r o u p u n d e r g o e s a 1 , 2 - m i g r a t i o n . W h e n 6 ( X = M e ) is r e a c t e d w i t h d i o x y g e n i n C H C 1 a n d t h e r e s u l t i n g s o l u t i o n is w o r k e d u p for its o r g a n i c p r o d u c t s , p h e n o l 9 , M e - P Y 2 , P Y 2 a n d f o r m a l d e h y d e ( d e t e c t e d as a N a s h a d d u c t ) are i s o l a t e d o r d e t e c t e d i n e x c e l l e n t y i e l d a n d w i t h g o o d m a t e r i a l balance (Figure 6). A n isotope-labeling experiment using 0 also e s t a b l i s h e d that the source o f o x y g e n i n 9 was d i o x y g e n a n d c o n f i r m a t i o n of the regiochemistry i n this p r o d u c t came f r o m a crystallographic study of a dicopper(II) c o m p l e x c o n t a i n i n g t h e p h e n o l a t e d e r i v e d f r o m 9. 2

4

2

2 +

2

3

2

2

2

2 +

2

2

2

1

8

2

T h e p r o c e s s o b s e r v e d is r e m i n i s c e n t o f t h e " N I H s h i f t " , o b s e r v e d previously i n i r o n hydroxylases, i n w h i c h a reactive iron-oxy species ( w i t h a n as y e t u n d e t e r m i n e d i d e n t i t y ) is a n e l e c t r o p h i l e , a t t a c k i n g a n arene substrate. T h i s results i n h y d r o x y l a t i o n - i n d u c e d migrations, d u e to t h e f o r m a t i o n o f c a r b o n i u m i o n i n t e r m e d i a t e s a n d r e t e n t i o n o f h e a v i e r

6.

M U R T H γ A N D KARLIN

Γ \ Ρ


>

C

U

2

Υ

177


+

PY

2+ Γ PYy—Cu.

Ν

Λ

>Υ-/—Cu

W

Υ-η

< ^ ^Cu \-ΡΥ /

Cu—\·ΡΥ

Τ

W

ΡΥ

ÇH

3

Ν.

3

H C=N+ Cu^ ^Cu VPY Ι ^ ρ γ \) ">Υ

V

9' Η 8

Η ι CH '

I

χ

1

2+ workup

Γ

^ ρ Ν^\, Ρ Υ τ — Cu ' Cu"—VPY

Ν

ΟΗ )

2

\

ΡΥ

ρ

γ

ρ

ΡΥ

γ

ΡΥ

Me-PY2

ΡΥ2

Figure 6. Scheme showing the nature of products (i.e., 9, PY2, formaldehyde and Me-PY2) obtained during the oxygenation of methyl-substituted xylyl ligand complexes [Cu (R-XYL-Me)] (6,X = Me). The proposed mechanism of copper mediated arene hydroxylation and "NIH shifts (1,2-migration) reactions is also outlined. 2+

2

substituents i n p r e f e r e n c e to - H , d u r i n g r e a r o m a t i z a t i o n . T h i s c o m p a r i s o n has l e a d us t o s u g g e s t a s i m i l a r r e a c t i o n p a t h w a y , a n " N I H s h i f t " in c o p p e r chemistry. T h u s , a d e t a i l e d p r o p o s e d m e c h a n i s m for the h y droxylation of dicopper(I) complexes [ C u ( R - X Y L - X ) ] 2

o u t l i n e d ( F i g u r e 6). [ C u ( R - X Y L - M e ) ] 2

0 , initially forming a C u 0 2

2

structure. This C u 0 2

2

2

2 +

(6), c a n

be

(6, X = Η o r M e ) r e a c t w i t h

2 +

a d d u c t s u g g e s t e d t o h a v e a μ-τ/ :?7 -ρβΓθχο 2

2

a d d u c t is c a p a b l e o f a c t i n g as a n e l e c t r o p h i l e , a n d

attacks the x y l y l l i g a n d π system (consistent w i t h lack o f

2-deuterium

i s o t o p e r a t e effect u p o n k ), w h i c h is l o c a t e d i n a f a v o r a b l e p r o x i m i t y . 4

I n fact, a m o l e c u l a r m o d e l o f [ C u ( R - X Y L - X ) ( 0 ) ] 2

2

2 +

(7) s u g g e s t s t h e

O - O v e c t o r is w e l l - a l i g n e d w i t h a n d c l o s e t o t h e p-7r o r b i t a l o f t h e a r e n e c a r b o n t h a t is a t t a c k e d , p o s s i b l y a n i m p o r t a n t f a c t o r i n o x y g e n a t o m t r a n s f e r r e a c t i o n s , as d i s c u s s e d b y S o r r e l l (49). loss o f H

+

F o r 7 (X = H ) , direct

from the cationic intermediate produces rearomatized [ C u ( R 2

XYL-0-)(OH)]

2 +

b u t loss o f C H

+

3

(8). F o r e i t h e r X = Η o r M e , a 1 , 2 - m i g r a t i o n is l i k e l y , is u n l i k e l y f o r X = C H , a n d r e a r o m a t i z a t i o n o c c u r s 3

w i t h "assistance" of the amine nitrogen lone pair. T h i s rearomatization l e a d s t o loss o f a n i m i n i u m i o n i n a r e t r o - M a n n i c h r e a c t i o n . U n d e r t h e experimental conditions employed, hydrolysis produces P Y 2 and the

178


f o r m a l d e h y d e o b s e r v e d , a n d s o m e r e d u c t i o n o f t h e i m i n i u m salt c a n lead to a small amount o f M e P Y 2 observed. O t h e r r e s e a r c h e r s (50-55) h a v e e x a m i n e d a l t e r n a t e x y l y l s y s t e m s s i m i l a r t o [ C u ( R - X Y L - H ) ] (6), u s i n g c h e l a t i n g g r o u p s o t h e r t h a n P Y 2 , seeing analogous h y d r o x y l a t i o n reactions d e p e n d i n g u p o n the exact n a t u r e o f t h e d i n u c l e a t i n g l i g a n d . S o r r e l l (49) h a s s t u d i e d c l o s e l y r e l a t e d complexes i n w h i c h 1-pyrazolyl or 2-imidazolyl donor groups fully or partially replace the 2 - p y r i d y l ligands i n X Y L - H . H y d r o x y l a t i o n does not occur u p o n oxygenation o f these dicopper(I) complexes and all react via four-electron reduction o f 0 to give bis(M-hydroxo)copper(II) d i m e r s . A l s o , i f - C H P Y i n s t e a d o f - C H C H P Y ( P Y is 2 - p y r i d y l ) a r m s are u s e d i n t h e x y l y l d i n u c l e a t i n g l i g a n d s , o n l y i r r e v e r s i b l e o x i d a t i o n a n d n o l i g a n d h y d r o x y l a t i o n takes place (K. D . K a r l i n a n d c o - w o r k e r s , u n p u b l i s h e d results). 2 +


2

2

2

2

2

T h e s e a n d o t h e r o b s e r v a t i o n s (51-55) s u g g e s t t h a t t h e t e n d e n c y t o w a r d s h y d r o x y l a t i o n i n t h e s e k i n d s o f c h e m i c a l systems is v e r y s e n s i t i v e to e l e c t r o n i c effects, as w e l l as c o p p e r c h e l a t i o n a n d p e r o x i d e p r o x i m i t y a n d o r i e n t a t i o n t o w a r d x y l y l s u b s t r a t e . T h i s v i e w is s u p p o r t e d b y o b servations i n v o l v i n g an u n s y m m e t r i c a l system, [ C u ( U N ) ] (56), a n a n 2 +

2

alogue o f [ C u ( X Y L ) ] 2

2 +

(6)

2+

[Cu^CUNtf

i n w h i c h o n e P Y 2 t r i d e n t a t e is d i r e c t l y a t t a c h e d t o t h e c e n t r a l p h e n y l ring. Low-temperature oxygenation provides [ C u ( U N ) ( 0 ) ] (X = 3 6 0 (e = 1 1 , 0 0 0 ) a n d 5 2 0 (e = 1 , 0 0 0 ) n m ) , w h i c h is so s t a b l e t h a t the 0 can be removed and cycling between [ C u ( U N ) ] and [Cu (UN)(0 )] is p o s s i b l e . H o w e v e r , w a r m i n g t o r o o m t e m p e r a t u r e gives h y d r o x y l a t e d product [ C u ( U N - 0 - ) ( O H ) ] , w i t h a structure analogous to that o b s e r v e d for [ C u ( X Y L - 0 - ) ( O H ) ] (8) ( F i g u r e 4 ) . T h e a c t u a l rate o f c o n v e r s i o n o f [ C u ( U N ) ( 0 ) ] to [ C u ( U N - 0 - ) ( O H ) ] has n o t y e t b e e n m e a s u r e d , b u t t h e p r o c e s s is c l e a r l y m u c h s l o w e r t h a n t h e h y d r o x y l a t i o n i n t h e p a r e n t x y l y l s y s t e m . T h e i m p l i c a t i o n is t h a t t h e u n s y m m e t r i c a l l i g a n d alters t h e o r i e n t a t i o n a n d e l e c t r o n i c s o f t h e p e r o x o ligand i n the [ C u ( U N ) ( 0 ) ] i n t e r m e d i a t e , disfavoring attack o n t h e arene. 2

2

2

2

2

2

2 +

m a x

2 +

2 +

2 +

2

2 +

2

2

2

2

2 +

2

2 +

2

2 +

6.


179


T h u s , t h e x y l y l s y s t e m d e s c r i b e d i n t h e p r e v i o u s p a r a g r a p h s is v e r y m u c h like that of an e n z y m e active site; h e r e , the active C u 0 2

2

inter-

m e d i a t e is f o r m e d w i t h i d e a l j u x t a p o s i t i o n to t h e a r e n e s u b s t r a t e .


Copper-Dioxygen

Chemistry and Amide

Hydrolysis

Because of the highly interesting 0 reactivity w i t h dicopper(I) of ligands l i k e N , X Y L , a n d U N , w e h a v e also e x p e n d e d s o m e efforts w i t h o t h e r modified analogues, i n c l u d i n g P D , based on a 1,3-phenylenediamine n u c l e u s ( P Y is 2 - p y r i d y l ) . 2

n

PD-OH

PD

A l t h o u g h a h y d r o x y l a t i o n r e a c t i o n occurs u p o n a d d i t i o n o f 0 to a d i copper(I) c o m p l e x of P D , t h e r e are m a r k e d differences i n the c h e m i s t r y , l e a d i n g us t o d i s c o v e r that t h e c o p p e r - d i o x y g e n c h e m i s t r y i n t h i s s y s t e m is c a p a b l e o f e f f e c t i n g t h e h y d r o l y s i s o f a n u n a c t i v a t e d a m i d e u n d e r m i l d c o n d i t i o n s . T h r o u g h t h i s c h e m i s t r y , w e c a n also i s o l a t e t h e h y d r o x y l a t e d l i g a n d P D - O H a n d its a n i o n f o r m s a d i n u c l e a r C u ( I I ) c o m p l e x p o s s e s s i n g c o o r d i n a t i o n a n d ligating properties w e l l suited for amide hydrolysis u n d e r h y d r o l y t i c (i.e., n o n o x i d a t i v e ) c o n d i t i o n s (57). 2

A Room-Temperature Stable 0 2 Adduct? T h u s , o x y g e n a t i o n o f [ C u ( P D ) ] (10) i n a c e t o n i t r i l e at r o o m t e m p e r a t u r e g e n e r a t e s a d a r k p u r p l e s p e c i e s w i t h c h a r a c t e r i s t i c a b s o r p t i o n at X = 5 5 8 n m (e = 3 3 0 0 M" c m ) , u n d o u b t e d l y a s s i g n a b l e as a c h a r g e - t r a n s f e r t r a n s i t i o n . A c o r r e s p o n d i n g s t a b l e p u r p l e s o l i d c a n b e i s o l a t e d , f o r m u l a t e d as [Cu (PD)(0 )] (11), b a s e d o n e l e m e n t a l a n a l y s i s , mass s p e c t r o m e t r i c d a t a , s o l u t i o n c o n d u c t a n c e a n d t h e o b s e r v e d C u : 0 = 2:1 ( m a n o m e t r y i n C H C N ) s t o i c h i o m e t r y o f its f o r m a t i o n ( F i g u r e 7) (58). A c e t o n i t r i l e a p p e a r s to b e i m p o r t a n t f o r its s o l u t i o n s t a b i l i t y , i n w h i c h it a p p e a r s t o be essentially diamagnetic, because it exhibits a sharp, n o r m a l l o o k i n g * H - N M R s p e c t r u m a n d has a m a g n e t i c m o m e n t 0 . 3 2 M / C U ( r o o m t e m perature) i n C D C N (Evans method). A s an isolated s o l i d , it does not c o n t a i n C H C N , a n d t h e m a g n e t i c c o u p l i n g is w e a k e r , i . e . , 1.30 M / C U ( r o o m t e m p e r a t u r e ) . T h i s m a t e r i a l d o e s possess a n 0 - o x i d i z i n g e q u i v a l e n t , as s e e n f r o m its r e a c t i o n c h e m i s t r y (see t h e n e x t s e c t i o n ) ; t h e o r i g i n a l d i n u c l e a t i n g l i g a n d r e m a i n s intact i n 1 1 , b a s e d o n the ability to recover u n h y d r o x y l a t e d P D ( 8 1 % , isolated) b y extraction u s i n g 2 +

2

m a x

1

- 1

2

2

2 +

2

3

B

3

3

B

2

180


2+

[Cu (PD)L]


I

2

2+

10a D = absent 10b D = C H C N 3

CH CN

PY-

PY

3

γ

PY

PY

Η [Cu (PD-0 )(0H )] 2

*7\

2+

[Cu (PD)(0 )]|2+ 2

2

11 Figure 7.

Copper (I)-0 chemistry involving the dinucleating PD ligand. 2

N H O H ( a q ) . T h u s , the spectroscopic properties and substrate reactivity 4

(e.g., w i t h H

o r P P h ) o f 11 a r e v e r y d i f f e r e n t f r o m o t h e r C u 0

+

3

peroxo-dicopper(II)) [Cu (N )(0 )] 2

n

2

2

species

such

as

[{(TMPA)Cu} (0 )] 2

2

2 +

(e.g.,

2

(3)

and

(5). W e d o n o t as y e t h a v e a n y c l e a r i d e a s c o n c e r n i n g

2 +

t h e s t r u c t u r e o f 1 1 ; o n e s p e c u l a t i o n is t h a t t h e m o l e c u l e is best d e s c r i b e d as a n C u ( I ) - 0 2

2

species e x h i b i t i n g a C u

0

metal-to-ligand charge-

2

t r a n s f e r ( M L C T ) a b s o r p t i o n [i.e., n o t p e r o x o - d i c o p p e r ( I I ) ] a n d t h a t t h e 0

2

m o l e c u l e m a y b e c o p p e r - b o u n d b u t also c l o s e l y a s s o c i a t e d w i t h t h e

p h e n y l ring of the P D ligand.

C u ( I ) - 0 Hydroxylation Reaction Accompanied by D M F Hydrolysis (57). E i t h e r b y r e a c t i o n o f [ C u ( P D ) ( 0 ) ] (11) w i t h d i 2

2

2

2

2 +

m e t h y l f o r m a m i d e ( D M F ) u n d e r a r g o n at r o o m t e m p e r a t u r e , o r b y d i r e c t addition of 0

2

to a D M F s o l u t i o n of [ C u ( P D ) ] 2

2 +

(10a), a r a p i d change

to g r e e n o c c u r s . W e o r i g i n a l l y e x p e c t e d t h a t a h y d r o x o - b r i d g e d a n d p h e n o x o - b r i d g e d d i c o p p e r ( I I ) c o m p l e x a n a l o g o u s t o 8 (i.e., [ C u ( P D 2

0 )(OH")] _

2 +

) m i g h t b e i s o l a t e d , b u t i t w a s n o t t h e case. I n s t e a d , t h e

p h e n o x o - b r i g e d a n d f o r m a t o - b r i d g e d species (12) is o b t a i n e d i n > 7 0

[Cu (PD-0~)(HC0 ")] 2

acetate-bridged complex [ C u ( P D - 0 ~ ) ( C H C 0 ~ ) ] 2

corresponding

2

2 +

% i s o l a t e d y i e l d ( F i g u r e 7). I n t e r e s t i n g l y , t h e 3

2

2 +

is p r o d u c e d i n a

reaction c a r r i e d out i n Ν,Ν-dimethylacetamide.

The

s t r u c t u r e o f 12 has b e e n c o n f i r m e d i n a X - r a y c r y s t a l l o g r a p h i c s t u d y ( F i g u r e 8). T h u s , t h i s r e a c t i o n has r e s u l t e d i n b o t h t h e h y d r o l y s i s o f D M F t o g i v e f o r m a t e , as w e l l as t h e h y d r o x y l a t i o n o f t h e P D l i g a n d , to g i v e t h e


6.

181



Figure 8. Perspective Chem3D drawing of formato-bridged complex [Cu (PD-0-)(HC0 ~)] (12). Cu---Cu' = 3.65 A and Cu-O -Cu' = 135.3°. 2

2

2+

phenolato

r e s u l t i n g p h e n o l a t e . A m i d e h y d r o l y s i s is also i n d i c a t e d b y t h e o b s e r v e d p r o d u c t i o n of d i e t h y l a m i n e ( G C - M S analysis), w h e n [ C u ( P D ) ] (10a) is r e a c t e d w i t h 0 i n Ν , Ν - d i e t h y l f o r m a m i d e . T h e s e t r a n s f o r m a t i o n s r e s e m b l e t h e m o n o o x y g e n a s e r e a c t i o n s d e s c r i b e d f o r t h e X Y L s y s t e m (i.e., 6 - ^ 8 , see p r e v i o u s p a r a g r a p h s ) , i n w h i c h o n e a t o m o f 0 is i n c o r p o r a t e d i n t o t h e a r e n e s u b s t r a t e , w h e r e a s t h e o t h e r e n d e d u p as a b r i d g i n g h y d r o x i d e l i g a n d . I n t h e p r e s e n t case, no c o r r e s p o n d i n g μ - h y d r o x o c o m p l e x ( O H " d e r i v e d f r o m 0 ; cf. F i g u r e 4) is p r o d u c e d , b e c a u s e a n a d d i t i o n a l h y d r o l y s i s o f D M F has o c c u r r e d . B e c a u s e f o r m a t o c o m p l e x [ C u ( P D 0)(HC0 )] (12) f o r m s d i r e c t l y f r o m [ C u ( P D ) ( 0 ) ] (11) u n d e r A r , the O-atom i n the phenol P D - O H and one atom i n the formato ligand i n 12 a r e s u g g e s t e d to b e d e r i v e d f r o m 0 . T h i s i n d e e d is t h e c a s e , b e c a u s e mass s p e c t r a l e v i d e n c e i n d i c a t e s f u l l i n c o r p o r a t i o n o f 1 8 - 0 i n free i s o l a t e d P D - O H after r e a c t i o n o f [ C u ( P D ) ] (10a) w i t h 0 . S t r o n g s u p p o r t i n g e v i d e n c e is also o b t a i n e d b y e l e c t r o s p r a y i o n i z a t i o n o r fasta t o m - b o m b a r d m e n t ( F A B ) mass s p e c t r o m e t r i c a n a l y s i s c a r r i e d o u t d i rectly on the metal complex product 12. T h u s , 2 +

2

2

2

2

2

2

2

+

2

2

2 +

2

2

[Cu (PD)] 2

2 +

(10a) +

1 8

0

2

+ HC(0)NMe [Cu (PD2

1 8

2 +

1 8

2

2

0)(HC0

1 8

0)]

2 +

(12) +

HNMe

2

182


T h e possible course of reaction involving both arene hydroxylation a n d D M F h y d r o l y s i s is o f c o n s i d e r a b l e

i n t e r e s t , (i) O n e c a n e n v i s i o n

a D M F - i n d u c e d hydroxylation of the arene i n a process somewhat analogous to the h y d r o x y l a t i o n r e a c t i o n 6 f o r m u l a t e d as [ C u ( P D - 0 " ) ( O H " ) ] 2

2 +

,

8, p r o d u c i n g a s p e c i e s

h o w e v e r , not having the struc


t u r e s h o w n i n F i g u r e 7; p r o d u c t i o n o f a h y d r o x o l i g a n d b o u n d t o o n l y one Cu(II) ion might t h e n attack D M F , p r o d u c i n g tively, the 0

(peroxo?) group in [ C u ( P D ) ( 0 ) ]

2

2

2

2 +

1 2 . (ii) A l t e r n a

(11) m i g h t d i r e c t l y

react w i t h D M F , and a subsequent intermediate c o u l d

hydroxylate

the r i n g . T h e s e possibilities are discussed i n subsequent paragraphs, in light of the additional structural chemistry and hydrolysis reactivity d i s c o v e r e d for dicopper(II) c o m p l e x e s w i t h the P D - O " l i g a n d .

D M F Hydrolysis in a Dinuclear Complex Containing Adja cent Exogenous Ligands. T h e s t r u c t u r e o f [ C u ( P D - 0 ) ( H C 0 ) ] 2

2 +

2

(12) s u g g e s t s t h a t t h e P D - O " d i n u c l e a t i n g l i g a n d m a y n o t b e s u i t a b l e for e x o g e n o u s l i g a n d μ-1,1-bridging (e.g., O H " ) , b u t stabilizes

1,3-

b r i d g i n g interactions (e.g., Ο,Ο'-carboxylato). I n fact u s i n g a d i n u c l e a t i n g l i g a n d s i m i l a r to P D - O " (but possessing p y r a z o l y l r a t h e r t h a n p y r i d y l d o n o r s ) , S o r r e l l a n d c o - w o r k e r s (59) s h o w e d t h a t μ - l , 3 - b r i d g i n g was p r e f e r r e d for acetate a n d azide ( N ~ ) , w h e r e a s μ-1,1-bridging 3

o c c u r s for the c o r r e s p o n d i n g

pyrazolyl-containing xylyl ligand anal

o g o u s to X Y L - O " . T h u s t h e P D - O " d i n u c l e a t i n g l i g a n d , b y " p i n n i n g back"

the C u ( I I ) ions v i a b i n d i n g to t h e 1 , 3 - p h e n y l e n e d i a m i n e

d o n o r s a n d b r i d g i n g to the p h e n o l a t o

O-atom,

N-

enforces C u · · · C u

d i s t a n c e s > 3 . 5 Â , u n s u i t a b l e f o r μ - 1 , 1 - b r i d g i n g ( S c h e m e 5: X = O H " , h a l i d e " , o r N " ; X - Y = X is N 3

3

" or R C 0 " ; X I a n d X 2 are n e u t r a l or 2

anionic ligands). These distances

suggest that the

[Cu (PD-0")] 2

n +

framework c o u l d facilitate adjacent coordination of two ligands, per haps a t e r m i n a l h y d r o x o l i g a n d a n d substrate (i.e., D M F ) , p o i s e d intramolecular reaction and hydrolysis This notion 0")(OMe") ] 2

1 +

is s u p p o r t e d

by

for

(57).

a structural analysis of

[Cu (PD2

(13), w h i c h is p r o d u c e d b y d i p h e n y l h y d r a z i n e r e d u c t i o n

PY

X Y L - O " ligand Cu...Cu

PD-O ligand

-3.1Â

Favors μ-Ι,Ι-bridging

C u . . . C u >3.5A Favors μ-13-bridging or terminal coordination

Scheme 5

6.

183



of [ C u ( P D - 0 ) ( H C 0 ) ] (12), f o l l o w e d b y 0 r e o x i d a t i o n o f t h e r e sulting dicopper(I) species i n m e t h a n o l . I n 13 ( F i g u r e 9), t w o adjacent t e r m i n a l m e t h o x i d e ligands are c o o r d i n a t e d to the copper(II) ions o f the d i n u c l e a r u n i t (57). 2

2 +

2

2

W i t h structure [ C u ( P D - 0 " ) ( O M e " ) ] (13), h a v i n g a d j a c e n t t e r m i n a l ligands, w e s u r m i s e d that this c o m p o u n d m i g h t w e l l be suitable i n p r o m o t i n g the hydrolysis of D M F , because w e should be able to generate a copper(II) c o o r d i n a t e d h y d r o x i d e l i g a n d a n d adjacent l a b i l e site for D M F b i n d i n g , i.e., a ( O H ) - C u · · · C u - ( L ) ( L = H 0 or D M F ) species. W e t r i e d to o p t i m i z e such conditions b y r e a c t i n g 13 w i t h D M F (23 °C) i n the presence of one e q u i v a l e n t of H C l 0 . Indeed, facile amide hydrolysis again occurs and [ C u ( P D 0)(HC0 )] (12) is g e n e r a t e d i n g o o d y i e l d ( > 6 0 % i s o l a t e d ) ( F i g u r e 10). A s f o l l o w e d b y U V - v i s s p e c t r o p h o t o m e t r i c measurements of the disappearence of 13 or appearence of 12, p r e l i m i n a r y k i n e t i c m e a s u r e m e n t s i n d i c a t e a p s e u d o - f i r s t - o r d e r p r o c e s s w i t h fc = 0 . 3 h " . T h e s u g g e s t e d r e a c t i o n i n t e r m e d i a t e f o r t h i s p r o c e s s is [ C u ( P D 0")(OH-)(S)] (S = H 0 , M e O H , o r D M F s u b s t r a t e ) , as d e p i c t e d i n F i g u r e 10.


2

2

1 +

2

4 ( a q )

2

2

2

+

1

obs

2

2 +

2

A s r e l a t e d to t h e h y d r o l y s i s r e a c t i o n p r o m o t e d b y d i c o p p e r c o m p l e x 1 3 o r [ C u ( P D - C T ) ( O H - ) ( D M F ) ] ( F i g u r e 1 0 ) , o n e n e e d s to c o n s i d e r 2 +

2

Figure 9. Perspective Chem3D drawing of [Cu (PD-0~) (OMe-) ] (13), with two adjacent terminally bound MeO~ ligands. Cu· · · Cu' = 3.74 h and Cu-O -Cu =137.4°. 2

phenolato

f

2

1+

184


2+

1+

ii_\.PY

PY

,^ΟΝ

Me

PY*

O

11

'

11

ργ

,,Ο

N

N C \ C u —Α- Ρ Y

Ç

Me

Η

[Cu (PD-0-)(OMe) ] 2

Z

γγΧ— C u

4 4

5-6hr,RT P Y ' Q r i


dimethylformamide dimethylformamide 10 (0.02M), (0.02 M) 1.2 eq^ dilHCIO

2

+

(13)

kobs-OJhr

1

[Cu (PD-0)(HC0 )]2+ 2

2

( 1 2

)

2+

P Y-f-Cu« ΡΥ-4—c

p/g^S

Cu»—)-ΡΥ

ργ

S = H 0 , MeOH, D M F 2

Figure 10. Complex 13 with two adjacent terminally bound ligands cat alyzes the hydrolysis of dimethylformamide, giving formato-bridged com plex 12.

t h e p o s s i b i l i t y that o n l y o n e o f t h e t w o m e t a l i o n s is i n v o l v e d ; w e c o n s i d e r this u n l i k e l y . S u p p o r t for this s u p p o s i t i o n comes f r o m studies o n the f o l l o w i n g m o n o n u c l e a r a n a l o g u e , w h i c h has b e e n c r y s t a l l o g r a p h i c a l l y characterized

(57):

R e a c t i o n of this O - b o n d e d D M F - a d d u c t w i t h one e q u i v N a O H in D M F solution p r o d u c e d no detectable formate, e v e n after 6 h . I n t e r ( a q )

6.

M U R T H γ A N D KARLIN


185

estingly, a computer-generated model of [ C u ( P D - 0 " ) ( O H - ) ( D M F ) ] ( F i g u r e 10) u s i n g t h e c o o r d i n a t e s f o r t h e C u ( I I ) - D M F m o i e t y o b s e r v e d i n t h e m o n o n u c l e a r analogue i n d i c a t e d that t h e c o o r d i n a t e d h y d r o x o oxygen atom could be within 2.5 À of the D M F carbonyl carbon a n d s u p p o r t e d t h e v i e w that n u c l e o p h i l i c attack m a y b e facilitated i n this dinuclear complex. 2 +


2

Possible Hydrolytic Mechanisms: Mononuclear Metal Centers. T h e r e is c o n s i d e r a b l e r e c e n t i n t e r e s t i n t h e h y d r o l y s i s o f a m i d e s b y m e t a l c o m p l e x e s (60-63), i n l a r g e p a r t d u e t o t h e i r o c c u r r e n c e i n b i o l o g i c a l s y s t e m s ; a t y p i c a l p e p t i d e a m i d e b o n d has a h a l f - l i f e o f 7 y at p H 7 a n d 2 5 ° C (64). M a n y o f t h e w e l l - k n o w n m e t a l l o p r o t e i n s i n v o l v e d i n h y d r o l y t i c p r o c e s s e s c o n t a i n m o n o n u c l e a r z i n c a c t i v e sites (65-67), a n d there have b e e n n u m e r o u s m o d e l systems s t u d i e d , i n p a r t i c u l a r those i n v o l v i n g zinc(II) o r cobalt(III) i o n s (61). C h i n (61) s u m m a r i z e d ( S c h e m e 6) s o m e o f t h e b a s i c i d e a s i n v o l v i n g s u c h m o n o n u c l e a r h y d r o l y s i s o f a m i d e s , i n v o l v i n g e i t h e r (a) L e w i s a c i d a c t i v a t i o n o f s u b s t r a t e , f a c i l i t a t i n g s o l u t i o n attack b y h y d r o x i d e , (b) a m e t a l - h y d r o x i d e m e c h a n i s m w h e r e b y b i n d i n g o f water to a L e w i s acidic m e t a l lowers its p K g i v i n g a b o u n d h y d r o x i d e , w h i c h a t t a c k s s u b s t r a t e , o r (c) a c o m b i n a t i o n m e c h a n i s m t h a t is l i k e l y i n m e t a l c o m p l e x e s w i t h t w o a d j a c e n t cis l a b i l e sites; h e r e , t h e m e t a l - b o u n d h y d r o x i d e effects a n i n t r a m o l e c u l a r a t t a c k u p o n t h e c o o r d i n a t e d amide substrate. a

Dinuclear Hydrolytic Catalysis. R e c e n t b i o c h e m i c a l a n d p r o tein crystallographic studies have r e v e a l e d that d i - o r t r i n u c l e a r m e t a l i o n c e n t e r s (i.e., w i t h Z n , M g , M n , F e , C o , o r N i ) effect p e p t i d a s e o r p h o s p h a t a s e (i.e., a m i d e o r p h o s p h a t e e s t e r h y d r o l y s i s ) r e a c t i o n s i n a v a r i e t y o f s y s t e m s , T a b l e II. P r o t e i n s y s t e m s t h a t c a r r y o u t a m i d e h y -

OH a Lewis acid

2+/ΌΗ M"r-b Metal-hydroxide Scheme 6

c Combination

186


d r o l y s i s r e a c t i o n s i n c l u d e a m i n o p e p t i d a s e s (68), w h i c h g e n e r a l l y possess e x c h a n g e a b l e m e t a l - b i n d i n g sites. X - r a y c r y s t a l l o g r a p h i c s t u d i e s h a v e r e v e a l e d t h e a c t i v e site s t r u c t u r e i n t w o cases. B o v i n e l e n s l e u c i n e a m i n o p e p t i d a s e (69) possesses a d i - z i n c a c t i v e site ( Ζ η · · · Ζ η = 3 . 1 5 À ) structure, a n d i n cobalt-dependent

methionine aminopeptidase

from


Escherichia coli (70), t h e t w o m e t a l s a r e 2 . 9 Â a p a r t (at 2 . 4 À r e s o l u t i o n ) . There have been a few reports of "first generation" coordination complex

structural models

for the phosphatase

enzyme

a c t i v e sites

(81,82), w h e r e a s t h e r e a r e s o m e e x a m p l e s o f e s t e r h y d r o l y s i s r e a c t i o n s i n v o l v i n g d i n u c l e a r m e t a l c o m p l e x e s (83-85). K i m a n d W y c o f f (74) as w e l l as B e e s e a n d S t e i t z (80) h a v e b o t h p u b l i s h e d s o m e w h a t d e t a i l e d discussions o f " t w o - m e t a l i o n " mechanisms, i n c o n n e c t i o n w i t h e n z y m e s involved i n phosphate

ester hydrolysis. C o m p a r e d to fairly

simple

c h e m i c a l m o d e l s y s t e m s , t h e p r o t e i n a c t i v e site m e c h a n i s t i c s i t u a t i o n is r a t h e r m o r e c o m p l e x , b e c a u s e s i d e - c h a i n residues near t h e active site are u n d o u b t e d l y i n v o l v e d i n the catalysis, i.e, v i a a c i d - b a s e o r h y d r o g e n b o n d i n g interactions that e i t h e r facilitate substrate b i n d i n g , h y d r o x i d e n u c l e o p h i l i c a t t a c k , o r s t a b i l i z a t i o n o f t r a n s i t i o n state(s). N e v e r t h e l e s s , a s i m p l e a n d v e r y l i k e l y r o l e o f t h e L e w i s - a c i d i c m e t a l i o n c e n t e r is t o

Table I I .

Peptidases and Phosphatases with Polymetal Active Sites

Metal and Active Site

Enzyme and Function

Ref.

leucine aminopeptidase methionine aminopeptidase (£. coli) arginase (L-arginine L-ornithine + urea) enolase (hydratase) urease (urea carbonic acid + ammonia)

69° 70° 71

alkaline phosphatase (phosphomonoesterase) phosphotriesterase (Pseudomonas diminuta) PI nuclease (endonuclease) phospholipase C, Bacillus cereus purple acid phosphatases ribonuclease H domain of HIV-1 reverse transcriptase (phosphodiesterase) E. coli D N A polymerase I (Klenow fragment) 3',5'-exonuclease activity)

74"

Peptidases 2Zn 2Co 2Mn 2Mn 2Ni Phosphatases 3Zn (2Zn, lMg) 2Zn 3Zn 3Zn 2Fe (Fe, Zn) 2Mn, 2 M 2 +

2(Mg , M n , or Z n ) 2+

a

2 +

2+

Protein X-ray structure is available.

72 73

75 76° 17° 78 79°

80

a

6.

MURTHY AND KARLIN


187


f a c i l i t a t e p r o t o n loss f r o m w a t e r , g e n e r a t i n g a h y d r o x i d e o r M - ( O H ) " n u c l e o p h i l e . L i p s c o m b a n d c o - w o r k e r s (86) f a v o r s u c h a " g e n e r a l - b a s e " m e c h a n i s m for the d i - z i n c c o n t a i n i n g l e u c i n e a m i n o p e p t i d a s e , b e c a u s e X - r a y s t r u c t u r a l studies s h o w that there are no active-site residues p r e s ent t h a t c o u l d t h e m s e l v e s d i r e c t l y p a r t i c i p a t e as n u c l e o p h i l e f o r c a r b o n y l c a r b o n attack. T h u s , it m a y b e u s e f u l t o d i a g r a m a n u m b e r o f p o s s i b i l i t i e s f o r d i n u c l e a r m e t a l i o n catalysis w i t h respect to p h o s p h a t e ester or a m i d e h y d r o l y s i s ( F i g u r e 11). Part a shows that substrate b i n d i n g m a y be a i d e d b y l i g a t i o n to one or b o t h metals a l t h o u g h l i g a t i o n to b o t h metals seems u n l i k e l y f o r a neutral a m i d e . T h e o t h e r m e t a l c o u l d t h e n d e l i v e r t h e hydroxide nucleophile, or alternatively, the hydroxide nucleophile may c o m e d i r e c t l y f r o m s o l v e n t w a t e r (85). T h e t r a n s i t i o n state m a y b e s t a b i l i z e d by metal-coordination of the developing negative charge on the O - a t o m o f t h e s u b s t r a t e g r o u p . P a r t b o f F i g u r e 11 s h o w s t h a t r e a c t i o n o f a b o u n d s u b s t r a t e (to o n e o r b o t h m e t a l s ) m a y o c c u r v i a a b r i d g i n g M - ( O H " ) - M g r o u p . I n e i t h e r o f t h e s e cases, t h e r e is a n u n d e r l y i n g p r e s u m p t i o n that b i n d i n g of w a t e r to a L e w i s - a c i d i c m e t a l or metals favors deprotonation and generation of the hydroxide nucleophile. Part c of

H Subst H

H

M'

M

(a)

OH

M

M'

(b)

2+

R

/

R

(0

Figure 11. Mechanistic features that may be important in catalysis ofphosphate ester or amide hydrolysis by a dinuclear metal center. See text for further discussion. (Adapted from references 74 and 80).


188

MECHANISTIC BIOINORGANIC CHEMISTRY

F i g u r e 11 shows that b a s e d o n the X - r a y structures available (Table II), p r o t e i n s i d e - c h a i n c a r b o x y l a t e (e.g., A s p o r G l u ) b r i d g i n g o f t w o m e t a l i o n s is r a t h e r c o m m o n i n t h e s e h y d r o l y t i c m e t a l l o e n z y m e s . O n e c a n speculate u p o n another mechanistic possibility, i n w h i c h substrate b i n d i n g m a y b e a c c o m p a n i e d b y a " c a r b o x y l a t e s h i f t " (87) o r d i s p l a c e m e n t (known to occur i n the redox-active d i - i r o n e n z y m e ribonucleotide r e d u c t a s e (88)), p l a c i n g a R C 0 ~ H o r R C 0 g r o u p as p o t e n t i a l a c i d o r b a s e n e x t t o t h e s u b s t r a t e ; i t s r o l e m i g h t b e as a p r o t o n d o n o r t o t h e R C ( 0 ~ ) ( O H ) - N H R ' t e t r a h e d r a l i n t e r m e d i a t e g e n e r a t e d after h y d r o x i d e attack o n substrate, thus facilitating p r o d u c t release. 2

2

I n t h o s e s i t u a t i o n s i n w h i c h t h r e e m e t a l i o n s a r e f o u n d at t h e a c t i v e site o f p h o s p h a t a s e s (74, 76-78), p o s s i b l e m e c h a n i s m s b e c o m e m o r e complicated and numerous. T h e third metal may b i n d and be present i n t h e a c t i v e site i n a s t r u c t u r a l r o l e o r as a n e n z y m e a c t i v a t i o n s t e p . F o r t h e catalytic event, t w o m e t a l ions m a y b e i n v o l v e d i n substrate b i n d i n g , w h i l e the third delivers the hydroxide nucleophile; other c o m binations are obviously possible.

Mechanistic Aspects of the D M F Hydrolyses Affected by 1 1 or 1 3 . T h e m e c h a n i s t i c c o n c e p t s d i s c u s s e d i n p r e v i o u s p a r a g r a p h s w o u l d seem to apply directly to the conversion o f [ C u ( P D 0")(OMe-) ] (13) t o [ C u ( P D - 0 - ) ( H C 0 - ) ] ( 1 2 ) , as a l r e a d y a l l u d e d t o i n F i g u r e 1 0 . T h e P D - O " l i g a n d is c a p a b l e o f s u p p o r t i n g l i g a t i o n b y two adjacent t e r m i n a l ligands. T h u s , addition o f H to 13 i n D M F w o u l d r e l e a s e m e t h a n o l , c o n v e r t i n g 1 3 t o a s p e c i e s s u c h as [ C u ( P D 0 ~ ) ( O H ~ ) ( H 0 ) ] , w i t h labile neutral water ligand. Facile exchange of the c o o r d i n a t e d water b y D M F substrate w o u l d give intermediate [Cu (PD-0)(OH)(DMF)] (Figure 12), well-suited for intramolecular attack b y h y d r o x i d e o n t h e c a r b o n y l c a r b o n , w i t h stabilization o f t h e tetrahedral intermediate product aided b y Cu(II) b i n d i n g . Release o f d i m e t h y l a m i n e gives f o r m a t e - b r i d g e d p r o d u c t 1 2 . 2

1 +

2

2

2

2 +

( a q )

+

2

2

2 +

2 +

2

T h e conversion of [ C u ( P D ) ( 0 ) ] (11) t o [ C u ( P D - 0 ) ( H C 0 ) ] (12) is a c o n s i d e r a b l y m o r e i n t e r e s t i n g p r o c e s s , b e c a u s e h y d r o l y s i s is accompanied b y P D ring hydroxylation. Qualitatively,the observed re a c t i o n o f 11 w i t h D M F is i m m e d i a t e , i . e . , m u c h faster t h a n t h a t o b s e r v e d in the p u r e l y h y d r o l y t i c process, [ C u ( P D - 0 - ) ( O M e - ) ] (13) [Cu (PD-0)(HC0 )] (12). O n e possible explanation for this obser vation c o u l d involve a different reaction pathway, i n w h i c h the 0 (peroxo) l i g a n d i n 11 acts as a s t r o n g α - n u c l e o p h i l e . T h u s , w e s p e c u l a t e t h a t 11 c o u l d r e a c t w i t h D M F i n s u c h a m a n n e r , p r o d u c i n g a p e r o x o - a m i d a t e i n t e r m e d i a t e ( F i g u r e 1 2 ) . W h e n t h i s i n t e r m e d i a t e is f o r m e d i n c l o s e p r o x i m i t y to t h e P D p h e n y l r i n g v i a C u coordination, it c o u l d have ox idative capabilities l i k e that o f a p e r a c i d , effecting t h e h y d r o x y l a t i o n reaction observed, l e a d i n g to the formato p r o d u c t 12. T h e r e are a n u m 2

2

2 +

2

2

2

2

2

2

1 +

2 +

2

2 +

6.

MURTHY A N D KARLIN

189


2+


PY

0

Q Me

Me

PY

[Cu (PD-0)(OMe) ] 2

H

+

2

( a q )

+

PY

PY

PY

PY

2+/ 2+

[Cu (PD)(0 )] (ll)

(13)

2

2

,DMF 12+

P^ ^Y7 - /L - CΓu

1 1

'

-i

ΡY

'CU°—\-PY

PYOH

Ο Η

2+

DV P Y

PY

r»*7

PY Η

N/

Ν

Peroxo-amidate

Terminal hydroxide

J—Cu

1 1

Cu

1 1

—\-PY

[Cu (PD-0)(HC0 )] 2

2

2 +

(12)

Figure 12. Summary of proposed mechanisms for hydrolysis of dimethylformamide starting with either 11 or 13. ber of recent examples i n w h i c h a m e t a l - p e r o x i d e group generated i n p r o x i m i t y to a b i o l o g i c a l s u b s t r a t e has b e e n s h o w n to act as a n u c l e o p h i l e (89-91). F o r e x a m p l e , R o b i n s o n (89) as w e l l as C o o n (90) a n d t h e i r c o w o r k e r s h a v e p r o v i d e d e v i d e n c e that a ( p o r p h y r i n ) i r o n - p e r o x i d e m o i e t y can attack an e x o c y c l i c a l d e h y d e , g e n e r a t i n g f o r m a l d e h y d e . R a n a a n d M e a r e s (91) h a v e also d e m o n s t r a t e d h i g h l y s p e c i f i c p e p t i d e a m i d e h y d r o l y s i s b y u s i n g h y d r o g e n p e r o x i d e ( a n d ascorbate) w i t h a n i r o n - E D T A m o l e c u l e t e t h e r e d to a p r o t e i n . Thus, the dicopper complexes w i t h the P D or P D - O " ligand provide v e r y n o v e l c h e m i s t r y , c l e a r l y e x h i b i t i n g cases o f d i n u c l e a r m e t a l - p r o m o t e d h y d r o l y t i c processes. T h e range o f possible substrates for this c o m p l e x has y e t t o b e s t u d i e d a n d o n e w o n d e r s i f s i m i l a r c h e m i s t r y c a n be observed for z i n c or other m e t a l analogues. A variety of mechanistic

190


investigations will be required (e.g., kinetics and p H dependencies) to provide further insight into the hydrolytic chemistry and corroboration for these proposed reaction pathways.


Summary Our interests in copper-dioxygen coordination chemistry relevant to copper proteins has led us to design and develop a variety of synthetically derived polydentate ligands, containing one or two metal ions. Reversible binding of 0 by mono- or dinuclear copper(I) complexes has been demonstrated for several ligand systems, leading to the structural and spectroscopic characterization of several types of C u 0 (peroxo dicopper(II)) complexes. The dinucleating X Y L , U N , and P D ligands involve chemistry in which C u 0 intermediates effect novel C - H activation reactions, i.e., the hydroxylation of an arene that is part of the dinucleating ligand framework. Such reactions are relevant to copper monooxygenases such as tyrosinase, and a variety of investigations involving copper complexes of X Y L , plus derivatives or analogues have provided mechanistic insights, involving electrophilic attack of the C u 0 moiety upon the arene substrate. An emerging area of metallobiochemistry is the occurrence of peptidase or phosphatase enzymes possessing di- or trinuclear metal ion-containing active sites. The chemistry of copper complexes with the dinucleating PD and P D - O " ligands not only involves Cu(I) /0 reactivity, but hydrolysis of an unactivated amide is also observed. The reaction chemistry and metal-complex structures observed in the system provide insights into the possible mechanisms. 2

2

2

2

2

2

2

2

2

Acknowledgment We thank the National Institutes of Health (GM 28962) for support of the research described herein. References

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