Zinc

complexes

of

the

biomimetic

N

N

O

ligand

family

of

substituted

-LRB-

-RRB-

propionates

the

formation

of

oxalate

from

pyruvate

The

coordination

chemistry

of

the

facial

triad

mimics

-LRB-

-RRB-

propionate

-LRB-

-RRB-

and

-LRB-

-RRB-

propionate

-LRB-

-RRB-

towards

was

studied

both

in

solution

and

in

the

solid

state

Different

coordination

modes

were

found

depending

both

on

the

stoichiometry

and

on

the

ligand

that

was

employed

In

the

ligand-to-metal

complex

-LSB-

Zn

-LRB-

-RRB-

-RSB-

the

ligand

coordinates

in

a

tridentate

tripodal

N

N

O

fashion

similar

to

the

facial

triad

However

the

ligand-to-metal

complexes

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

and

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

were

crystallographically

characterized

and

found

to

be

polymeric

in

nature

A

new

bridging

coordination

mode

of

the

ligands

was

observed

in

both

structures

comprising

N,N-bidentate

coordination

of

the

ligand

to

one

zinc

atom

and

O-monodentate

coordination

to

a

zinc

second

atom

A

rather

unique

transformation

of

pyruvate

into

oxalate

was

found

with

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

which

resulted

in

the

isolation

of

the

new

oxalato

bridged

zinc

coordination

polymer

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

the

structure

of

which

was

established

by

X-ray

crystal

structure

determination

Introduction

The

facial

triad

is

a

structural

motif

of

increasing

prominence

among

structurally

characterized

metalloenzymes

Next

to

the

rapidly

growing

subgroup

of

non-heme

iron

enzymes

-LSB-

-RSB-

several

mononuclear

zinc

enzymes

also

feature

this

triad

at

their

active

site

-LSB-

-RSB-

The

proteases

thermolysin

carboxypeptidase

and

neutral

protease

for

example

catalyze

the

hydrolysis

of

peptide

bonds

The

zinc

ion

in

these

enzymes

is

coordinated

by

three

endogenous

residues

i.e.

one

glutamate

and

two

histidine

residues

-LRB-

Fig.

-RRB-

The

fourth

coordination

site

of

the

pseudo-tetrahedral

zinc

center

is

occupied

by

a

catalytically

important

water

or

hydroxide

ligand

This

facial

triad

is

a

variation

of

the

most

commonly

observed

structural

motif

for

the

active

sites

of

zinc-containing

enzymes

Typically

the

tetrahedral

zinc

centers

in

these

enzymes

are

bound

by

a

combination

of

histidine

-LRB-

N

-RRB-

glutamate

or

aspartate

-LRB-

O

-RRB-

and/or

cysteine

-LRB-

S

-RRB-

residues

The

resulting

NxOySz

donor

set

determines

its

biological

function

-LSB-

-RSB-

Accordingly

it

is

important

to

understand

how

a

particular

combination

of

donor

groups

modulates

the

reactivity

of

the

Zn

-LRB-

II

-RRB-

metal

center

Fig.

site

of

a

zinc-containing

enzyme

that

features

the

facial

triad

neutral

protease

from

Bacillus

cereus

-LRB-

Protein

Data

Bank

accession

code

pdb

-RRB-

-LSB-

-RSB-

The

study

of

small

synthetic

analogues

has

focused

on

establishing

a

basis

for

such

a

structure

function

relationship

for

these

mononuclear

zinc-containing

enzymes

-LSB-

-RSB-

Initially

pioneering

studies

by

the

groups

of

Vahrenkamp

Parkin

Kitajima

and

others

employed

all-N

donor

ligands

such

as

the

trispyrazolylborates

-LSB-

-RSB-

In

order

to

obtain

close

structural

models

for

the

facial

triad

containing

zinc

enzymes

one

would

preferentially

like

to

construct

small

analogues

based

on

a

tripodal

N

N

O

ligand

framework

that

incorporates

the

biologically

relevant

donor

groups

Of

the

complexes

with

a

mixed

N/O

donor

set

reported

to

date

-LSB-

-RSB-

only

a

few

make

use

of

such

tridentate

tripodal

N

N

Ocarboxylato

ligands

These

tripodal

ligands

should

be

particularly

well

suited

for

the

structural

modeling

of

tetrahedral

metal

centers

-LSB-

-RSB-

Dowling

and

Parkin

-LSB-

-RSB-

and

Ghosh

and

Parkin

-LSB-

-RSB-

reported

the

first

example

of

an

N

N

O

model

complex

with

a

carboxylato

donor

group

which

resulted

from

the

insertion

of

carbon

dioxide

into

a

borohydride

bond

More

recently

the

groups

of

Burzlaff

-LSB-

-RSB-

and

Carrano

-LSB-

-RSB-

have

reported

studies

on

the

zinc

coordination

chemistry

of

the

bispyrazolylacetate

ligand

family

Beck

et

al.

-LSB-

-RSB-

for

instance

reported

that

a

ligand

zinc

complex

was

obtained

with

bis

-LRB-

-RRB-

acetate

-LRB-

bdmpza

-RRB-

a

ligand

closely

related

to

-LRB-

-RRB-

propionate

-LRB-

-RRB-

These

complexes

were

obtained

regardless

of

the

ratio

of

reactants

i.e.

even

with

stoichiometric

amounts

of

ligand

and

zinc

-LRB-

II

-RRB-

Very

recently

Friese

et

al.

-LSB-

-RSB-

constructed

mononuclear

zinc

models

via

a

new

approach

i.e.

by

the

use

of

sterically

hindered

carboxylato

and

N-donor

ligand

building

blocks

We

have

been

studying

the

copper

and

iron

coordination

chemistry

of

the

new

ligand

family

of

the

substituted

-LRB-

-RRB-

propionates

as

accurate

structural

mimics

of

the

facial

triad

-LSB-

-RSB-

These

ligands

incorporate

the

biologically

relevant

donor

groups

i.e.

two

imidazoles

and

a

carboxylate

group

into

a

monoanionic

tripodal

framework

Their

general

biomimetic

potential

has

been

illustrated

by

the

structurally

characterized

copper

-LSB-

-RSB-

and

iron

-LSB-

-RSB-

complexes

of

these

ligands

Here

our

studies

are

expanded

to

the

structural

modeling

of

the

zinc-containing

enzymes

and

describe

the

zinc

coordination

chemistry

of

the

ligands

and

-LRB-

-RRB-

propionate

-LRB-

-RRB-

-LRB-

Fig.

-RRB-

Furthermore

the

attempted

synthesis

of

zinc

complexes

with

-LRB-

-RRB-

acetate

-LRB-

-RRB-

a

direct

analogue

of

the

bispyrazolylacetates

is

described

During

the

course

of

these

studies

we

found

that

zinc

complexes

of

ligand

catalyze

the

unexpected

and

unprecedented

conversion

of

pyruvate

to

oxalate

in

aqueous

solution.Fig

-LRB-

-RRB-

propionate

-LRB-

-RRB-

-LRB-

-RRB-

propionate

-LRB-

-RRB-

and

-LRB-

-RRB-

acetate

-LRB-

-RRB-

and

the

synthesis

of

the

zinc

complexes

-LSB-

Zn

-LRB-

-RRB-

-RSB-

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

and

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

Materials

and

methods

Air-sensitive

organic

reactions

were

carried

out

under

an

atmosphere

of

dry

oxygen-free

using

standard

Schlenk

techniques

Tetrahydrofuran

-LRB-

THF

-RRB-

and

diethyl

ether

were

dried

over

sodium

benzophenone

ketyl

and

distilled

under

prior

to

use

Methanol

was

dried

over

magnesium

methoxide

and

distilled

under

prior

to

use

and

NMR

spectra

were

recorded

using

a

Varian

a

Varian

Inova

or

a

Varian

Mercury

spectrometer

operating

at

°C

IR

spectra

were

recorded

with

a

PerkinElmer

Spectrum

One

Fourier

transform

IR

instrument

Elemental

microanalyses

were

carried

out

by

the

Microanalytisches

Laboratorium

Dornis

Kolbe

Mulheim

a.d.

Ruhr

Germany

ESI

MS

spectra

were

recorded

using

a

Micromass

liquid

chromatography

time-of-flight

mass

spectrometer

at

the

Biomolecular

Mass

Spectrometry

Group

Utrecht

University

Bis

-LRB-

-RRB-

methane

-LRB-

-RRB-

-LSB-

-RSB-

-LRB-

-RRB-

propionic

acid

-LRB-

-RRB-

potassium

and

tetrabutylammonium

-LRB-

-RRB-

propionate

-LRB-

K

-LSB-

-RSB-

and

-LSB-

-RSB-

-LSB-

-RSB-

-RRB-

-LSB-

-RSB-

potassium

-LRB-

-RRB-

propionate

-LRB-

K

-LSB-

-RSB-

-RRB-

-LSB-

-RSB-

and

zinc

bis

-LRB-

trimethylsilyl

-RRB-

amide

-LSB-

-RSB-

were

prepared

according

to

published

procedures

All

other

chemicals

were

obtained

commercially

and

used

as

received

Benzyl

bis

-LRB-

-RRB-

acetate

To

a

cooled

solution

of

-LRB-

g

mmol

-RRB-

in

dry

THF

-LRB-

mL

-RRB-

at

°C

was

added

dropwise

a

solution

of

n-butyl

lithium

in

hexane

-LRB-

mL

mmol

-RRB-

The

reaction

mixture

was

stirred

for

h

at

°C

after

which

benzylchloroformate

-LRB-

mL

mmol

wt

solution

in

toluene

-RRB-

was

added

dropwise

During

the

addition

a

white

precipitate

formed

The

solution

was

allowed

to

warm

to

room

temperature

overnight

The

reaction

mixture

was

quenched

with

-LRB-

mL

-RRB-

and

all

volatiles

were

removed

in

vacuo

The

aqueous

layer

was

extracted

with

diethyl

ether

-LRB-

mL

-RRB-

and

the

combined

organic

layers

were

dried

over

filtered

and

concentrated

in

vacuo

The

crude

oil

was

purified

by

column

chromatography

-LRB-

ethyl

acetate

methanol

-RRB-

Benzyl

bis

-LRB-

-RRB-

acetate

-LRB-

-RRB-

was

isolated

as

a

yellow

oil

in

yield

-LRB-

g

mmol

-RRB-

NMR

-LRB-

MHz

°C

-RRB-

δ

-LRB-

s

-RRB-

-LRB-

s

-RRB-

-LRB-

s

CH

-RRB-

-LRB-

s

Him

-RRB-

-LRB-

s

Him

-RRB-

-LRB-

s

HPh

-RRB-

ppm

Anal

for

-LRB-

-RRB-

calc

C

H

N

found

C

H

N

IR

-LRB-

solid

-RRB-

ν

cm

ESI

MS

m/z

-LRB-

-LSB-

M

Cl

-RSB-

calc

-RRB-

-LSB-

Zn

-LRB-

-RRB-

-RSB-

To

a

hot

colorless

solution

of

-LRB-

mg

mmol

-RRB-

in

dry

acetonitrile

-LRB-

mL

-RRB-

was

added

a

solution

of

Zn

-LSB-

N

-LRB-

-RRB-

-RSB-

-LRB-

mg

mmol

-RRB-

in

dry

diethyl

ether

-LRB-

mL

-RRB-

via

a

cannula

The

resulting

colorless

clear

solution

was

stirred

for

h

at

elevated

temperature

during

which

gradually

a

white

precipitate

formed

The

reaction

mixture

was

concentrated

in

vacuo

to

give

the

crude

product

as

a

white

powder

Recrystallization

from

an

acetone

water

mixture

-LRB-

v/v

-RRB-

gave

-LSB-

Zn

-LRB-

-RRB-

-RSB-

as

a

colorless

crystalline

solid

-LRB-

mg

-RRB-

NMR

-LRB-

MHz

°C

-RRB-

δ

-LRB-

d

J

Hz

-RRB-

-LRB-

s

-RRB-

-LRB-

t

J

Hz

-RRB-

-LRB-

s

Him

-RRB-

-LRB-

s

Him

-RRB-

ppm

-LCB-

-RCB-

NMR

-LRB-

MHz

°C

-RRB-

δ

ppm

Anal

for

-LRB-

-RRB-

calc

C

H

N

found

C

H

N

IR

-LRB-

solid

-RRB-

ν

cm

ESI

MS

m/z

-LRB-

-LSB-

M

H

-RSB-

calc

-RRB-

-LRB-

-LSB-

M+N

a

-RSB-

calc

-RRB-

-LRB-

-LSB-

M

K

-RSB-

calc

-RRB-

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

To

a

hot

colorless

solution

of

K

-LSB-

-RSB-

-LRB-

mg

mmol

-RRB-

in

dry

methanol

-LRB-

mL

-RRB-

was

added

a

solution

of

-LRB-

mg

mmol

-RRB-

in

methanol

-LRB-

mL

-RRB-

via

a

cannula

Immediately

upon

addition

a

white

precipitate

formed

and

the

suspension

was

stirred

at

elevated

temperature

for

h

The

white

precipitate

was

separated

by

centrifugation

and

washed

with

methanol

-LRB-

mL

-RRB-

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

was

obtained

as

a

white

powder

in

almost

quantitative

yield

-LRB-

mg

-RRB-

NMR

-LRB-

MHz

°C

-RRB-

δ

-LRB-

d

J

Hz

-RRB-

-LRB-

s

-RRB-

-LRB-

t

-RRB-

-LRB-

s

Him

-RRB-

-LRB-

s

Him

-RRB-

ppm

-LCB-

-RCB-

NMR

-LRB-

MHz

°C

-RRB-

δ

ppm

Anal

for

-LRB-

-RRB-

calc

C

H

N

found

C

H

N

IR

-LRB-

solid

-RRB-

ν

cm

ESI

MS

m/z

-LRB-

-LSB-

M

Cl

-RSB-

calc

-RRB-

-LRB-

-LSB-

M

H

-RSB-

calc

-RRB-

-LRB-

-LSB-

Zn

H

-RSB-

calc

-RRB-

-LRB-

-LSB-

Zn

H

-RSB-

calc

-RRB-

-LRB-

-LSB-

Cl

-RSB-

calc

-RRB-

-LRB-

-LSB-

Zn

-RSB-

calc

-RRB-

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

Colorless

crystals

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

suitable

for

X-ray

diffraction

were

obtained

upon

standing

of

a

concentrated

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

for

several

weeks

The

coordination

polymer

obtained

is

insoluble

in

all

common

organic

solvents

and

water

of

neutral

pH.

Anal

for

-LRB-

-RRB-

calc

C

H

found

C

H

N

IR

-LRB-

solid

-RRB-

ν

cm

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

To

a

colorless

solution

of

-LRB-

mg

mmol

-RRB-

in

dry

methanol

-LRB-

mL

-RRB-

was

added

a

solution

of

K

-LSB-

-RSB-

-LRB-

mg

mmol

-RRB-

in

dry

methanol

-LRB-

mL

-RRB-

via

a

cannula

The

clear

solution

was

stirred

overnight

at

room

temperature

and

evaporated

in

vacuo

The

product

was

redissolved

in

dichloromethane

and

insoluble

KCl

was

separated

off

by

centrifugation

The

solution

was

filtered

over

Celite

and

concentrated

in

vacuo

to

give

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

as

a

white

powder

-LRB-

mg

-RRB-

Colorless

crystals

suitable

for

X-ray

diffraction

were

obtained

from

a

methanolic

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

upon

standing

NMR

-LRB-

MHz

°C

-RRB-

δ

-LRB-

d

J

Hz

-RRB-

-LRB-

d

J

Hz

-RRB-

-LRB-

t

J

Hz

-RRB-

-LRB-

d

J

Hz

-RRB-

-LRB-

m

-RRB-

-LRB-

J

-RRB-

-LRB-

J

-RRB-

-LRB-

t

J

Hz

-RRB-

-LRB-

s

Him

-RRB-

ppm

-LCB-

-RCB-

NMR

-LRB-

MHz

°C

-RRB-

δ

ppm

Anal

for

-LRB-

-RRB-

calc

C

H

N

found

C

H

N

IR

-LRB-

solid

-RRB-

ν

cm

ESI

MS

m/z

-LRB-

-LSB-

-RSB-

calc

-RRB-

-LRB-

-LSB-

M

H

-RSB-

calc

-RRB-

-LRB-

-LSB-

M

K

-RSB-

calc

-RRB-

-LRB-

-LSB-

-RSB-

calc

-RRB-

-LRB-

-LSB-

Cl

-RSB-

calc

-RRB-

-LRB-

-LSB-

H

-RSB-

calc

-RRB-

-LRB-

-LSB-

H

-RSB-

calc

-RRB-

-LSB-

Zn

-LRB-

-RRB-

-RSB-

To

a

hot

solution

of

-LRB-

mg

mmol

-RRB-

in

dry

methanol

-LRB-

mL

-RRB-

was

added

a

solution

of

anhydrous

-LRB-

mg

mmol

-RRB-

in

dry

MeOH

-LRB-

mL

-RRB-

via

a

cannula

The

reaction

mixture

was

stirred

at

elevated

temperature

for

h

and

gradually

the

product

formed

as

a

white

precipitate

The

product

-LSB-

Zn

-LRB-

-RRB-

-RSB-

was

separated

by

centrifugation

and

was

obtained

as

a

white

powder

in

quantitative

yield

Single

crystals

suitable

for

X-ray

analysis

were

obtained

by

slow

evaporation

of

a

solution

of

-LSB-

Zn

-LRB-

-RRB-

-RSB-

in

acetone

NMR

-LRB-

MHz

°C

-RRB-

δ

-LRB-

-RRB-

-LRB-

s

-RRB-

-LRB-

s

CH

-RRB-

-LRB-

d

J

Hz

Him

-RRB-

-LRB-

d

J

Hz

Him

-RRB-

-LRB-

m

HPh

-RRB-

-LRB-

m

HPh

-RRB-

ppm

-LCB-

-RCB-

NMR

-LRB-

MHz

°C

-RRB-

δ

ppm

Anal

for

-LRB-

-RRB-

calc

C

H

N

found

C

H

N

IR

-LRB-

solid

-RRB-

ν

cm

ESI

MS

m/z

-LRB-

-LSB-

M

Cl

-RSB-

calc

-RRB-

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

-LRB-

direct

synthesis

-RRB-

To

a

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

-LRB-

mg

mmol

-RRB-

in

water

-LRB-

mL

-RRB-

was

added

a

solution

of

potassium

oxalate

hydrate

-LRB-

mg

mmol

-RRB-

in

water

-LRB-

mL

-RRB-

The

solution

was

stirred

overnight

at

room

temperature

during

which

gradually

a

white

precipitate

formed

The

precipitate

was

separated

by

centrifugation

and

washed

three

times

with

water

-LRB-

mL

-RRB-

The

product

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

was

dried

in

vacuo

and

obtained

as

a

white

powder

in

yield

-LRB-

mg

mmol

-RRB-

Anal

for

-LRB-

-RRB-

calc

C

H

N

found

C

H

N

IR

-LRB-

solid

-RRB-

ν

cm

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

reaction

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

with

sodium

pyruvate

For

NMR

investigation

of

reaction

mixtures

stock

solutions

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

-LRB-

mg

mmol

-RRB-

in

-LRB-

mL

-RRB-

and

sodium

pyruvate

-LRB-

mg

mmol

-RRB-

in

-LRB-

mL

-RRB-

were

prepared

NMR

tubes

were

filled

with

mL

of

each

stock

solution

and

kept

either

at

room

temperature

or

heated

to

°C

The

NMR

samples

were

analyzed

at

different

times

after

mixing

the

reagents

Before

acquisition

of

the

NMR

spectrum

mL

was

added

to

the

reaction

mixture

Crystals

usually

deposited

within

or

days

in

the

NMR

tube

In

the

case

of

the

catalytic

runs

mL

of

a

solution

containing

equiv

of

sodium

pyruvate

was

added

to

mL

of

the

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

stock

solution

and

dimethyl

sulfoxide

-LRB-

equiv

μL

-RRB-

was

added

as

an

internal

standard

The

reaction

mixture

was

kept

at

°C

and

the

NMR

spectrum

was

recorded

with

addition

of

mL

after

h.

On

a

preparative

scale

to

a

solution

of

-LRB-

mg

mmol

-RRB-

and

K

-LSB-

-RSB-

-LRB-

mg

mmol

-RRB-

in

-LRB-

mL

-RRB-

was

added

sodium

pyruvate

-LRB-

mg

mmol

-RRB-

The

solution

was

heated

to

°C

and

gradually

an

off-white

precipitate

was

formed

After

week

the

product

was

separated

by

centrifugation

-LRB-

mg

-RRB-

The

IR

spectrum

of

the

product

was

identical

to

that

of

independently

synthesized

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

X-ray

crystal

structure

determinations

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

-LRB-

-RRB-

-RSB-

-LSB-

-LRB-

-RRB-

-RSB-

and

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

Reflections

were

measured

with

a

Nonius

Kappa

CCD

diffractometer

with

a

rotating

anode

-LRB-

graphite

monochromator

λ

Å

-RRB-

at

°C

The

structures

were

refined

with

-LSB-

-RSB-

against

of

all

reflections

Non-hydrogen

atoms

were

refined

with

anisotropic

displacement

parameters

Geometry

calculations

and

checking

for

higher

symmetry

were

performed

with

the

PLATON

program

-LSB-

-RSB-

Further

details

are

given

in

Table

Table

data

for

compounds

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

-LRB-

-RRB-

-RSB-

-LSB-

-LRB-

-RRB-

-RSB-

and

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

-LSB-

-LRB-

-RRB-

-RSB-

-LSB-

-LRB-

-RRB-

-RSB-

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

Crystal

size

-LRB-

-RRB-

Crystal

colorColorlessColorlessColorlessColorlessColorlessCrystal

systemOrthorhombicMonoclinicMonoclinicMonoclinicTriclinicSpace

-LRB-

no.

-RRB-

Cc

-LRB-

no.

-RRB-

-LRB-

no.

-RRB-

-LRB-

no.

-RRB-

a

-LRB-

Å

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

b

-LRB-

Å

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

c

-LRB-

Å

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

α

-LRB-

-RRB-

-LRB-

-RRB-

β

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

γ

-LRB-

-RRB-

-LRB-

-RRB-

V

-LRB-

Å

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

g

cm

-RRB-

μ

-LRB-

mm

-RRB-

Absorption

correctionMultiscanMultiscanMultiscanMultiscanMultiscanAbsorption

correction

sin

-LRB-

θ/λ

-RRB-

max

-LRB-

Å

-RRB-

Reflections

-LRB-

measured/unique

-RRB-

-LSB-

I

2σ

-LRB-

I

-RRB-

-RSB-

-LRB-

all

reflections

-RRB-

Flack

parameter

-LSB-

-RSB-

-LRB-

-RRB-

-LRB-

-RRB-

Residual

density

-LRB-

e

Å

-RRB-

-LRB-

-RRB-

propionate

-LRB-

-RRB-

propionate

and

benzyl

bis

-LRB-

-RRB-

acetate

bis

-LRB-

-RRB-

methane

For

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

the

structure

was

solved

with

-LSB-

-RSB-

using

direct

methods

All

hydrogen

atoms

were

located

in

the

difference

Fourier

map

and

refined

freely

with

isotropic

displacement

parameters

For

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

the

structure

was

solved

with

-LSB-

-RSB-

using

automated

Patterson

methods

Refinement

was

performed

as

an

inversion

twin

All

hydrogen

atoms

were

located

in

the

difference

Fourier

map

and

refined

with

a

riding

model

For

-LRB-

-RRB-

-RSB-

the

structure

was

solved

with

-LSB-

-RSB-

using

automated

Patterson

methods

All

hydrogen

atoms

were

located

in

the

difference

Fourier

map

and

refined

with

a

riding

model

For

-LSB-

-LRB-

-RRB-

-RSB-

the

structure

was

solved

with

-LSB-

-RSB-

using

Direct

methods

All

hydrogen

atoms

were

located

in

the

difference

Fourier

map

and

refined

freely

with

isotropic

displacement

parameters

For

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

the

crystal

was

nonmerohedrally

twinned

with

a

twofold

rotation

about

the

crystallographic

c-axis

as

a

twin

operation

This

twin

law

was

taken

into

account

during

the

intensity

integration

using

the

program

EvalCCD

-LSB-

-RSB-

The

structure

was

solved

on

the

nonoverlapping

reflections

with

-LSB-

-RSB-

using

automated

Patterson

methods

All

hydrogen

atoms

were

located

in

the

difference

Fourier

map

and

refined

with

a

riding

model

The

twin

fraction

refined

to

-LRB-

-RRB-

Crystallographic

data

-LRB-

without

structure

factors

-RRB-

for

the

structures

reported

in

this

paper

have

been

deposited

with

the

Cambridge

Crystallographic

Data

Centre

-LRB-

CCDC

-RRB-

as

supplementary

publication

nos

for

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

for

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

for

-LRB-

-RRB-

-RSB-

for

-LSB-

-LRB-

-RRB-

-RSB-

and

for

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

Copies

of

the

data

can

be

obtained

free

of

charge

from

the

CCDC

-LRB-

Union

Road

Cambridge

UK

Tel.

Fax

e-mail

deposit@ccdc.cam.ac.uk

Web

site

-RRB-

Results

As

part

of

our

efforts

to

study

the

coordination

chemistry

of

the

substituted

-LRB-

-RRB-

propionate

ligand

family

the

complexes

of

and

with

were

synthesized

and

structurally

characterized

-LRB-

Fig.

-RRB-

is

the

parent

ligand

of

the

family

and

offers

the

most

steric

hindrance

of

the

ligands

studied

so

far

The

coordination

chemistry

of

and

with

zinc

was

found

to

be

stoichiometry-dependent

Zinc

complexes

of

The

formation

of

different

species

upon

addition

of

either

or

equiv

of

to

a

solution

of

the

potassium

salt

of

in

is

evidenced

by

the

respective

NMR

spectra

in

-LRB-

Fig.

-RRB-

Fig.

MHz

NMR

spectra

of

the

titration

of

K

-LSB-

-RSB-

with

in

at

room

temperature

a

K

-LSB-

-RSB-

b

K

-LSB-

-RSB-

and

c

K

-LSB-

-RSB-

and

Asterisks

denote

the

residual

solvent

peak

All

four

resonances

associated

with

ligand

-LRB-

spectrum

a

-RRB-

shifted

upon

addition

of

equiv

of

-LRB-

spectrum

b

-RRB-

The

observation

of

two

sharp

signals

of

equal

intensity

for

the

imidazole

protons

shows

that

all

four

imidazole

groups

are

equivalent

This

is

indicative

of

symmetric

binding

of

both

ligands

to

the

zinc

ion

The

resonances

of

the

methyl

groups

and

the

methine

proton

at

the

bridging

carbon

shift

downfield

relative

to

the

free

ligand

whereas

the

propionate

protons

shift

upfield

Note

that

the

methine

proton

resonance

of

the

free

ligand

is

hidden

under

the

residual

solvent

signal

in

spectrum

a

The

lack

of

any

other

resonances

suggests

the

clean

formation

of

a

neutral

-LSB-

Zn

-LRB-

-RRB-

-RSB-

complex

Upon

addition

of

another

equiv

of

several

resonances

shift

and

signal

broadening

is

observed

-LRB-

spectrum

c

-RRB-

Especially

one

of

the

two

imidazole

signals

is

severely

broadened

Again

no

free

ligand

is

observed

in

the

spectrum

These

observations

indicate

a

dynamic

system

with

an

overall

ligand

zinc

stoichiometry

The

isolation

and

purification

of

the

complex

formed

with

equiv

of

with

respect

to

proved

troublesome

The

separation

of

the

inorganic

salts

formed

as

a

by-product

in

the

synthesis

by

means

of

repetitive

washing

in

all

cases

resulted

in

partial

loss

of

coordinated

ligand

-LRB-

as

observed

by

NMR

-RRB-

regardless

of

the

A

-LSB-

-RSB-

salt

-LRB-

A

is

K

-LSB-

-RSB-

-RRB-

originally

employed

We

therefore

attempted

the

synthesis

of

this

complex

by

the

reaction

of

equiv

of

the

acid

with

Zn

-LSB-

N

-LRB-

-RRB-

-RSB-

Zinc

bis

-LRB-

trimethylsilyl

-RRB-

amide

can

be

synthesized

in

sizeable

quantities

-LSB-

-RSB-

and

was

found

to

be

a

convenient

reagent

in

this

case

Indeed

the

reaction

of

Zn

-LSB-

N

-LRB-

-RRB-

-RSB-

with

equiv

of

in

acetonitrile

resulted

in

the

formation

of

a

white

precipitate

which

was

recrystallized

from

an

acetonitrile

water

solution

and

was

identified

as

the

complex

-LSB-

Zn

-LRB-

-RRB-

-RSB-

Unfortunately

all

attempts

at

obtaining

single

crystals

of

-LSB-

Zn

-LRB-

-RRB-

-RSB-

failed

On

the

basis

of

ESI

MS

IR

and

the

previously

described

NMR

analysis

we

propose

that

-LSB-

Zn

-LRB-

-RRB-

-RSB-

-LRB-

Fig.

-RRB-

is

isostructural

to

the

crystallographically

characterized

analogous

complex

-LSB-

CuII

-LRB-

-RRB-

-RSB-

-LSB-

-RSB-

The

position

of

the

symmetric

and

asymmetric

carbonyl

stretching

vibrations

proved

to

be

indicative

of

the

binding

mode

of

-LRB-

Bruijnincx

et

al.

submitted

-RRB-

-LSB-

-RSB-

The

νas

-LRB-

C

=O

-RRB-

and

νs

-LRB-

C

=O

-RRB-

are

found

at

and

cm

respectively

indicative

of

a

monodentate

binding

mode

of

the

carboxylate

-LSB-

Δ

-LRB-

νas

νs

-RRB-

cm

identical

to

Δionic

-RSB-

-LSB-

-RSB-

Furthermore

the

clean

ESI

MS

spectrum

of

-LSB-

Zn

-LRB-

-RRB-

-RSB-

confirmed

the

structure

of

a

mononuclear

neutral

species

with

-LSB-

M

X

-RSB-

-LRB-

X

is

H

K

-RRB-

as

the

prominent

ions

Fig.

complex

-LSB-

Zn

-LRB-

-RRB-

-RSB-

The

complex

-LSB-

Zn

-LRB-

-RRB-

Cl

-RRB-

-RSB-

was

synthesized

by

the

reaction

of

equimolar

amounts

of

and

K

-LSB-

-RSB-

in

dry

methanol

This

led

to

the

precipitation

and

isolation

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

almost

quantitative

yield

The

broadened

signals

in

the

NMR

spectrum

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RRB-

-RSB-

in

prompted

us

to

study

this

complex

by

variable-temperature

NMR

-LRB-

Fig.

-RRB-

As

complex

-LSB-

Zn

-LRB-

-RRB-

Cl

-RRB-

-RSB-

is

insoluble

in

organic

solvents

the

variable-temperature

NMR

studies

were

limited

to

aqueous

solutions

which

restricted

the

temperature

range

that

could

be

studied

Spectra

were

recorded

in

the

range

from

to

°C

Fig.

NMR

resonances

of

the

imidazole

rings

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

at

various

temperatures

in

Figure

shows

that

at

elevated

temperatures

two

sharp

imidazole

resonances

are

observed

In

the

spectrum

recorded

at

°C

the

-LRB-

small

-RRB-

coupling

between

the

two

imidazole

protons

and

can

also

be

discerned

The

imidazole

signal

at

higher

field

broadens

upon

cooling

and

ultimately

splits

into

two

separate

-LRB-

broad

-RRB-

resonances

This

implies

that

at

higher

temperature

the

imidazole

protons

-LRB-

Fig.

-RRB-

become

magnetically

equivalent

whereas

at

lower

temperature

exchange

slows

down

with

the

result

that

decoalesence

into

two

broad

resonances

occurs

This

behavior

can

be

tentatively

explained

by

the

possibility

of

two

different

spatial

orientations

of

the

imidazole

rings

with

respect

to

the

carboxylate

group

of

a

second

ligand

upon

coordination

to

zinc

-LRB-

vide

infra

-RRB-

which

would

result

in

nonequivalent

imidazole

protons

at

lower

temperature

At

higher

temperatures

these

orientations

average

on

the

NMR

timescale

and

only

one

signal

is

observed

The

asymmetric

and

symmetric

carbonyl

stretch

vibrations

of

isolated

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

were

observed

at

and

cm

-LSB-

Δ

-LRB-

νas

νs

-RRB-

cm

-RSB-

respectively

The

asymmetric

stretch

thus

shifted

to

higher

wavenumbers

compared

with

that

observed

for

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

and

a

different

but

still

monodentate

coordination

mode

of

the

carboxylate

must

therefore

be

present

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

The

ESI

MS

spectrum

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

showed

the

presence

of

several

different

species

with

ions

corresponding

to

e.g.

-LSB-

Zn

-RSB-

-LSB-

-LRB-

-RRB-

Zn

H

-RSB-

-LSB-

-LRB-

-RRB-

Cl

-RSB-

-LSB-

-LRB-

-RRB-

Zn

H

-RSB-

and

-LSB-

-LRB-

-RRB-

-RSB-

On

the

basis

of

the

NMR

IR

and

ESI

MS

data

the

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

can

be

described

as

an

oligomeric/polymeric

species

both

in

the

solid

state

and

in

solution

This

was

confirmed

by

the

single-crystal

structure

determination

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

Crystal

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

Colorless

single

crystals

of

complex

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

suitable

for

X-ray

diffraction

were

obtained

from

a

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

upon

standing

The

molecular

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

is

depicted

in

Fig.

with

selected

bond

lengths

and

angles

presented

in

Table

Fig.

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

in

the

crystal

showing

three

molecules

of

the

carboxylato-bridged

coordination

polymer

forming

a

one-dimensional

chain

in

the

crystallographic

c-direction

C

H

hydrogen

atoms

have

been

omitted

for

clarity

Displacement

ellipsoids

are

drawn

at

the

probability

level

Symmetry

operation

a

x

y

z

bond

lengths

-LRB-

angstroms

-RRB-

and

bond

angles

-LRB-

degrees

-RRB-

for

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

BondBond

lengthAngleBond

angleAngleBond

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Symmetry

operation

a

x

y

z

The

single-crystal

structure

determination

reveals

that

the

structure

of

the

metal

complex

is

that

of

a

coordination

polymer

The

zinc

atom

is

coordinated

by

two

groups

of

one

ligand

while

the

carboxylato

group

of

this

ligand

coordinates

to

a

neighboring

zinc

atom

In

this

way

an

infinite

one-dimensional

chain

parallel

to

the

crystallographic

c-axis

is

formed

The

chlorido

anion

and

a

coordinated

water

molecule

complete

the

coordination

sphere

around

each

zinc

center

and

render

it

five-coordinate

Thus

a

new

bridging

coordination

mode

of

is

observed

in

the

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

comprising

N,N-bidentate

coordination

to

one

metal

center

and

O-monodentate

coorrdination

to

a

second

one

This

coordination

mode

complements

the

alternative

N,N,O-tridentate

facial

capping

mode

of

the

ligand

which

is

commonly

observed

for

divalent

transition

metals

-LSB-

-RSB-

The

coordination

geometry

around

the

five-coordinate

Zn

atom

is

distorted

trigonal

bipyrimidal

-LRB-

τ

-RRB-

-LSB-

-RSB-

The

equatorial

positions

are

occupied

by

and

the

monoanionic

carboxylato

and

chlorido

ligands

with

and

angles

of

-LRB-

-RRB-

-LRB-

-RRB-

and

-LRB-

-RRB-

respectively

-LRB-

Σangles

-RRB-

The

axial

positions

are

occupied

by

of

the

water

molecule

and

imidazole

-LSB-

-LRB-

-RRB-

-RSB-

The

and

bond

lengths

are

different

-LSB-

-LRB-

-RRB-

and

-LRB-

-RRB-

Å

-RSB-

consistent

with

their

respective

axial

and

equatorial

positions

The

distance

of

-LRB-

-RRB-

Å

is

slightly

longer

than

the

Zn

Ocarboxylato

bond

length

observed

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

-LRB-

Å

-RRB-

-LSB-

-RSB-

-LSB-

is

-LRB-

-RRB-

-LRB-

-RRB-

acetate

-RSB-

in

which

a

carboxylato

group

is

similarly

coordinated

to

the

metal

center

The

zinc-aquo

distance

of

-LRB-

-RRB-

Å

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

is

rather

long

compared

with

most

reported

Zn

distances

-LRB-

mean

Zn

distance

for

five-coordinate

zinc

complexes

is

Å

Cambridge

Structural

Database

version

-RRB-

-LSB-

-RSB-

In

the

related

coordination

polymer

-LSB-

Zn

-LRB-

bpatBu

Me

-RRB-

-LRB-

-RRB-

-RSB-

-LRB-

-RRB-

-LSB-

-RSB-

-LSB-

bpatBu

Me

is

bis

-LRB-

-RRB-

acetate

-RSB-

where

the

water

molecule

occupies

a

position

in

the

basal

plane

of

the

trigonal

bipyramid

the

zinc

water

distance

for

example

amounts

to

Å

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

crystallizes

in

the

noncentrosymmetric

space

group

and

the

determination

of

the

Flack

parameter

indicates

that

the

crystal

is

enantiomerically

pure

The

one-dimensional

linear

chains

in

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

are

interconnected

via

hydrogen-bonding

interactions

into

a

two-dimensional

network

-LRB-

Fig.

Table

-RRB-

The

water

molecule

binds

via

its

two

hydrogen

atoms

by

hydrogen

bonding

to

a

carbonyl

O

and

a

chlorido

anion

as

hydrogen

acceptors

of

a

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

molecule

in

a

neighboring

strand

Fig.

network

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

Hydrogen

bonds

connect

the

infinite

one-dimensional

chains

into

a

two-dimensional

network

C

H

hydrogen

atoms

have

been

omitted

for

clarity

Symmetry

operations

i

x

y

z

ii

x

y

zTable

hydrogen

bond

lengths

-LRB-

angstroms

-RRB-

and

angles

-LRB-

degrees

-RRB-

for

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

Donor

H

acceptorD

HH

AD

AD

H

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Symmetry

operations

i

x

y

z

ii

x

y

z

Zinc

complexes

of

In

order

to

assess

the

influence

of

the

presence

of

steric

bulk

in

the

ligand

framework

we

also

studied

the

zinc

coordination

chemistry

of

ligand

The

ethyl

and

isopropyl

substituents

of

this

ligand

provide

significant

steric

hindrance

and

moreover

increase

the

solubility

of

its

complexes

in

organic

solvents

The

complex

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

was

synthesized

by

the

reaction

of

equimolar

amounts

of

and

K

-LSB-

-RSB-

in

methanol

The

complex

was

isolated

in

almost

quantitative

yield

The

IR

spectrum

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

showed

the

asymmetric

and

symmetric

carbonyl

stretch

vibrations

at

and

cm

-LSB-

Δ

-LRB-

νas

νs

-RRB-

cm

-RSB-

respectively

The

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

was

determined

by

X-ray

crystal

structure

determination

Crystal

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

Colorless

single

crystals

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

suitable

for

X-ray

diffraction

were

obtained

from

a

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

methanol

The

molecular

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

is

depicted

in

Fig.

with

selected

bond

lengths

and

angles

presented

in

Table

The

crystal

structure

shows

that

whereas

like

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

also

crystallizes

as

a

coordination

polymer

the

molecular

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

is

noticeably

different

Unlike

in

the

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

no

water

molecule

is

found

to

coordinate

to

zinc

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

Instead

of

the

five-coordinate

structure

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

the

zinc

atom

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

is

four-coordinate

It

has

a

pseudotetrahedral

coordination

geometry

with

two

imidazole

groups

of

one

ligand

a

chlorido

and

a

carboxylato

group

of

a

neighboring

ligand

coordinated

to

it

The

bridging

mode

of

observed

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

is

the

same

as

found

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

The

deviation

from

ideal

tetrahedral

geometry

is

reflected

in

the

observed

bond

angles

-LSB-

-LRB-

-RRB-

-LRB-

-RRB-

-RSB-

The

smallest

angle

-LRB-

-RRB-

is

caused

by

the

inherent

geometrical

restrictions

imposed

by

the

ligand

and

the

largest

angle

-LRB-

-RRB-

probably

reflects

the

steric

influence

of

the

isopropyl

groups

The

Zn

N

Zn

O

and

Zn

Cl

bond

lengths

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

are

shorter

than

the

corresponding

distances

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

which

reflects

the

stronger

Lewis

acidity

of

zinc

-LRB-

II

-RRB-

in

a

four-coordinate

versus

a

five-coordinate

geometry

The

bond

length

of

-LRB-

-RRB-

Å

is

comparable

to

values

reported

for

other

tetrahedral

N

N

O

zinc

complexes

with

a

monodentate

carboxylate

-LSB-

-RSB-

The

different

coordination

geometry

at

zinc

results

in

a

more

folded

zigzag

polymer

chain

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

compared

with

the

more

stretched

zigzag

chain

observed

for

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

Fig.

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

the

crystal

showing

three

molecules

of

the

carboxylato-bridged

coordination

polymer

C

H

hydrogen

atoms

have

been

omitted

for

clarity

Displacement

ellipsoids

are

drawn

at

the

probability

level

Symmetry

operation

a

x

y

z

bond

lengths

-LRB-

angstroms

-RRB-

and

bond

angles

-LRB-

degrees

-RRB-

for

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

BondBond

lengthAngleBond

angleAngleBond

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Symmetry

operation

a

x

y

z

The

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

and

more

generally

the

coordination

chemistry

of

with

Zn

in

methanol

solution

were

studied

by

NMR

spectroscopy

and

ESI

MS.

The

NMR

spectra

of

a

titration

experiment

comprising

the

addition

of

to

the

potassium

salt

of

in

methanol

solution

are

shown

in

Fig.

Fig.

MHz

NMR

spectra

of

the

titration

of

K

-LSB-

-RSB-

with

in

at

room

temperature

a

K

-LSB-

-RSB-

and

b

K

-LSB-

-RSB-

and

c

K

-LSB-

-RSB-

and

d

K

-LSB-

-RSB-

and

Asterisks

denote

the

residual

solvent

peak

and

Comparison

of

the

NMR

spectra

of

K

-LSB-

-RSB-

-LRB-

Fig.

spectrum

a

-RRB-

with

that

of

an

equimolar

K

-LSB-

-RSB-

mixture

shows

significant

shifts

pointing

to

the

formation

of

a

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

complex

-LRB-

spectrum

b

-RRB-

In

the

NMR

spectrum

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

one

sharp

resonance

is

observed

for

the

imidazole

protons

at

ppm

which

is

shifted

to

lower

field

compared

with

that

of

the

free

ligand

The

two

imidazole

rings

are

equivalent

on

the

NMR

timescale

suggesting

that

they

are

symmetrically

bound

to

zinc

Importantly

the

resonance

of

the

ethyl

groups

is

shifted

and

split

into

two

signals

of

equal

intensity

-LRB-

and

ppm

-RRB-

Similarly

the

methyl

groups

of

the

isopropyl

substituent

now

appear

as

two

doublets

of

equal

intensity

These

splittings

confirm

that

the

-LRB-

Et

-RRB-

and

-LRB-

iPr

-RRB-

groupings

contain

diastereotopic

protons

and

methyl

groups

respectively

No

splitting

or

change

in

multiplicity

of

the

resonances

associated

with

the

propionate

backbone

is

observed

which

is

indicative

of

mirror

symmetry

of

the

complex

in

solution

Although

at

first

sight

the

NMR

data

would

allow

an

assignment

of

the

solution

structure

for

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

as

a

mononuclear

zinc

complex

with

a

facially

capped

ligand

a

bridged

oligomeric

species

-LRB-

similar

as

the

one

discussed

before

for

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

-RRB-

is

preferred

ESI

MS

data

support

the

latter

description

since

trimeric

dimeric

and

monomeric

species

are

observed

Prominent

ions

corresponding

to

-LSB-

Zn

-LRB-

-RRB-

Cl

H

-RSB-

-LSB-

-LRB-

-RRB-

H

-RSB-

and

-LSB-

-LRB-

-RRB-

H

-RSB-

are

for

instance

observed

The

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

solution

can

therefore

best

be

described

as

a

coordination

polymer

similar

to

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

Upon

addition

of

equiv

of

K

-LSB-

-RSB-

to

in

-LRB-

Fig.

spectrum

c

-RRB-

a

second

species

is

formed

next

to

the

complex

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

The

fact

that

two

species

are

observed

indicates

that

an

equilibrium

is

obtained

i.e.

the

clean

formation

of

a

symmetrical

to

zinc

complex

as

previously

observed

for

does

not

occur

Further

inspection

of

the

NMR

spectrum

indicated

that

all

resonances

of

the

groups

of

the

new

species

are

split

into

two

signals

of

equal

intensity

e.g.

the

imidazole

ring

protons

at

and

ppm

This

suggests

that

the

two

imidazole

groups

are

inequivalent

and

experience

a

drastically

different

magnetic

environment

For

instance

the

two

resonances

of

the

CH

protons

of

the

two

isopropyl

groups

are

found

at

and

ppm

Furthermore

the

methine

proton

at

the

bridging

carbon

is

still

a

single

triplet

whereas

the

group

of

the

propionate

backbone

has

become

diastereotopic

Variable-temperature

NMR

studies

over

a

temperature

range

from

to

°C

did

not

show

significant

spectral

changes

The

ESI

MS

spectrum

of

a

K

-LSB-

-RSB-

solution

showed

prominent

ions

corresponding

to

the

-LSB-

Zn

-LRB-

-RRB-

H

-RSB-

and

-LSB-

Zn

-LRB-

-RRB-

-RSB-

cations

On

the

basis

of

these

data

the

structure

of

the

new

species

is

proposed

to

be

a

ligand-to-zinc

complex

-LSB-

Zn

-LRB-

-RRB-

-RSB-

in

which

each

ligand

is

coordinated

via

its

carboxylate

group

and

one

imidazole

group

resulting

in

a

four-coordinated

zinc

-LRB-

II

-RRB-

ion

-LRB-

Fig.

-RRB-

The

coordination

of

two

of

the

three

donor

atoms

in

a

ligand-to-metal

complex

has

also

been

observed

with

bulky

N

N

S

-LRB-

thiolate

-RRB-

ligands

in

the

complexes

-LSB-

Zn

-LRB-

-RRB-

-RSB-

-LSB-

is

-LRB-

-RRB-

bis

-LRB-

pyrazolyl

-RRB-

methane

-RSB-

and

-LSB-

Zn

-LRB-

-RRB-

-RSB-

-LSB-

is

-LRB-

-RRB-

-RSB-

-LSB-

-RSB-

The

addition

of

a

third

equivalent

of

K

-LSB-

-RSB-

-LRB-

spectrum

d

-RRB-

results

in

the

disappearance

of

the

signals

associated

with

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

and

both

free

ligand

K

-LSB-

-RSB-

and

-LSB-

Zn

-LRB-

-RRB-

-RSB-

are

detected

No

attempts

to

isolate

-LSB-

Zn

-LRB-

-RRB-

-RSB-

were

undertaken

Fig.

structure

for

-LSB-

Zn

-LRB-

-RRB-

-RSB-

The

structure

was

calculated

by

molecular

mechanics

geometry

optimization

-LRB-

Spartan

SGI

-LSB-

-RSB-

-RRB-

Attempted

synthesis

of

a

zinc

bis

-LRB-

-RRB-

acetate

complex

Recently

the

zinc

coordination

chemistry

of

bis

-LRB-

pyrazolyl

-RRB-

acetates

-LRB-

bpa

-RRB-

has

been

actively

explored

to

mimic

the

facial

triad

found

in

several

different

zinc

enzymes

-LSB-

-RSB-

The

backbone

of

bpa

is

more

rigid

than

the

backbone

of

the

ligands

and

used

in

the

present

study

In

particular

the

bridging

N,N-bidentate-O-monodentate

coordination

mode

reported

here

is

less

favorable

for

bpa

for

which

a

strong

predisposition

to

an

N

N

O

facial

capping

mode

is

expected

The

synthesis

of

zinc

complexes

of

would

therefore

be

desirable

since

it

would

allow

a

direct

comparison

of

the

respective

pyrazole

and

imidazole

donor

groups

-LRB-

Fig.

-RRB-

Fig.

benzyl

bis

-LRB-

-RRB-

acetate

-LRB-

-RRB-

and

bis

-LRB-

pyrazolyl

-RRB-

acetate

-LRB-

bpa

-RRB-

and

the

synthesis

of

complexes

-LSB-

-LRB-

-RRB-

-RSB-

and

-LSB-

-LRB-

-RRB-

-RSB-

We

attempted

the

synthesis

of

ligand

but

found

that

the

common

synthetic

procedure

i.e.

lithiation

of

followed

by

reaction

with

carbon

dioxide

-LSB-

-RSB-

did

not

result

in

product

formation

in

acceptable

yields

Instead

it

was

found

that

the

ligand

or

an

ester

precursor

of

the

ligand

decarboxylates

rather

easily

as

was

also

observed

by

Peters

et

al.

-LSB-

-RSB-

The

benzyl

ester

of

bis

-LRB-

-RRB-

acetic

acid

-LRB-

-RRB-

however

was

sufficiently

stable

and

could

be

isolated

and

purified

after

reaction

of

lithio

bis

-LRB-

-RRB-

methane

with

benzylchloroformate

Since

hydrolysis

and

hydrogenolysis

of

the

ester

moiety

resulted

in

decomposition

of

the

ligand

the

zinc

dichloride

complex

with

was

synthesized

in

the

hope

that

autocatalytic

ester

hydrolysis

by

the

zinc

complex

would

yield

the

desired

zinc

bis

-LRB-

-RRB-

acetate

complex

A

similar

approach

involving

the

autocatalytic

saponification

of

a

zinc

bis

-LRB-

picolyl

-RRB-

glycine

ethyl

ester

complex

has

been

reported

by

Abufarag

and

Vahrenkamp

-LSB-

-RSB-

The

reaction

of

equimolar

amounts

of

and

gave

the

complex

-LSB-

-LRB-

-RRB-

-RSB-

as

a

white

powder

in

quantitative

yield

The

structure

of

-LSB-

-LRB-

-RRB-

-RSB-

was

determined

by

X-ray

diffraction

studies

and

showed

the

ligand

bound

to

the

zinc

center

in

an

N,N-bidentate

way

-LRB-

Fig.

top

-RRB-

However

stirring

of

-LSB-

-LRB-

-RRB-

-RSB-

in

at

room

temperature

in

an

attempt

to

obtain

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

resulted

in

decomposition

of

the

ligand

and

formation

of

-LSB-

-LRB-

-RRB-

-RSB-

which

was

isolated

as

one

of

the

decomposition

products

-LSB-

-LRB-

-RRB-

-RSB-

was

also

characterized

crystallographically

-LRB-

Fig.

bottom

-RRB-

On

the

basis

of

these

findings

it

was

concluded

that

the

monoanion

is

too

unstable

for

practical

studies

and

the

pursuit

of

this

ligand

was

abandoned

Fig.

structures

of

-LSB-

-LRB-

-RRB-

-RSB-

-LRB-

top

-RRB-

and

-LSB-

-LRB-

-RRB-

-RSB-

-LRB-

bottom

-RRB-

in

the

crystal

Displacement

ellipsoids

are

drawn

at

the

probability

level

All

hydrogen

atoms

have

been

omitted

for

clarity

Selected

bond

lengths

-LRB-

angstroms

-RRB-

as

follows

-LSB-

-LRB-

-RRB-

-RSB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LSB-

-LRB-

-RRB-

-RSB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Reaction

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

with

sodium

pyruvate

oxalate

formation

In

an

attempt

to

prevent

the

formation

of

coordination

polymers

of

and

to

obtain

mononuclear

complexes

with

the

desired

N

N

O

facial

capping

mode

of

the

ligand

several

different

monoanionic

bidendate

coligands

were

used

In

the

course

of

this

study

we

also

investigated

the

reaction

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

with

sodium

pyruvate

The

addition

of

equiv

of

sodium

pyruvate

to

a

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

resulted

in

the

appearance

of

a

new

singlet

at

ppm

in

the

NMR

spectrum

-LRB-

Fig.

top

spectrum

-RRB-

The

signal

is

not

shifted

with

respect

to

the

signal

observed

for

free

sodium

pyruvate

which

indicates

that

the

interaction

between

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

and

the

pyruvate

anion

is

weak

at

best

The

ESI

MS

spectrum

of

an

aqueous

solution

of

equimolar

amounts

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

and

sodium

pyruvate

however

did

show

some

major

ions

corresponding

to

a

mononuclear

-LCB-

-LSB-

Zn

-LRB-

-RRB-

-LRB-

pyruvate

-RRB-

-RSB-

-RCB-

and

a

dinuclear

-LCB-

-LSB-

-LRB-

-RRB-

-LRB-

pyruvate

-RRB-

-RSB-

-RCB-

cation

in

addition

to

the

ions

observed

in

the

ESI

MS

spectrum

of

a

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

water

Fig.

NMR

spectra

of

a

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

-LRB-

asterisk

-RRB-

after

addition

of

equiv

of

sodium

pyruvate

and

the

same

solution

after

h

However

when

the

mixture

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

and

pyruvate

in

was

followed

in

time

by

NMR

spectroscopy

the

gradual

decrease

in

intensity

of

the

signal

of

the

pyruvate

methyl

group

was

noticed

until

it

ultimately

disappeared

-LRB-

Fig.

bottom

spectrum

-RRB-

After

several

days

colorless

crystals

suitable

for

X-ray

diffraction

studies

were

formed

in

the

NMR

tube

To

our

surprise

the

X-ray

crystal

structure

showed

the

structure

of

the

zinc

complex

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

has

the

structure

of

a

coordination

polymer

involving

-LSB-

Zn

-LRB-

-RRB-

-RSB-

cations

bridged

by

oxalato

dianions

To

unequivocally

prove

the

relevance

of

the

structure

obtained

zinc

coordination

polymer

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

was

also

synthesized

independently

Indeed

the

addition

of

equiv

of

to

an

aqueous

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

yielded

a

white

insoluble

powder

This

powder

was

identified

as

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

by

elemental

analysis

and

IR

spectroscopy

Typical

features

of

the

IR

spectrum

of

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

include

absorptions

at

and

cm

which

can

be

attributed

to

the

oxalato

and

carboxylato

groups

in

the

polymer

Crystallization

of

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

proved

difficult

given

its

general

insolubility

Single

crystals

could

however

be

obtained

via

the

gel

crystallization

method

-LSB-

-RSB-

A

gel

formed

from

a

solution

of

tetramethoxysilane

and

potassium

oxalate

hydrate

in

water

was

layered

with

an

aqueous

solution

of

K

-LSB-

-RSB-

and

Single

crystals

were

obtained

after

several

days

and

could

be

unequivocally

identified

as

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

by

X-ray

crystal

structure

determination

Crystal

structure

of

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

The

molecular

structure

of

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

is

shown

in

Fig.

with

selected

bond

lengths

and

angles

presented

in

Table

The

polymeric

structure

of

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

comprises

two

crystallographically

inequivalent

zinc

atoms

Both

zinc

centers

are

five-coordinate

and

differ

only

in

the

slightly

different

bond

lengths

and

angles

Each

zinc

atom

is

coordinated

in

an

N,N-bidentate

fashion

by

the

groups

of

one

ligand

two

oxygen

atoms

of

a

bis

O,O-bidentate

bridging

oxalato

group

and

a

carboxylato

O

donor

atom

of

a

neighboring

ligand

The

combination

of

the

bridging

oxalato

and

ligands

constructs

a

polymeric

structure

leading

to

the

formation

of

two-dimensional

sheets

Fig.

structure

of

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

in

the

crystal

C

H

hydrogen

atoms

and

all

solvent

water

molecules

have

been

omitted

for

clarity

Displacement

ellipsoids

are

drawn

at

the

probability

levelTable

bond

lengths

-LRB-

angstroms

-RRB-

and

angles

-LRB-

degrees

-RRB-

for

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

lengthAngleBond

angleAngleBond

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Symmetry

operations

b

x

y

z

c

x

y

z

d

x

y

z

The

coordination

geometry

around

each

zinc

center

is

best

described

as

a

severely

distorted

trigonal

bipyramid

with

τ

values

of

and

for

and

respectively

-LSB-

-RSB-

The

equatorial

positions

are

occupied

by

and

the

anionic

carboxylato

and

oxalato

ligands

for

respectively

The

axial

positions

are

occupied

by

of

the

oxalato

group

and

imidazole

for

-LSB-

O

Zn

N

angles

of

-LRB-

-RRB-

-LRB-

-RRB-

-RSB-

The

planar

oxalato

moieties

are

rather

asymmetrically

bound

to

the

metal

centers

with

the

and

distances

amounting

to

-LRB-

-RRB-

and

-LRB-

-RRB-

Å

for

instance

This

asymmetry

has

also

been

observed

in

other

bisbidentate

bridged

zinc

oxalato

complexes

with

five-coordinated

metal

centers

and

is

consistent

with

the

occupation

of

one

equatorial

and

one

axial

site

of

the

trigonal

bipyramid

-LSB-

-RSB-

The

shortest

Zn

Zn

distances

via

the

bridging

oxalato

group

are

-LRB-

-RRB-

Å

for

and

-LRB-

-RRB-

Å

for

The

distances

of

the

metal

centers

to

the

donor

atoms

of

follow

the

same

trend

as

observed

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

The

crystal

structure

of

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

is

further

stabilized

by

different

hydrogen-bonding

interactions

which

involve

the

cocrystallized

water

molecules

the

oxalato

bridges

and

the

carboxylato

groups

-LRB-

Fig.

-RRB-

The

oxalato

groups

are

for

instance

involved

in

two

chelated

three-centered

hydrogen

bonds

with

two

water

molecules

via

four

O

H

O

hydrogen

bonds

Fig.

bonding

network

and

crystal

packing

of

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

Discussion

The

aim

of

this

investigation

was

to

explore

the

biomimetic

modeling

potential

of

the

ligand

family

with

respect

to

mononuclear

zinc

enzymes

featuring

the

facial

triad

Complex

-LSB-

Zn

-LRB-

MImPr

-RRB-

-RSB-

shows

that

the

facial

capping

mode

of

as

earlier

observed

with

copper

-LSB-

-RSB-

and

iron

-LRB-

Bruijnincx

et

al.

submitted

-RRB-

-LSB-

-RSB-

is

also

accessible

for

zinc

The

crystal

structure

of

the

complex

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

however

shows

that

can

also

adopt

other

coordination

modes

The

formation

of

the

oligomeric/polymeric

structure

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

both

in

solution

and

in

the

solid

state

can

be

attributed

to

the

flexibility

of

the

ligand

due

to

the

spacer

of

the

propionate

backbone

The

formation

of

polymeric

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

is

further

aided

by

the

insolubility

of

the

resulting

coordination

polymer

Two

strategies

were

explored

to

circumvent

polymer

formation

i.e.

increasing

the

steric

bulk

of

the

ligand

and

elimination

of

the

spacer

The

latter

approach

demanded

the

synthesis

of

the

bis

-LRB-

-RRB-

acetate

analogue

of

which

was

found

to

be

rather

unstable

and

its

zinc

complexes

could

not

be

obtained

The

effect

of

more

steric

bulk

was

studied

with

which

contains

the

sterically

more

demanding

isopropyl

and

ethyl

substituents

Zinc

complexes

of

are

polymeric

in

nature

as

well

albeit

with

a

different

coordination

geometry

at

the

zinc

atom

as

observed

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

The

first

coordination

spheres

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

and

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

are

compared

in

Fig.

The

added

steric

bulk

in

causes

the

zinc

ion

to

adopt

a

pseudotetrahedral

geometry

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

instead

of

the

distorted

trigonal

bipyramid

observed

for

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

The

coordination

around

zinc

in

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

resembles

the

first

coordination

sphere

of

the

active

sites

of

the

zinc

enzymes

thermolysin

carboxypeptidase

A

and

neutral

protease

The

polymeric

rather

than

monomeric

nature

of

the

complex

however

clearly

limits

its

potential

as

a

biological

mimic

Fig.

of

the

first

coordination

spheres

of

the

zinc

atoms

in

the

coordination

polymers

-LSB-

Zn

-LRB-

-RRB-

Cl

-LRB-

-RRB-

-RSB-

-LRB-

top

-RRB-

and

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

-LRB-

bottom

-RRB-

The

isolation

of

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

from

the

reaction

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

with

sodium

pyruvate

was

rather

unexpected

and

is

to

the

best

of

our

knowledge

the

first

report

of

the

nonoxidative

formation

of

oxalate

from

pyruvate

-LRB-

Scheme

-RRB-

Interestingly

Takeste

and

Vahrenkamp

-LSB-

-RSB-

very

recently

reported

a

trispyrazolylborato

zinc

complex

with

pyruvate

representing

the

first

structurally

characterized

zinc

complex

of

an

α-keto

acid

Although

in

their

case

the

zinc

pyruvate

complex

obtained

was

stable

unexpected

cleavage

reactions

with

other

α-keto

acids

such

as

benzoylformic

acid

and

α-diketones

were

observed.Scheme

observed

transformation

of

pyruvate

to

oxalate

mediated

by

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

A

control

experiment

showed

that

an

aqueous

sodium

pyruvate

solution

is

stable

under

the

reaction

conditions

Apparently

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

mediates

the

conversion

of

pyruvate

to

oxalate

The

product

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

invariably

deposited

as

crystals

in

experiments

done

on

the

NMR

scale

On

a

preparative

scale

-LRB-

mmol

-RRB-

the

reaction

also

takes

place

yet

the

product

was

isolated

as

an

insoluble

white

powder

The

IR

spectrum

of

this

powder

was

identical

to

that

obtained

for

independently

synthesized

-LSB-

-LRB-

-RRB-

-LRB-

ox

-RRB-

-RSB-

Most

importantly

further

experiments

revealed

that

the

reaction

is

catalytic

in

zinc

For

example

addition

of

equiv

of

sodium

pyruvate

to

a

solution

of

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

in

water

under

ambient

conditions

resulted

in

ten

turnovers

after

h

The

disappearance

of

the

pyruvate

methyl

signal

was

also

observed

in

a

solution

containing

and

sodium

pyruvate

without

any

further

additives

Concomitantly

a

precipitate

was

observed

in

the

NMR

tube

However

the

composition

of

this

precipitate

i.e.

the

formation

of

oxalate

could

not

be

unambiguously

established

Since

it

is

known

that

pyruvate

keto

enol

tautomerization

is

catalyzed

by

divalent

metal

ions

such

as

Zn

-LRB-

II

-RRB-

-LSB-

-RSB-

the

disappearance

of

the

methyl

signal

could

in

principle

also

be

attributed

to

consecutive

H/D-exchange

steps

This

would

yield

the

deuterated

anion

which

is

also

invisible

in

NMR

spectroscopy

To

be

able

to

exclude

this

possibility

experiments

were

performed

in

and

samples

were

diluted

with

equiv

of

just

before

the

measurement

The

same

observations

were

made

as

previously

i.e.

gradual

disappearance

of

the

methyl

signal

and

slow

crystallization

of

the

product

in

the

NMR

tube

The

presence

of

appreciable

amounts

of

enolate

should

also

lead

to

the

detection

of

the

dimerization

product

of

pyruvate

-LSB-

-RSB-

This

pyruvate

dimer

which

results

from

an

aldol

condensation

reaction

and

has

characteristic

signals

at

-LRB-

singlet

-RRB-

and

-LRB-

AB

pattern

-RRB-

ppm

-LSB-

-RSB-

was

not

observed

under

these

conditions

Phenyl

pyruvic

acid

-LRB-

and

other

α-ketoacids

-RRB-

is

oxidized

by

molecular

oxygen

to

give

benzaldehyde

and

oxalate

or

the

carbon

oxides

-LRB-

CO

and/or

-RRB-

-LSB-

-RSB-

This

reaction

is

catalyzed

by

several

metal

ions

such

as

Mn

-LRB-

II

-RRB-

Fe

-LRB-

II

-RRB-

and

Cu

-LRB-

II

-RRB-

but

not

by

Zn

-LRB-

II

-RRB-

-LSB-

-RSB-

and

has

been

attributed

to

the

presence

of

the

enol

tautomer

which

is

capable

of

reacting

with

dioxygen

-LSB-

-RSB-

In

the

absence

of

dioxygen

i.e.

under

an

Ar

atmosphere

pyruvate

does

react

with

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

to

form

oxalate

The

anaerobic

reactivity

can

not

be

attributed

to

any

residual

dioxygen

traces

since

phenyl

pyruvate

-LRB-

a

substrate

more

prone

to

the

reaction

with

dioxygen

-RRB-

did

not

show

any

reactivity

under

these

conditions

The

observed

conversion

of

pyruvate

to

oxalate

under

anaerobic

conditions

clearly

places

it

outside

previously

observed

formation

of

oxalate

from

oxidative

transformations

of

α-keto

acids

-LSB-

-RSB-

The

observation

is

important

since

pyruvate

is

a

major

metabolic

junction

and

it

is

therefore

of

prime

importance

to

understand

its

reactivity

At

present

no

biological

counterpart

has

been

reported

for

the

pyruvate

oxalate

conversion

catalyzed

by

-LSB-

Zn

-LRB-

-RRB-

Cl

-RSB-

The

chemical

transformation

as

reported

here

however

takes

place

at

room

temperature

and

physiological

pH

and

should

therefore

be

considered

as

a

possible

alternative

pathway

in

the

reactivity

of

pyruvate

The

mechanism

of

this

conversion

is

currently

not

clear

No

other

products

could

be

detected

by

NMR

during

the

reaction

which

precludes

the

formulation

of

a

mass

balance

for

the

reaction

and

clearly

hampers

a

mechanistic

interpretation

In

any

case

the

pyruvate

to

oxalate

conversion

requires

the

scission

of

a

C

C

bond

On

the

other

hand

the

reactivity

of

zinc

enzymes

and

their

model

complexes

is

often

of

hydrolytic

nature

This

can

be

attributed

to

the

generation

of

a

nucleophilic

hydroxide

species

and/or

the

activation

of

a

coordinated

substrate

towards

attack

of

such

a

nucleophile

-LSB-

-RSB-

The

formation

of

oxalate

from

pyruvate

via

a

hydrolytic

mechanism

is

however

difficult

to

envision

Further

investigations

have

to

be

performed

to

address

the

mechanistic

questions

concerning

this

transformation

Conclusions

The

difference

in

applied

steric

bulk

by

the

ligands

and

is

reflected

in

the

coordination

chemistry

of

the

two

ligands

towards

Octahedral

-LRB-

-RRB-

versus

tetrahedral

-LRB-

-RRB-

and

trigonal

pyramidal

-LRB-

-RRB-

versus

tetrahedral

-LRB-

-RRB-

coordination

geometries

were

obtained

in

the

and

ligand-to-metal

complexes

respectively

The

bridging

binding

mode

of

the

two

crystallographically

characterized

coordination

polymers

illustrates

the

intrinsic

flexibility

of

the

-LRB-

-RRB-

propionate

ligand

framework

The

polymeric

nature

of

the

complexes

could

limit

their

biological

relevance

with

respect

to

the

facial

triad

in

the

case

of

zinc

On

the

other

hand

attempts

aimed

at

obtaining

structurally

more

faithful

mononuclear

complexes

led

to

the

observation

of

the

unprecedented

Zn-mediated

pyruvate

to

oxalate

conversion

This

new

nonoxidative

transformation

of

an

important

metabolic

junction

is

intriguing

and

warrants

further

investigation


Brief Report : Adults with Mild Autism Spectrum Disorders -LRB- ASD -RRB- : Scores on the Autism Spectrum Quotient -LRB- AQ -RRB- and Comorbid Psychopathology While knowledge about symptom presentation of adults with mild ASD , including comorbid psychopathology , is limited , referral of adults with suspected mild PDD is increasing . We report on pilot research investigating whether patients diagnosed with mild ASD -LRB- n = 15 -RRB- and patients who were not diagnosed with ASD -LRB- n = 21 -RRB- differed in terms of -LRB- a -RRB- AQ scores and -LRB- b -RRB- Axis I and II disorders , assessed by the SCAN and the IPDE . Additionally , AQ scores were compared with those from non-ASD patients referred to a general outpatient clinic -LRB- n = 369 -RRB- . The results showed very few differences between ASD patients and non-ASD patients . Self-report may not differentiate mild ASD patients from non-ASD patients and Axis I and II disorders seem equally prevalent among these two groups . Introduction Although there is consensus -LRB- APA , 1994 -RRB- about DSM IV criteria for children and adolescents with Autistic Disorder and Asperger 's disorder , the largest category , PDDNOS , remains difficult to classify . The latter is even more true for adult patients since the DSM-IV criteria are not formulated with adult age in mind -LRB- Gillberg , 1998 ; Tamtam , 1991 ; Vermeulen , 2002 -RRB- . The Autism Diagnostic Interview -- Revised -LRB- ADI-R , Lord , Rutter , & Le Couteur , 1994 -RRB- and the Autism Diagnostic Observation Schedule-Generic -LRB- ADOS-G ; Lord et al. , 2000 -RRB- are validated only for children and adolescents . Follow-up studies of adolescents and adults with autism indicate that a slow decrease in symptoms across time occurs in a small group , particularly the less severely affected patients -LRB- Seltzer , Shattuck , Abedutto , & Greenberg , 2004 -RRB- . However , there is a lack of knowledge about adults with mild ASD , i.e. , Asperger 's Disorder and PDDNOS . In light of this limited knowledge on symptom presentation in adults , the present paper reports on a pilot research-project that was done with two aims : -LRB- a -RRB- to test the Autism Spectrum Quotient -LRB- AQ ; Baron-Cohen , Wheelwright , Skinner , Martin , & Clubley , 2001 -RRB- as an instrument for screening adult non-mentally retarded patients for ASD . We hypothesised that scores would be higher for an ASD group than for two non-ASD comparison groups ; -LRB- b -RRB- there is `` a clinical feeling '' that mild ASD symptoms often mix with other disorders -LRB- e.g. , Obsessive Compulsive Disorder or Schizoid Personality Disorder -RRB- . Therefore , in patients referred to an ASD expertise-centre , prevalences of Axis I and II comorbid disorders were estimated to test the hypothesis that certain diagnoses are more prevalent among ASD patients than non-ASD patients . Method Participants Two groups of patients were investigated ; the first group -LRB- n = 36 -RRB- consisted of patients referred to the `` Autism Team North Netherlands '' -LRB- ATN -RRB- . The ATN is the ASD outpatient center of expertise for the three Northern provinces of the Netherlands -LRB- 1.5 million inhabitants -RRB- . On a yearly basis , about 80 new adult patients are referred for diagnostic evaluation and -LRB- advice for -RRB- treatment . Since the ATN is a `` third line '' center of expertise , all patients were referred by psychiatrists and psychologists , working in the field of adult -LRB- but not forensic -RRB- psychiatry . Only patients with parents who were able to give the required information were included in the present study . They were 18 years or older , with an estimated IQ higher than 80 . Over a span of 10 months from February 2003 through October 2003 , 60 eligible patients were asked to participate , of which 35 patients and their parents consented . The patients were randomly assigned to two experienced -LRB- child -RRB- psychiatrists -LRB- CK or EH -RRB- for diagnostic assessment . The second group -LRB- n = 369 -RRB- consisted of patients from the same region , who were referred in this same period to the general outpatient psychiatric clinic of the University Medical Centre Groningen . This group from the general outpatient clinic -LRB- GOC -RRB- enabled us to compare the scores on the AQ screening instrument . Instruments The clinical standardized diagnostic protocol that was used in the intake of ATN-referred patients consisted of a semi-structured interview -LRB- taken from at least one of the parents -RRB- , and observations from the ADI-R , ADOS-G , as well as clinical experience . Actual ASD symptoms were translated in the interview as much as possible to the adult-world situation . Questions about the past were used to reconstruct the developmental history of the patient as adequately as possible . The information derived from the diagnostic protocol was subsequently used to score the DSM-IV criteria on ASD . Intelligence was assessed by using a short version of the `` Groninger Intelligentie Test '' -LRB- GIT , Luteijn , 1966 -RRB- . For classification of PDDNOS , the minimal amount of positive DSM-IV criteria was two , of which at least one derived from the social interaction domain . For Asperger 's Disorder at least two items on the social domain and at least one item on the stereotypic domain needed to be present with no early delay of language . For High Functioning Autism at least six items were needed to be present , with at least two items on the social domain and at least one positive item on each of the other two domains , with onset of abnormal functioning before the age of three years . The reliability of the diagnostic protocol was tested by assessing a series of seven patients simultaneously by two experienced -LRB- child -RRB- psychiatrists -LRB- CK and EH -RRB- . These independent classifications differed only on one patient -LRB- PDDNOS versus non-ASD -RRB- . The seven patients were not included in the present study , which started after having determined diagnostic reliability . The AQ was translated in Dutch and was named AQ-D -LRB- Dutch -RRB- . This self-report screening questionnaire has 50 items , which score on 5 domains of behavior : social skill , attention switching , attention to detail , communication , and imagination . Each domain has a maximum score of 10 -LRB- for details on this instrument , see Baron-Cohen et al. , 2001 -RRB- The AQ-D was completed by the patient before the clinical procedure started . The investigators were blind to the outcome of AQ-D scores . Internal consistency reliability estimates -LRB- Cronbach 's α -RRB- for AQ subscales were acceptable for the ASD-group but somewhat on the lower side for the non-ASD groups . Averaged across the five subscales Cronbach 's α was .67 for the ASD group , .62 for the non-ASD group referred to the ATN , and .59 for the GOC group . For the total scale internal consistency reliability was acceptable in all three groups : i.e. , .85 , .82 , and .79 , respectively . Present and life-time comorbidity were assessed by using the Schedules for Clinical Assessment in Neuropsychiatry -LRB- SCAN-2.1 , Giel & Nienhuis , 1996 ; World Health Organisation , 1992 -RRB- and the International Personality Disorder Examination -LRB- IPDE , Loranger et al. , 1994 -RRB- . IQ , SCAN and IPDE assessments were done by a psychologist -LRB- JB -RRB- who was blind to the outcome of the ASD psychiatric diagnosis . JB was formally trained by the Groningen WHO Training Center for administering the SCAN . Statistical Analysis Chi-square tests and analyses of variance were conducted to analyze possible differences between the groups . Results Fifteen of the 36 patients were diagnosed with ASD . In this ASD-group , 10 patients classified as PDDNOS , 4 patients as Asperger 's Disorder and 1 patient as High Functioning Autism . The number of positive DSM-IV items ranged from 2 to 8 , with an average score of 3.8 . Table 1 shows gender , age , and IQ of ASD and non-ASD patients . Also included in this table are gender and age of the GOC patients . The significant differences between the groups were -LRB- a -RRB- the younger age of the ASD patients relative to the other patients groups ; -LRB- b -RRB- the younger age of the non-ASD group referred to the ATN relative to the GOC patients ; and -LRB- c -RRB- the predominance of males in the ATN-referred patients compared with the GOC patients . Table 1Characteristics of participantsDiagnosisASD -LRB- n = 15 -RRB- No ASD -LRB- n = 21 -RRB- General outpatient clinic -LRB- n = 369 -RRB- Male/femaleam = 12 , f = 3m = 18 , f = 3m = 180 , f = 189 Average ageb -LRB- range , sd -RRB- 22 years -LRB- 18 -- 24 , 5 -RRB- 27 years -LRB- 18 -- 55 , 9 -RRB- 35 years -LRB- 14 -- 73 , 11 -RRB- Mean IQ -LRB- sd -RRB- 104 -LRB- 10 -RRB- 105 -LRB- 12 -RRB- a Difference between GOC group and non-ASD group -LRB- chi-square = 14.2 , df = 1 , p < 0.0001 -RRB- ; difference between GOC group and ASD group -LRB- chi-square = 5.8 , df = 1 , p < 0.05 -RRB- ; no difference between ASD group and non-ASD groupb GOC group differs from non-ASD group -LRB- p < 0.01 -RRB- and from ASD group -LRB- p < 0.0001 -RRB- ; no difference between ASD group and non-ASD group Table 2 shows AQ-D sub-domain and total scores for the three groups . Generally , there were no significant differences between the three groups . The one significant difference was on the sub-domain Communication between the ASD group and the general outpatient group . Further , within the ASD group , average AQ-D scores varied with the severity of ASD : High Functioning Autism : 31 -LRB- n = 1 -RRB- ; Asperger 's Disorder : 24 -LRB- n = 4 -RRB- , and PDDNOS : 21 -LRB- n = 10 -RRB- . In light of the small sample sizes the latter differences were not tested for statistical significance . Table 2Mean scores AQ-D -LRB- sd -RRB- and ANOVA tests for differences in mean scoresASD -LRB- n = 15 -RRB- No ASD -LRB- n = 21 -RRB- General outpatient clinic -LRB- n = 369 -RRB- Social skill5 .0 -LRB- 2.8 -RRB- 4.2 -LRB- 2.6 -RRB- 4.1 -LRB- 2.6 -RRB- Attention switching5 .1 -LRB- 2.6 -RRB- 5.3 -LRB- 2.4 -RRB- 5.3 -LRB- 2.3 -RRB- Attention to detail3 .5 -LRB- 2.3 -RRB- 4.4 -LRB- 2.2 -RRB- 4.2 -LRB- 2.3 -RRB- Communication * 4.5 -LRB- 2.1 -RRB- 3.5 -LRB- 2.2 -RRB- 2.8 -LRB- 1.8 -RRB- Imagination4 .4 -LRB- 2.4 -RRB- 4.3 -LRB- 2.0 -RRB- 3.5 -LRB- 1.9 -RRB- Total22 .5 -LRB- 8.4 -RRB- 21.8 -LRB- 7.6 -RRB- 19.9 -LRB- 7.0 -RRB- * Significant difference between ASD group and GOC group at p < 0.01 Table 3 reports Axis I diagnoses in ASD and non-ASD patients as assessed by the SCAN . With one exception , there were no differences in either Axis I or Axis II diagnoses between the two groups . This held for both actual and lifetime -LRB- not reported -RRB- Axis I diagnoses . The one exception was that more patients were diagnosed with actual psychotic disorder NOS in the non-ASD group than in the ASD group . When we aggregated separate categories into more broad diagnostic categories , i.e. , anxiety disorders , psychotic disorders , and mood disorders , there were no differences between the two groups in past-month or lifetime diagnoses either , except for actual psychotic disorders -LRB- results not shown -RRB- . Table 3SCAN-derived actual -LRB- past month -RRB- DSM IV Axis I diagnosesASD -LRB- N = 15 -RRB- n -LRB- % -RRB- No ASD -LRB- N = 21 -RRB- n -LRB- % -RRB- No disorder7 -LRB- 47 -RRB- 7 -LRB- 33 -RRB- Mood disorder with psychotic symptoms2 -LRB- 13 -RRB- -- Mood disorder without psychotic symptoms2 -LRB- 13 -RRB- 3 -LRB- 14 -RRB- Substance abuse 3 -LRB- 20 -RRB- 2 -LRB- 10 -RRB- Sleep disorders4 -LRB- 27 -RRB- 6 -LRB- 29 -RRB- Psychotic disorder NOS -- 4 -LRB- 19 -RRB- * Schizophrenia -- -- Social Phobia3 -LRB- 20 -RRB- 4 -LRB- 19 -RRB- Panic attacks/Agoraphobia2 -LRB- 13 -RRB- 1 -LRB- 5 -RRB- Other anxiety disorders1 -LRB- 7 -RRB- -- Obsessive compulsive disorders1 -LRB- 7 -RRB- 1 -LRB- 5 -RRB- Other disorders1 -LRB- 7 -RRB- 2 -LRB- 10 -RRB- * Significant difference between ASD group and no ASD group at p < 0.05 Table 4 reports Axis II diagnoses as assessed by the IPDE . ASD and non-ASD patients did not differ on individual Axis 2 diagnoses . Also , when we tested whether ASD and non-ASD groups differed with regard to the total number of patients with any complete , partial , or either of these two , Axis 2 disorders -LRB- bottom two rows , Table 4 -RRB- , we found no difference between the two groups . Table 4IPDE derived Axis II diagnoses by ASD statusASD -LRB- N = 15 -RRB- No ASD -LRB- N = 21 -RRB- Completen -LRB- % -RRB- Partialn -LRB- % -RRB- Completen -LRB- % -RRB- Partialn -LRB- % -RRB- Paranoïd -- -- -- 1 -LRB- 5 -RRB- Schizoïd 1 -LRB- 7 -RRB- 2 -LRB- 13 -RRB- 1 -LRB- 5 -RRB- 1 -LRB- 5 -RRB- Schizotypical -- 1 -LRB- 7 -RRB- -- -- Antisocial -- 1 -LRB- 7 -RRB- -- -- Borderline 1 -LRB- 7 -RRB- -- -- 1 -LRB- 5 -RRB- Avoidant 1 -LRB- 7 -RRB- 1 -LRB- 7 -RRB- 2 -LRB- 10 -RRB- -- Obsessive compulsive -- -- 3 -LRB- 14 -RRB- 1 -LRB- 5 -RRB- Personality disorder NOS1 -LRB- 7 -RRB- 2 -LRB- 13 -RRB- 3 -LRB- 14 -RRB- 1 -LRB- 5 -RRB- Any personality disorder3 -LRB- 20 -RRB- 6 -LRB- 40 -RRB- 8 -LRB- 38 -RRB- 3 -LRB- 14 -RRB- Any personality disorder partial or complete7 -LRB- 47 -RRB- 10 -LRB- 48 -RRB- Discussion Thus far , publications about screening instruments for adult ASD use the Autism-Spectrum Quotient -LRB- AQ ; Baron-Cohen et al. , 2001 -RRB- or the Autism Spectrum Disorder in Adults Screening Questionnaire -LRB- ASDASQ ; Nylander & Gillberg , 2001 -RRB- . With the help of the latter instrument , Nylander & Gillberg -LRB- 2001 -RRB- and Chang et al. -LRB- 2003 -RRB- estimated a 1.4 and 0.6 % ASD prevalence in a general psychiatry outpatient clinic for adults . The AQ was investigated by Baron-Cohen in 2001 in Asperger 's Disorder or High Functioning Autism patients and compared with several subgroups in the general population , and was tested again in 2005 at the national diagnostic clinic for Asperger 's Disorder -LRB- Woodbury-Smith , Robinson , Wheelwright , & Baron-Cohen , 2005 -RRB- . The AQ differentiated the ASD patients adequately from healthy controls , and ASD patients from non-ASD patients . The present study tried to replicate the findings of Baron-Cohen . However , our results showed that the AQ-D did not differentiate between an ASD group -LRB- predominantly PDDNOS -RRB- and two non-ASD patient groups . Only for the communication domain , the ASD patients had higher scores relative to the general outpatient group . It is of interest to mention here that this domain was also one of the two domains that differentiated parents of autistic patients from healthy controls -LRB- Bishop et al. , 2004 -RRB- . The most probable explanation of this discrepant outcome is the fact that the Dutch patients were less severely affected than the British patients . The ASD patients but also the non-ASD patients in the Baron-Cohen papers had higher total mean scores on the AQ -LRB- for ASD : 35.8 and 35.6 and for non-ASD : 26.2 -RRB- than our patients -LRB- ASD : 22.5 , non-ASD and general outpatients : 21.8 and 19.9 -RRB- . By comparison , British , non-psychiatric , control groups typically have total scores of around 16 -- 17 -LRB- Baron-Cohen et al. , 2001 -RRB- . Interestingly , the mean score on the recent Japanese version of the AQ was 29.4 in ASD patients and 22.2 in non-psychiatric controls -LRB- Kurita , Koyoma , & Osada , 2005 -RRB- . The Japanese authors , like we , reasoned that part of the Japanese patients may have been less severely affected relative to the British patients . They also argued that it is possible that autistic related behavior as assessed by the AQ is more prevalent in the Japanese population than in the British . In the absence of the actual diagnoses of the non-ASD patients in both the British and one of the Dutch samples , it remains difficult to pinpoint why scores between the British and Dutch non-ASD patients -LRB- 26.2 and 21.8 / 19.9 , respectively -RRB- differ . The absence of differences between scores of the AQ-D in the present study suggests that there might be `` ASD-like '' symptoms , as felt by the patients themselves , present in the non-ASD patients in the ATN-referred group and in the patients of the general outpatient clinic , and revealed by self-report . Indeed , the individuals in the non-ASD group were referred to the ATN for the possible presence of an ASD diagnosis , so ASD-like symptoms must have been voiced by these patients even if these could not be diagnosed as such on the basis of the standardized diagnostic protocol . In sum , although there are still many open questions , for example about differences in scores cross-culturally , the present data suggest that self-report questionnaires are not adequate for differentiating less severe ASD patients from other patient groups . Another study is needed to investigate the merits of an alternative approach to this problem ; i.e. , a parents/caregivers questionnaire as a screening tool for adult ASD . Our second aim was to look into possible differences in comorbidity of Axis I and Axis II DSM IV classifications in ASD and non-ASD groups . This because of the notion that mild ASD symptoms often mix with symptoms of other disorders such as Obsessive Compulsive Disorder or Schizoid Personality Disorder . There is a scarcity of research on this topic . For example , -LRB- comorbid -RRB- diagnoses of the British patients were not reported in the paper of Woodbury-Smith et al. -LRB- 2005 -RRB- . For the Dutch , ATN-referred group , however , we took a systematic approach to diagnosing DSM IV Axis I and II disorders . The results indicated that , except for Psychotic Disorder NOS which was diagnosed in roughly 20 % of the non-ASD group and not in the ASD group , there were no significant differences in the pattern of diagnoses between the ASD and non-ASD patients . Possibly , the difference in Psychotic Disorder partly accounts for the referral to the ATN and for the `` ASD-like '' symptoms in these patients as discussed in the above paragraph . However , the general picture indicated by our data is that clinical accounts of a relatively high prevalence and/or a specific profile of comorbid disorders in the ASD group relative to the non-ASD group could not be confirmed . There are important limitations to this study , among which is the small number of patients in the ATN-referred group . This major drawback precludes any definite conclusions . Of note is further that the ASD patients in this investigation belonged to the less-severe side of the spectrum . This makes it difficult to compare results with the investigations by Baron-Cohen and collegues . Clinical experience indicates that ASD patients , compared to non-ASD patients , benefit more from treatment by structuring , long-term repetitive treatment , and adaptations of the environment . This may hold even more when comorbid conditions are present . Since the prevalence of patients with less severe ASD is relatively high compared to the more severe ASD categories , efficient and valid screening of this group and charting possible comorbidity is consequently an even more important issue . The present study provided a modest contribution in improving our knowledge in this direction ; clearly , much more research is needed .

O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

autism spectrum quotient
pddnos
comorbidity

adult autism spectrum disorders
personality disorders