COORDINATION CHEMISTRY OF ORGANIC MOIETIES CONTAINING ELECTRON RICH P, N AND / OR S CENTRES DIS8BRTATION SttMffrriD IN PARTIAL FULTIIMENT Of THE nQUIRBMMn fOn THE AWARD Of THE DB6RU Of M^ttx of $f)iloKopl^ IN CHEMISTRY BY Viji Jacob Mathew DEPARTMENT OF CHEMISTRY ALIGARH MUSLIM UNIVERSITY AUGARH (INDU) 1992
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COORDINATION CHEMISTRY OF ORGANIC MOIETIES CONTAINING ELECTRON
RICH P, N AND / OR S CENTRES
DIS8BRTATION SttMffrriD IN PARTIAL FULTIIMENT Of THE nQUIRBMMn
fOn THE AWARD Of THE DB6RU Of
M^ttx of $f)iloKopl^ IN
CHEMISTRY
BY
Viji Jacob Mathew
DEPARTMENT OF CHEMISTRY ALIGARH MUSLIM UNIVERSITY
AUGARH (INDU)
1 9 9 2
mmii DS2473
PHONR
DEPARTMENT OF CHEMISTRY ALIGARH MUSLIM L NlVIiRSl'lY
A LI C. /\ R H . 2(12 OO'J Utilftl.
CERTIFICATE
Certified that the work embodied in this
dissertation Is the result of original
researches carried out under my supervision
by Mr. Viji Jacob Mathew and is suitable for
the award of M.Phil, degree of Aligarh Muslim
University, Aligarh
Dt^m, (Dr. ^ f a r Ahmad Siddiq i ) ^
Reader
ACKNOWLEDGMENT
I take this opportunity to express my deepest gratitude
and thanks to my supervisor, Dr. Zafar Ahmad Siddiqi, Reader,
Department of Chemistry, Aligarh Muslim University, Aligarh,
who guided me throughout with the best of his abilities. His
sincerity, determination and exceptional abilities remain a
constant encouragement to me.
I would like to thank Prof. M.A. Beg, Chairman,
Department of Chemistry for providing necessary research
facilities.
It is difficult to express my indebtedness to my parents
and brothers for their keen interest and encouragement in my
academic persuits all along. The valuable suggestions and
assistance rendered by all my colleagues and friends specially
Mr. Arif Ali Khan are gratefully acknowledged.
Finally I thank Mr. Mohd. Ayub Khan for typing the
manuscript.
i, Lix^.^'
[Viji Jacob Mathew]
C O N T E N T S
PAGE
1. INTRODUCTION
2. PRESENT WORK
3. EXPERIMENTAL METHODS
4. EXPERIMENTAL
5. RESULTS AND DISCUSSION
6, REFERENCES
1
13
15
26
29
42
I N T R O D U C T I O N
INTRODUCTION
Macrocyclic ligands are multidentate cyclic molecules
consisting of an organic framework made up of heteroatoms which
are capable to interacting with a variety of species. Macro-
polycyclic ligands are a three-dimensional extension of macro-
monocycles, in which more than one macrocycle is incorporated
in the same molecule. The wide spread interest in these mole
cules is due to their unique and exciting chemistries in that
they can function as receptors for metal ions, molecular cations
neutral molecules or molecular ions of widely differing physical
and chemical properties. These macrocyclic systems displays
various interesting properties such as stable complex formation,
transport capabilities and catalysis. All of these features,
which result from association of two or more species, form what
has been coined a supramolecular (macromolecular) chemistry.
Over the past years the field of macrocycles has grown
rapidly that now an extensive series of macrocyclic ligands are
available. Naturally occurring macrocyclic complexes of the
porphyrin or corrin ring systems and the industrially important
metal-phthalocyanine complexes have been studied for many years^
Synthetic ring complexes which copy aspects of these naturally 3
occurring complicated macrocyclic ring systems are known and at
present the study of such compounds is receiving much attention.
Although the results obtained do not always closely parallel
: 2 :
those in nature, a knowledge of the chemistry is being deve
loped and the biochemical role of metal ions in the natural
systems is begining to be better understood, A large number of
other macrocyclic ligands have been extensively studied. These
ligands are classified into two broad subdivisions.
The cyclic polyethers of the * crown* type as shown by 4
structure-I is a typical example of the first category.
Ligands of this general category have received much attention
Str - I
because of their unusual behaviour towards a range of non-tran-5
sition metal ions . Majority of such polyether ligands however
show a limited tendency to form complexes with transition metal
ions^'^.
The second category of macrocyclic ligands incorporates
: 3 :
the synthetic ring systems containing donor atoms other than
oxygen. The majority of such ligands contain nitrogen donor
atoms although, ligands incorporating sulfur ^ as well as
phosphorus are also known. Ligands belonging to this
8 9 10a category as shown by structures II , III , IV form strong
complexes with transition metal ions.
H
N N
,N
S S
II III IV
Macrocyclic ligands have been prepared by conventional
organic synthesis as well as employing in-situ procedures
involving cyclization in the presence of a metal ion. The
crown polyethers are examples of raacrocycles which have been
prepared mainly by direct synthesis . Reactions shown by
equations (1) and (2) are examples of two synthetic route for
two such systems as below :
^^^°" ^^v^OH
+ 2 CI 0 ->a: o A ^
(1
P H^N
0 H2N
SH (i) Ni
W SH ("\\ //
Br Br
(2)
In some reactions the presence of a metal ion is required.
The metal is said to act as a •template* and such reactions
have been termed tr ?tal assisted 'template synthesis'. Schiff-
base condensation between a carbonyl compound and an organic
amine in presence of a metal ion to yield an imine linkage has
11 12 led to the synthesis of many aza macrocycle ' complexes as
illustrated by equation (3)
o. CH«0
M = Ni " , Cu "*"
(3)
Although the above synthetic methods provide an easy
approach to prepare various macrocyclic ligands, it is now
understood that there is a need in several areas for a rational
approach toward ligand design for selective complexation of
metal ion in solution. Selection of donor atoms is based on
ideas such as the hard and soft acid and base principle of
: 5 :
Pearson or the A and B type acids of Schwarzenbach or Arhland
et al. However, the role of ligand design architecture is
much less well understood and limited to such ideas as size-match
selectivity in macrocycles. Size-match selectivity is the idea
that a metal ion will form its most stable complexes with the
number of a series of macrocycles where the match in size bet
ween the metal ion and the cavity in the ligand is closest.
13 The size of the hole greaty influences the properties of the
complexes relative to those of open chain analogues. The cavity
size can be related to ligand structure for both conjugated and
14 non conjugated ligands . The 'hole size* for coordination
depends on the number of atoms in the ring.
Macrocyclic complexes can adopt a wide range of conformers
15 of fairly similar energies , These conformations present the
metal ions with a range of best-fit M-L lengths, allowing strong
complexation by metal ions while lying coordinated out of the
macrocyclic cavity. It is due to this reason that N-donor and
0-donor macrocycles show little difference in their size selec
tivity towards metal ion compared to their open-chain analogues.
The macrocycles are thus rather too flexible to show genuine
size-match selectivity. Moreover, their selectivity patterns
are controlled by the same factors that control the selectivity
patterns of open-chain ligands, such as chelate ring size and
the size-match selectivity inherent in the coordinating proper
ties of the neutral oxygen donor atoms.
: 6 :
Knowledge of substrate binding preferences and structure
can be efficiently utilized in the synthesis of receptor ligands
by introducing site and geometry control into receptor design.
Interaction between the macrocyclic ligand and substrates can
be fine-tuned by appropriate selection of the binding sites and
its environment, and overall ligand topology. Specifically to
be considered are (1) electronic effects* e.g. charge, polarity
and polarizability and (2) structural effects, important from
the stand point of both site and geometry.
The significant chemical behaviour of transition metal
complexes very often depends on their facile redox properties.
This has been found true to a large degree for the natural and
synthetic complexes involving macrocyclic ligands. These sub
stances undergo a diverse array of chemical reactions, such as
ligand oxidative dehydrogenation, metal alkylation, ligand sub
stitution and hydrogenation. The success of some of these
reactions is closely linked with the ability of higher and lower
oxidation states of metal ions in these complexes to function
as reactive intermediates.
The ability of macrocyclic ligands to stabilize a wide
range of oxidation states of a coordinated metal ion has been
amply demonstrated by the work of Olson and Vasilevskis^^.
Simultaneous and subsequent work conducted by D.H. Busch et al.
• 7 •
17
and by Endicott and coworkers has proven the generality of
the above observations* Macrocyclic complexes in general have the following
18 characteristics :
1. A marked kinetic inertness both to the formation of
the complexes from the ligand and metal ion, and to the
reverse, the extrusion of the metal ion from the ligand,
19 2. They can stabilize high oxidation states - that are not
normally readily attainable such as Cu(lll) or Ni(lll).
3. They have high thermodynamic stability - the formation
constants for N^ macrocycles may be orders of magnitude
greater than the formation constants for non-macrocyclic
N^ ligands. Thus for Ni the formation constant for the
macrocyclic cyclam is about five orders of magnitude 20
greater than for the non-macrocyclic tetradentate ligand.
The large increase in stability which has been termed 21
as the macrocyclic effect cannot be attributed to the usual
chelate effect because there is an additional enhancement in
stability beyond that expected from gain in translational
entropy. The differences in configurational entropy is because
a greater loss in entropy would be expected in the complexation
of the open-chain ligand than in the macrocyclic ligand.
: 8 :
Unlike the chelate effect, which is largely entropic in origin,
the macrocyclic effect has both enthalpic and entropic compo
nents* An early suggestion for the additional stability was
that for the macrocycle the donor atoms were constrained near
the required coordination sites and so the ligand was
*prestrained* as compared with the non-macrocycle. The macro-
cyclic effect is best understood by considering the thermody-
21 22 namics * of metal-complexation reactions. The configuration
and solvation of the free macrocyclic ligand compared to the
noncyclic ligand undoubtedly are very important to this effect.
An explanation of the macrocyclic effect has been given
23 on the basis of equilibrium and calorimetry studies carried
out for NiCcyclam) "*" [str-V] and Ni(2,3,2-tet)^"*" [Str-Vlj
complexes.
^2+
J
2+
Ni (Cyclam)
V
2+ Ni (2,3,2-tet)
VI
2+
: 9
Although it is quite reasonable to assign the macrocyclic
effect to the entropy factor, the results of equilibrium and
21 calorimetry studies suggest that the actual reason for the
greater stability of the macrocyclic complex is due to a more
favourable change in the enthalpy, AH*^ (a difference of -14
kcal/mol) which overcomes a less favourable change in entropy,
A S ° ( a difference of -16 cal/C°K mol) for the reaction. The
favourable change in enthalpy is well understood by considering
the llgand solvation effect in the thermodynamics of the metal
complexation reaction.
24
The effect of ligand solvation permits several predic
tions. The macrocyclic effect should be independent of the
metal as long as there is not an unfavourable geometry in the
coordination of the metal ion within the macrocycle. Similar
2+ enhancements of the stability constants are found for Cu and
2+ Ni with hexamethyl derivatives of eye lam. It is proposed
that use of solvent with weaker primary solvation of the ligand
will increase the relative contribution due to the configura-
tional entropy, as the importance of solvation effect is
diminished.
The effect of ligand solvation on metal stability constants
should be particularly important to biological systems.
Obviously, the magnitude of metal ion binding constants to
: 10 :
proteins and other biological species may be very much influ
enced by solvation and could differ from that of smaller,
more flexible molecules by very large factors.
The present investigation is intended to study the intera
ction of different metal ions that are of biological signifi
cance with macrocyclic ligand having amide functional groups.
Amide bonds or groups provide the linkage between adjacent
amino acid residues in proteins. When condensation of two amino
acid yields a dipeptide, the resulting amide bond is often
referred to as a peptide bond (or group).
An amide group offers two potential binding atoms, the
oxygen and nitrogen, for complexation of protons and metal ions.
They are planar with 409 double-bond character in the carbon-
25 nitrogen bond and strongly favours the trans form as shown
below:
R /H R, . H \ - / \ ( + ). /C N < > C • N
^ / R '0
60% 409
A free or 'unconnected' amide is a weak coordinating group due
to the weakly basic amide oxygen atom and weak acidity of hydro
gen. With such weakly basic 0-atoms (pk — -l)^^ strong metal
: 11 :
coordination will not occur at that site. On the other hand,
substitution of a nitrogen bound hydrogen by a metal ion should
create a very strong bond. However, the very weak acidity of
the hydrogen (pk ^ 15) implies that alkali and alkaline
earth metal ions will not effect its removal. Transition metal
ions promise to be more effective in substituting for a nitrogen
bound amide hydrogen, but they suffer metal ion hydrolysis and
precipitation in neutral and basic solutions. Therefore metal
ions must be capable of substituting a nitrogen bound amide
hydrogen. To do so in neutral solutions, metal ions require an
effective anchor (primary ligating site) to inhibit metal ion
hydrolysis* In macrocycles containing amide bonds other donor
sites like amino groups within the cycle or terminal groups
function as the primary ligating site. Where such sites are
not available drastic conditions are needed for complex forma
tion.
28 The X-ray single crystal structure studies suggest that
peptide (amide) nitrogen does not bear both a proton and a
metal ion. The metal ion substitutes for the proton at the
trigonal peptide nitrogen. The planarity of the amide group is
maintained in the deprotonated trigonal peptide nitrogen com-Oft
plexes of all metal ions studied , Crystal structures reveal
that as compared to the free or peptide oxygen complexed ligands
complexation of the peptide nitrogen shortens the peptide C-N
: 12 :
and lengthens the C-0 bond . Upon substitution of an amide
proton by a metal ion the bond lengths changes are in the
direction of more double bond character in the C-N bond and
less double bond character in the C-0 bond. This suggests that
both the C-0 bond and C-N bonds possess appreciable amounts of
double-bond character before and after substitution of a metal
ion for the peptide hydrogen.
The most basic site in the amide groups is always the one
that is protonated or metalated. In a neutral amide the most
basic site is the oxygen and metal ion complexation occur at
that atom. After amide deprotonation, the most basic site is
the N-atoms where either protonation or metal ion complexation
takes place. When either protonation or complexation has occu
rred at an ionized amide nitrogen, the amide oxygen becomes the
most basic centre. Any additional rapid protonation or complex-30 atlon then occurs at the oxygen . Amide groups (bonds) in
macrocycles thus provide a polar binding site and llgand
stiffening.
Macrocycles of the above type when complexed with metal
ions are possible models for important proteins and enzymes.
P R E S E N T W O R K
PRESENT WORK
A large number of naturally occurring simple and oligo
peptides are knovm to have important physiological roles and
31 metal ion chelation is often involved in them. Indeed, in
contrast to plants and bacteria, the modulators of metal ion
metabolism in higher animals are peptides and proteins.
Whether or not a physiological function is involved, the chela
tion properties of peptides have generated considerable interest
because of the versatility of their chelating modes and because
of the change in reactivity of the peptide itself. The signi
ficant chemical behaviour of this interaction can be attributed
to factors such as ligand oxidative dehydrogenation and its
ability to stabilize a wide range of oxidation states which can
act as reactive Intermediates.
The chemical interest in interaction and activation (by
redox reactions) of molecular oxygen by copper-proteins has
32 grown considerably during recent years . Copper (ll) and
nickel (II) can promote the reactions between 0^ and peptides,
where Cu(III) and Ni(IIl) peptide complexes were considered as
intermediates. Cu(III) and Ni(lII) ions have been obtained
with complexes of peptides and macrocyclic polyamines. Some 33
dioxotetramines and pentamine macrocycles have been synthesiied
that would serve as mimic systems to redox systems.
: 14 :
The present work is to study some novel macrocyclic
llgands resembling macrocyclic tetrapeptides» their metal
ion interaction and chemical behaviour upon complexation.
The work is in progress and herein we report the synthesis
and characterization of the new ligand and its reactivity
towards a few metal ions. The newly synthesized compounds
have been characterized using physico-chemical methods,
magnetic susceptibility measurements and IR, UV-visible
(solution as well as solid i.e., reflectance) and H-NMR
spectroscopic studies. The work on template reactions and