Key points from last lecture

• Many “inorganic” elements are essential for

life
• Organisms make economic use of available
resources, but also have developed
mechanisms to accumulate certain elements
• Despite the low amount of metal ions present
in living systems, they are enormously
important for virtually all life processes
• Both deficiency and overload/excess lead to
illness

1
Bio-Inorganic Chemistry

Lecture 2:
Basic Principles and Concepts

2
 Overview
a) Synopsis of important properties of metal ions

b) Geometries and electronic structures of metal ions in

Biological System
c) Thermodynamics: complex stability and site selectivity
• Stability constants
• Charge
• Ionic radii
• HSAB principle
• Irving-Williams Series
• Other effects
• pKa values and the competition of metals with protons

d) Properties important for catalysis

• Lewis acidity
• Redox potentials and electron transfer rates
• Ligand exchange rates

e) Effect of metal environment created by protein

3
 General properties

Characteristics Na+, K+ Mg2+, Ca2+ Zn2+, Ni 2+ Fe, Cu, Co,

Mo, Mn
Predominant +1 +2 +2 see Table 4
oxidation state
stability of very low low or high high (except
complexes medium Fe2+ and
Mn2+,
medium )
preferred O O N, S N, S
donor atoms (sometimes
O for high
oxidation
states)
mobility in high medium low to low to
biological medium(esp. medium
systems Zn) (Fe2+ and
Mn2+)
4
 Geometries
Metal ion Preferred geometries in small high-

spin complexes with O and N donors

Cu(II), d9 tetragonal > 5-coord. > tetrahedral

Mn(III) d4
Cu(I) d10 linear, trigonal planar, or tetrahedral

Co(II) d7 octahedral > tetrahedral>others

Zn(II) d10 tetrahedral > octahedral > 5-coord.

Fe(III), d5
Co(III), d6 Causes: see Ligand-field
theory and steric factors
Cr(III), d3 octahedral > others
Mn(II), d5
Ni(II) d8
5
 Oxidation states
+7 X
+6 X X X
+5  X X
+4   X  
+3  X 
    
+2  X X X      
+1    
K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn

: common in chemistry
: Less common in chemistry
X : Not available to biology

6
Common spin states for some metal ions
Table: Common spin states for some metal ions
Metal M2+ M3+
Mn high-spin d5 high-spin d4
Fe low-spin or high-spin d5
6
high-spin d
7 6
Co high-spin d low-spin d
6 7
Ni high-spin d low-spin d

7
Stability aspects: Thermodynamics
of metal binding
• Important for Understanding of:
– Metal uptake and distribution
– Specificity of metal binding (bio)molecules
– Catalysis by metalloenzymes
– Interactions of metals with nucleic acids

8
 Stability constants
L + M LM

[LM]
K
[L] [M]

Often expressed as log K:

e.g.: K = 1015  log K = 15

The dissociation constant Kd is K-1  log Kd = -15

9
 Stability constants - ranges

Rough rule of thumb:

• Strong complexes: log K > 10
• Weak complexes log K < 4

10
 Stability Aspects: What governs
stability ?
1. charge effects

• Rule of thumb: The higher the charge of the cation, the

more stable the complex
• Biophysical reason: Charge recombination is favourable
• But see later: HSAB principle

11
 2. Ionic radii
• Ionic radii are dependent on:
– position in periodic system
– charge (the higher, the smaller)
– coordination number (the higher, the larger)
• If covalence (due to differences in
electronegativity), steric hindrance etc.
would not operate, z/r (charge/radius)
would dictate order of stabilities
• In reality: seldom observed, only with very
small ligands, e.g. F-
12
 Hard and Soft Acids and Bases
Hard Borderline Soft

Acids: Fe2+, Co2+, Ni2+, Cu2+, Cu+, Ag+, Au+, Pt2+,

H+, Na+, K+, Mg2+, Zn2+ Pb2+, Hg2+, Cd2+
Ca2+, Cr3+, Fe3+, Co3+

Bases: Ar-NH2, Imidazole RS-, RSR

NH3, RNH2, H2O, OH-,
O2-, ROH, RO-,
RCO2-, PO43-

13
• See Handout
Hard and Soft Acids

14
 Stability Aspects:
The Irving-Williams Series
• Stability order for high-spin divalent metal ion
complexes
• Always peaks at Cu(II)
• Mn(II) always
the minimum
• Underlying
reasons:
a) ionic radii
b) LFSE Zn(II)

15
Stability Aspects: Interplay between HSAB
principle and the Irving-
Williams Series:

• High-spin M(II)
S,N X Y
complexes M
• Bidentate ligands
log K

• Trend more pronounced

the softer the ligand
O,O

N,O N,N

Figure from Sigel and

Fe Cu McCormick, Acc. Chem. Res. 16
3, 201 (1970).
 Competition with protons
• Both metal ions and H+ are positively charged
and have an affinity for bases
• The actual concentration of a complex ML
therefore depends on [M], [L], and [H+]
• Low pH  high [H+]: ML complexes dissociate
 Effective (or apparent or conditional) stability
constants

17
 Competition between protons and metal ions:
Conditional stability constants of the four most common zinc
logK’ ligands in proteins
10
Zn-Cys
9
Calculated with:
Cys (S,N)
8 logK’ =
7
Zn-His
His (N,N)
logK + logKa –
6 Asp (N,O) log (Ka+[H+])
5 Glu (N,O) Zn-Asp and
Zn-Glu and values for logK for the 1:1
4 Zn(aa) complexes (taken from the
IUPAC stability constants database).
3

2 -logKa (= pKa):
1
Cys: 8.5
His: 6-7
0 Asp/Glu: 4
0 2 4 6 8 10 12 18
pH
 Other contributions to stability
• Chelate effect
• Preferred coordination geometry
• Dielectric constant of the medium:
Interiors of proteins can be very different
from water – usually more hydrophobic 
lower dielectric constant: Enhances charge
recombination and therefore complex
formation

19
Catalysis in Metalloenzymes

20
 Properties of metal ions exploited for
enzymatic catalysis
• Lewis acidity: affinity for electrons OR'
2+ -
- polarisation of substrates: Zn O + + OH-
R
- facilitation of attack by external base
- increasing attacking power of bound base
- pKa values of coordinated ligands are lowered
E.g.: aquo-ions: pKa usually 9-10
in zinc enzymes as low as 7.
• Orienting the substrate and stabilising it in a
conformation conducive to reaction
• Redox activity
21
 Lewis acidity: Effect on pKa of bound
ligands

NB: Hydrolysis of
aquocomplexes

22
From Lippard and Berg
 Importance of redox chemistry in
biological systems
• Electron transfer reactions: Energy generation for life is
based on flow of electrons - e.g. from “fuel” to O2
(respiration)

http://highered.mcgraw-hill.com/sites/0072437316/student_view0/chapter9/animations.h

23
 Standard reduction potentials (pH 0)
Species E0 (V)
Cu2+/Cu+ +0.153
Fe3+/Fe2+ +0.771
Oxidising power
Mn3+/Mn2+ +1.51
increases
Co3+/Co2+ +1.842
O2 /O2– – 0.33
O2 + H+/ HO2 – 0.13
NB: Redox potentials of metal
O2 + 2H+ / H2O2 +0.281
ions are highly dependent on
environment and coordinated
O2 + 4H+ / 2H2O +0.815
ligands
O2– + 2H+ / H2O2 +0.89
OH + H+ / H2O +2.31

H+/H2 (pH 7): -0.4 V Biology (ie chemistry in water)

O2/OH- (pH 7): +0.8 V is limited to this range.
24
 Kinetic aspects
• Water exchange rates
Expressed as lifetime of complexes
Useful to characterise reactivity in
ligand exchange reactions

inert labile

25
 Proteins tune the properties of
metal ions
• Co-ordination number:
– The lower the higher the Lewis acidity
• Co-ordination geometry
– Proteins can dictate distortion
– Distortion can change reactivity of metal ion
• Weak interactions in the vicinity: second shell
effects
– Hydrogen bonds to bound ligands
– Hydrophobic residues: dielectric constant can change
stability of metal-ligand bonds

• We’ll look at these in more detail later (lectures on zinc,

copper, and iron enzymes) 26
 Summary
• The behaviour of metal ions in biological
systems can be understood by combining
the principles of coordination chemistry with
a knowledge of the special environment
created by biomolecules

27