The introduction to this thesis is in the form of a review entitled 'Aspects of Selectivity in Lipase Catalysed Biotransformations'. Each of the most widely used lipases have been discussed. The reactions of each lipase have been extensively reviewed with the aim of establishing whether any trends have appeared in the characteristics of compounds accepted as substrates.



The remaining chapters cover five unrelated studies in areas of resolutions of chiral compounds using biotransformations. In Chapter 2 the resolution of a P-blocker precursor was attempted via lipase-catalysed hydrolysis. l-Chloro-2- hydroxy-3[4(2-acetoxyethyl) phenoxy] propane was obtained in high enantiomeric excess from hydrolysis of the corresponding butyrate ester with lipases from Mucor or Rhizopus sp. Yields were low however, owing to enzyme inhibition by the butyric acid byproduct.



In Chapter 3 the resolution of methyl 3-hydroxy-4-(p- chlorophenylthio)-butanoate was carried out. Hydrolysis of the corresponding butanoate ester with lipase P gave the R enantiomer of the desired compound in high enantiomeric excess. Transesterification of the racemic alcohol with vinyl acetate, again catalysed by lipase P, furnished the opposite enantiomer in 62%ee.



Chapter 4 is concerned with the resolution of a chiral acid, namely 3-methyl-4-oxo-4(4-aminobenzyl) butanoic acid. This was attempted by hydrolysis of an ester using pig liver esterase and various lipases and via microbial reduction of the corresponding unsaturated compound. The reactions were all found to be non-stereoselective.



Chapters 5 and 6 discuss novel methods for the enzymatic resolution of ketones.

The enantioselective enzymatic hydrolysis of oxime esters is discussed in Chapter 5. The resulting optically enriched oximes may readily be cleaved to the ketones. This method was unsuccessful in the resolution of the 2-methyl- and 2,6- dimethylcyclohexanones. A low enantiomeric excess was achieved in the resolution of norcamphor, and attempts to improve this using a purified enzyme and by variation of the ester chain were unsuccessful. However, this represents the first example of the indirect enzymatic resolution of ketones.



In Chapter 6 the enantioselective hydrolysis of enol acetates of three ketones was attempted. This method of resolution was unsuccessful in the resolution of 2-methyl and 2,6- dimethylcyclohexanones. In the case of norcamphor the ketone was obtained in low enantiomeric excess

Knap, J.

Ortiz, M.

Opelt, Susan M.

Warwick Research Archives Portal Repository

Applications of enzymes to the preparation of optically active compounds

We address the question of whether results obtained for small indenters scale to indenter sizes in the experimental range. The quasicontinuum method is used in order to extend the computational cell size to 2 × 2 × 1 μm^3, nominally containing of order 

2.5 × 10^(11) atoms, and in order to permit consideration of indenter radii in the range 70−700 Å. The dislocation structures for the large indenter are found to be less sharp and to extend over a larger region than for the small indenter. In addition, the large-indenter force-displacement curve differs from that corresponding to the small indenter in one important respect, namely, the absence of force drops during indentation, despite profuse dislocation activity. Based on these observations, we conclude that the indenter force is not a reliable indicator of the onset of dislocation activity and plastic deformation for indenter sizes in the experimental range

Caltech Authors - Main

P H Y S I C A L R E V I E W L E T T E R S week ending6 JUNE 2003VOLUME 90, NUMBER 22Effect of Indenter-Radius Size on Au(001) Nanoindentation
J. Knap and M. Ortiz
Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California 91125, USA
(Received 3 November 2002; published 3 June 2003)226102-1We address the question of whether results obtained for small indenters scale to indenter sizes in the
experimental range. The quasicontinuum method is used in order to extend the computational cell size
to 2 2 1 m3, nominally containing of order 2:5 1011 atoms, and in order to permit consid-
eration of indenter radii in the range 70 700 A. The dislocation structures for the large indenter are
found to be less sharp and to extend over a larger region than for the small indenter. In addition, the
large-indenter force-displacement curve differs from that corresponding to the small indenter in one
important respect, namely, the absence of force drops during indentation, despite profuse dislocation
activity. Based on these observations, we conclude that the indenter force is not a reliable indicator of
the onset of dislocation activity and plastic deformation for indenter sizes in the experimental range.
DOI: 10.1103/PhysRevLett.90.226102 PACS numbers: 02.70.–c, 31.15.–p, 46.15.–xX Y
Z
2.0 2.0
1.0
[ m]µ
[ m]µ
[ m]µ
FIG. 1 (color online). Geometry of the computational cell andK  jIIEKj b ; (1) initial mesh.The objective of this work is to ascertain the effect of
indenter radius on the mechanics of nanoindentation of
ductile fcc crystals at zero temperature (see, e.g., [1–9] for
experimental background). For definiteness, we specifi-
cally focus on the indentation of Au(001) by spherical
indenters of tip radii 70 and 700 A. One reason why the
tip radius size is of concern is that straight molecular
dynamics calculations have often relied on artificially
small indenters in order to reduce the size of the computa-
tional cell [10–20], and the scaling of the results to larger
indenters is not straightforward. In particular, it is not
immediately clear how dislocation activity depends on —
and how effective properties such as the force vs depth-
of-indentation relation scales with — indenter size.
The technique we use in order to sidestep the size
restrictions of straight molecular dynamics is the quasi-
continuum method of Tadmor and co-workers [21–23].
Thus, by coarsening the level of spatial resolution of the
computational mesh away from the indenter we are able
to span realistic material samples of the order of 2 2
1 m3, which nominally contain 2:5 1011 atoms. This
helps to capture the elastic field of the indenter without
introducing spurious or parasitic effects associated with
periodicity or small sample sizes. By adapting the mesh
size to the deformation field, the calculations provide full
atomistic resolution over an appropriate region under the
indenter. In this manner, the calculation is reduced to a
coarse-grained system of size several orders of magnitude
smaller than the original one, without appreciable loss of
accuracy. In addition, this model reduction enables us to
consider a wide range of indenters (70 to 700 A in the
work presented here).
The particular implementation of the quasicontinuum
method used in the calculations has been described in
[23]. In particular, following [21–23] we adopt as adap-
tion indicator
q hK0031-9007=03=90(22)=226102(4)$20.00where K denotes a simplex in the triangulation, IIEK
denotes the second invariant of the Lagrangian strain
tensor in the simplex K, hK is the size of K, and b is
the Burgers vector magnitude. It follows from its defini-
tion that K is invariant under rotations. The simplex K
is targeted for refinement if
K > TOL (2)
for a prescribed tolerance TOL  2 103. The effect of
the choice of tolerance on the accuracy of the method has
been systematically investigated in [23]. The tolerance
used in the present calculations ensures that the mesh
resolution is fully atomistic well in advance of the nu-
cleation or passage of a dislocation.
The material under consideration is fcc gold. The
computational cell adopted in calculations is 2 2
1 m3 and oriented along the cube directions (Fig. 1).
The cell encompasses approximately 0:24 1012 atoms. 2003 The American Physical Society 226102-1
FIG. 2 (color). Dislocation structures for the 70 A indenter at
an indentation depth of 9:2 A.
X Y
Z
FIG. 3 (color online). Cross section of the computational
mesh for the 70 A indenter at an indentation depth of 9:2 A.
P H Y S I C A L R E V I E W L E T T E R S week ending6 JUNE 2003VOLUME 90, NUMBER 22The bottom surface of the cell rests on a rigid half-space,
whereas all other surfaces are traction-free. The energy of
the crystal is modeled using the embedded-atom method
potential of Johnson et al. [24,25]. Following Kelchner
and co-workers [13,20], we model the indenter as an ad-
ditional external potential of the form AHR rR r3,
where R is the indenter radius, r denotes the distance
between an atom and the center of the indenter, A 
5:3 nN= A2 is the force constant, and Hr is the step
function. Two values of indenter radius are considered:
70 and 700 A. The former radius represents a typical
value used in previous atomistic simulations [13,20],
whereas the latter radius corresponds to the nanoindenta-
tion experiments of Kiely and Houston [3].
The initial triangulation of the cube is specifically
tailored to the nanoindentation geometry (Fig. 1). Thus,
in a small region of the crystal located directly under-
neath the indenter, full atomistic resolution is supplied
from the outset. Away from this region, the triangulation
becomes gradually coarser. The resulting number of rep-
resentative atoms in the initial mesh is 25 329, which
represents a 7 order-of-magnitude reduction in the size
of the calculation relative to direct atomistic simulation.
The indenter is driven into the slab in small displacement
increments, and at each step the new stable equilibrium
configuration is computed using the Polak-Ribiere vari-
ant of the conjugate gradient method [26].
In order to reliably identify the defects in the crystal,
we resort to the technique of Kelchner et al. [13], which
relies on the value of the centrosymmetry parameter in
order to detect and identify lattice defects. The centro-
symmetry parameter is defined as
P 
X6
i1
jRi  Rij2; (3)
where Ri andRi are the vectors corresponding to the six
pairs of opposite nearest neighbors in the fcc lattice. By
way of illustration, the centrosymmetry parameter takes
the value of zero for an atom in the perfect Au lattice,
24:9 A for a surface atom, 8:3 A for an atom in a stacking
fault, and 2:1 A for an atom at the core of a partial
dislocation. In all subsequent dislocation structure plots,
the atoms are colored according to the magnitude of the
centrosymmetry parameter with blue corresponding to
surfaces, red to partial dislocations, and yellow to stack-
ing faults.
The computed dislocation structures for a 70 A-radius
indenter at a depth of indentation of 9:2 A are shown in
Fig. 2. As expected, slip occurs predominantly on f111g
planes, the dominant slip planes in fcc crystals. In par-
ticular, slip is observed on four sets of distinct f111g slip
planes that terminate at the 001 surface. After a certain
amount of slip, dislocation loops gliding in these planes
react to form locks and arrest. Further indentation then
induces activity on neighboring slip planes which carry226102-2all the plastic deformation until they, too, become inac-
tive, the entire process repeating itself several times in the
course of the calculation.
The deformed computational mesh at a depth of pene-
tration of 9:2 A is shown in Fig. 3. The total number of
representative atoms in this configuration is 203 816,
which represents almost an order of magnitude increase
with respect to the initial triangulation. All new repre-
sentative atoms are inserted in the vicinity of the inden-
ter, with the result that the induced dislocation structures
are contained in a fully atomistic region. The permanent
imprint left on the surface of the crystal after retraction is
also clearly visible in the deformed mesh.
The computed force vs displacement curve for inden-
tation and retraction is plotted in Fig. 4. As may be seen
from this figure, the curve ceases to be monotonic at
6:75 A, at which point an abrupt force drop is observed.
This drop is followed by another interval of monotonic
increase of the force, in excellent agreement with experi-
mental results [3]. Upon retraction, the force decreases,
with the indenter detaching from the crystal surface
at a penetration depth of 3 A. This behavior owes to the
presence of stable self-equilibrated dislocation struc-
tures left in the crystal upon retraction of the indentor,226102-2
X Y
Z
FIG. 6 (color online). Cross section of the computational
mesh for the 700 A indenter at an indentation depth of 7:5 A.
0 2 4 6 8 10
 δ [Å]
0
0.02
0.04
0.06
0.08
0.1
f [
µN
]
FIG. 4 (color online). Force vs displacement curve for the
70 A-radius indenter.
P H Y S I C A L R E V I E W L E T T E R S week ending6 JUNE 2003VOLUME 90, NUMBER 22resulting in permanent plastic deformation in the vicinity
of the indenter.
The computed dislocation structures for a 700 A-radius
indenter at a depth of indentation of 7:5 A are shown
in Fig. 5. A defect structure consisting of a complex array
of extended partial dislocation loops is clearly visible
in the figure. This dislocation structure differs in notable
respects from that which develops under the 70 A in-
denter. Thus, the large-indenter dislocation structure is
less sharp and more delocalized and contains well-
developed dislocation loops bounding stacking faults.
In addition, the dislocation structure extends over a
larger region than in the case of the small indenter, in
keeping with the correspondingly larger size of the con-
tact area.
The deformed computational mesh at a depth of pene-
tration of 7:5 A is shown in Fig. 6. A comparativelyFIG. 5 (color). Dislocation structures for the 700 A indenter
at an indentation depth of 7:5 A.
226102-3larger atomistic region is needed in the case of the
700 A indenter in order to encompass the dislocation
structure. The larger imprint size left after retraction is
also noteworthy.
Figure 7 finally shows the force vs displacement curve
for indentation and retraction. As in the 70 A indenter
case, the curve rises during indentation and upon retrac-
tion reduces to zero at the indentation depth of 3 A.
However, the curve differs from that corresponding to
the 70 A indenter in one important respect, namely,
the absence of force drops during indentation, despite
profuse dislocation activity. The absence of force drops
may be attributed to the large contact area, which aver-
ages out the local traction fluctuations introduced by the
dislocations.
These observations immediately call into question the
correlation between dislocation nucleation events andFIG. 7 (color online). Force vs displacement curve for the
700 A-radius indenter.
226102-3
P H Y S I C A L R E V I E W L E T T E R S week ending6 JUNE 2003VOLUME 90, NUMBER 22drops in the force-displacement curve. Specifically, for
indenters in the size range actually used in experiment,
dislocation activity takes place well in advance of the first
force drop, in line with the findings of Kramer et al. [9].
Conversely, the first force drop probably occurs as a result
of a dislocation avalanche involving large numbers of
previously nucleated dislocations.
It has also been suggested that the onset of the plastic
deformation is marked by the deviation of the force curve
from the profile obtained by the application of the
Hertzian theory of elastic contact. In the investigations
of single crystal Au(111) nanoindentation reported by
Kiely et al. [2], this deviation takes the form of abrupt
force drops. By contrast, the experimental Au(111) force
curves measured by Michalske and Houston [8] and Kiely
et al. [4] do not exhibit any ostensible force drops as they
depart from the Hertzian relationship. In these studies,
the initial plastic yield is reported to take place at inden-
tation depths in the 70–80 A range, or more than an order
of magnitude in excess of the values predicted by our
calculations.
In conclusion, the indenter force is not a reliable in-
dicator of the onset of dislocation activity and plastic
deformation for indenter sizes in the experimental range.
Support from the DOE through Caltech’s ASCI/ASAP
Center for the Simulation of the Dynamic Response of
Solids is gratefully acknowledged.22610[1] A. Gouldstone, K. Van Vliet, and S. Suresh, Nature
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Effect of Indenter-Radius Size on Au(001) Nanoindentation

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Applications of enzymes to the preparation of optically active compounds

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