Chemistry Reference
In-Depth Information
an inadvertent trigger, such as adding catalyst last to
reaction mixtures or adding initiators to polymeris-
able monomers. Such mishaps can be avoided easily
by running the reaction at higher temperature to
consume and to avoid the accumulation of reactive
intermediates, running at lower temperature to
increase heat transfer efficiency and to lower the
reaction rate, and controlling the exotherm by
the reagent addition rate or by having a continuous
process. Safety is the primary concern when a
process is being scaled up and it is not negotiable
because no waste is greater than that of human lives.
is not to make it in the first place. Given a choice,
the impurity that displays the greatest difference in
chemical or physical behaviour compared with the
product is usually easier to remove. As a general
rule, the synthesis should be designed in such a way
that maximum difference between starting material
and product is maintained in the steps comprising it.
For example, coupling of a carboxylic acid with an
amine base (Scheme 12.1) would fulfil this criterion
because the product amide differs significantly from
both starting materials, whereas methylation of
tetralone (Scheme 12.2) does not because the
product, impurities and precursor are similar in both
composition and physical properties.
2.2 Increasing complexity
To minimise waste, an efficient synthesis should
have increasing complexity and increasing mole-
cular weight as the synthesis evolves from starting
material to product (see Schemes 12.1 and 12.2).
This translates into the maximum use of chemose-
lective reactions and the minimum use of protecting
groups. The virtue of convergent synthesis is empha-
sised in every synthetic text for the precise reason
that it is more effective at increasing molecular com-
plexity than a linear synthesis.
2.4 Choice of starting material
As a general rule, commercial sources of starting
material should be considered first for reasons of
speed, economy and quality. This not only saves
development time and frees R&D and manufactur-
ing capacity, but also has the added benefits of waste
reduction. Pollution also is easier to prevent at a ded-
icated manufacturing site than at a diversified site.
One should try to incorporate as many carbon atoms
from the purchased starting material as possible. A
caveat in purchasing raw material is the long-term
stability of a particular source. For example, a by-
product from an agrochemical company may serve
as an ideal and cheap source for a new synthetic
route but this source can dry up quickly when the
suppliers improve their process and no longer offer
the by-product. Also, an ecologically acceptable
material today may face some serious questioning in
future years. An integral part of the sourcing strat-
egy is the examination of sustainability of the chem-
istry used to make the starting material by the
vendor.
2.3 Means of purification
To ensure product quality and synthetic efficiency,
various checkpoints must be built into the synthesis
to remove impurities. Crystalline intermediates are
highly desirable and may even be worth an extra
step or two to obtain. Process optimisation often
leads to the best way to remove an impurity, which
1.
i
-BuOCOCl, NMM
2. R'CH
2
NH
2
RCO
2
H
RCONHCH
2
R'
1
2
2.5 Yields
Scheme 12.1
Although the overall yields have been used exten-
sively as a measure for total synthesis elegance, it is
but one aspect in evaluating the overall efficiency in
an industrial setting. Factors such as reagent cost,
solvent usage, ease of separations, process safety and
waste treatment concerns are not usually displayed
conspicuously in a synthetic scheme. Often, when a
starting material is cheap and separation is facile, a
low-yielding step may fit well in the early stages of
Me
Me
Me
O
OMe
O
O
MeI
NaH
+
+
O
O
O
O
3
4
5
6
Scheme 12.2
