Synthesis, which in general terms can be defined as the
preparation of a chemical compound starting from substances with a simpler
structure, occupies, together with structure and reactivity, a central position
in contemporary chemistry. It concerns organic, inorganic and organometallic
substances, in the form of chemical individuals, polymers and materials. Modern
synthesis has evolved towards methodologies guided by the ever greater
understanding of its chemical-physical parameters and by theoretical calculation
with the aid of computational systems.
In this way the synthesis has become less empirical and much
more complex as regards its planning, but also simpler and more effective on an
experimental level. For example, the best knowledge of the effect of the
solvent on organic reactions has allowed, for each reaction, the choice of the
solvent with the most suitable characteristics of acidity, basicity,
coordination capacity, polarity, etc., thus achieving reaction speed. , yields
and selectivity enormously higher than those obtained in the past with the use
of the same standard solvent for very different reactions.
In chemical synthesis
it is possible to distinguish two branches: the first is aimed at the synthesis
of a certain type of product, while the second aims at a general methodology
for obtaining the formation and / or breaking of certain types of bonds. The
two branches can be designated respectively as targeted syntheses and synthesis
methodologies.
The former make use
of the latter to achieve the specific objective they propose, while the latter
offer general solutions. For example, the synthesis of ethanol belongs to the
category of targeted syntheses, while the methodologies that can be used refer
to the hydration of olefins, the carbonylation of alcohols, the oxidation of
hydrocarbons, and so on.
Similarly the
synthesis of a zeolite is targeted, while the methods below refer to the
combination of metal oxides in general. Targeted synthesis and synthesis
methodologies, however, feed each other. The latter will be considered first as
they form the foundation of targeted syntheses.
In recent decades there has been a radical change in the
chemical landscape. Determining factors were the advent of catalytic,
biocatalytic and molecular assembly methodologies through weak interactions,
the development of quantum mechanics and the better knowledge of the
chemical-physical parameters that affect the speed, yield and selectivity of
chemical reactions. We will therefore consider some of the most significant
aspects on which modern synthesis methodologies hinge.
Summary
1. Methods of synthesis. 2. Targeted synthesis. □
Bibliography.
1. Methods Of Synthesis
The synthesis methodologies include organic, inorganic and
organometallic syntheses. For many years organic synthesis has been dominated
by a series of reactions. To enumerate just a few, we recall the condensation
reactions and the Grignard reactions , in which species formally designated as
polar organometallic carbanions (eg, ethyl in EtMgBr) attack carbon atoms of
reduced electron density; the reactions of Friedel-Crafts , in which the active
species is formally constituted by carbocations of polar organometallic (eg.,
in the ethyl EtAlCl 4 ) and the substrate is provided by aromatic electron
donors or from similar species; homolytic reactions in which the attacking
species is a radical; The Wittig reactions, in which a phosphorus-carbon
zwitter-ion (which contains a positive and a negative charge in the same
molecule) attacks carbonyl groups and, finally, Diels-Alder or electrocyclic
reactions .
The reactions were traditionally carried out by heating in
solvents such as ethyl ether, benzene or chloroform, in the presence of
organometallic reagents sensitive to protic solvents and in ethanol or ethanol-water
otherwise. As far as the inorganic syntheses are concerned, they were
essentially based on exchange or redox processes mainly in aqueous solution.
Only more recently has the need to work with labile species in catalytic
processes led to the use of synthesis techniques in an inert and non-protic
environment.
High Efficiency And Selectivity Catalytic Synthesis
Although catalytic syntheses have been an industrial reality
for several decades, they have evolved spectacularly by increasing efficiency,
in terms of speed, turnover (molecules transformed per mole of product), yield
(moles of useful product per mole of substrate put into reaction) and
selectivity (moles of useful product per mol of converted substrate). By
selectivity we mean not only chemoselectivity (i.e. the choice of one molecular
species over another), but also regioselectivity (choice of an attack site in
preference to another), stereoselectivity (choice of an space rather than
another) and enantioselectivity (choice of an optically active form in
preference to another).
Acid / base catalysis
Important progress has been made in the field of acid / base
catalysis of organic reactions through the use of solid, acid or basic
catalysts. Thus, the well-known Friedel-Crafts reactions are currently
achievable through the use of metal oxides, in particular of zeolites (mixed
oxides of silicon and aluminum that form structures crossed by channels capable
of hosting substrates and reactants). A proton species linked to zeolite oxygen
(with OZ = zeolite residue) is believed to be responsible for the formation of
the reactive intermediate, such as the alkylation of benzene with an olefin (R
= alkyl, aryl) ( Fig. 2 ).
Similarly, many reactions catalyzed by acids, such as the
oxidation of olefins to epoxides with hydrogen peroxide, the oxidation of
phenols to diphenols and acid transpositions are advantageously carried out
with solid catalysts of the zeolitic type. Acidic solids also catalytically
intervene in cracking and dehydrogenation processes of various types of olefin
hydrocarbons.
The art of conducting
oxygen to the reactive surface of the catalyst underlies the development of
these techniques, which, in many cases, involve the movement of ions in a solid
lattice. Not unlike the solid acid catalysts, the basic ones represent the most
modern version of the synthesis catalysed by bases in solution.
Catalysis with transition metals
The field of catalysis that has developed and continues to
develop faster is based on the use of transition metals in homogeneous or
heterogeneous phase in various oxidation states and mainly in the form of
organometallic complexes. In this case, the coordinating capacity of metals is
exploited in order to establish directional bonds with molecules or with
organic or inorganic groups, which are thus activated, i.e. transformed into
reactive species. In this way hydrogen can be split with the formation of two
metal-hydrogen bonds H − M − H and oxygen can give rise to the formation of
metal bonds oxo M = O or peroxo M (−O − O−) and to various other species, while
hydrocarbon carbon is activated through the formation of reactive carbon metal
MC species. Various types of reactions can occur on these bonds, such as those
of insertion of unsaturated compounds (olefins, carbon monoxide, etc.) followed
by reductive elimination, which restores the metal to its initial oxidation
state thus allowing it to act as a catalyst. Alternatively, many other reaction
stages can take place which allow the transformation of the chain bound to the
metal before its final elimination. A simplified representation of the
functioning of a catalyst M in various types of reactions is contained in
Alternatively, many other reaction stages can take place which allow the
transformation of the chain bound to the metal before its final elimination. A
simplified representation of the functioning of a catalyst M in various types
of reactions is contained in Alternatively, many other reaction stages can take
place which allow the transformation of the chain bound to the metal before its
final elimination. A simplified representation of the functioning of a catalyst
M in various types of reactions is contained,
Catalytic reactions of this type and various others have
found industrial application. Research is now aimed at developing high
efficiency and selectivity syntheses. Chemistry offers the researcher several
options ranging from varying the metal and its oxidation state to designing
ligandsand the use of different reaction media. In fact, it is a question of
using metals for each reaction that have the right potential to favor the
desired synthesis path.
The fine conditioning of the metal then takes place through
the use of ligands which can be very sophisticated as they have the task of
controlling the movement of electrons towards- or from the catalytic center and
the access of the substrate and the reagent to the same center in such a way to
avoid the establishment of unwanted secondary reactions. The solvent, or the
reaction medium in general, can exert a decisive influence on the association
of ligands and substrates to the metal center and on their dissociation. It
should be noted that binders, substrates and reagents can cause inhibition of
the catalytic activity following the formation of too stable complexes. This
represents a major problem in the development of efficient catalytic systems.
No less important is the problem of identifying the factors responsible for
controlling selectivity in its aspects of chemo-, regio-, stereo- and
enantio-selectivity. The catalytic system, in fact, may prefer a molecule or a
position or a spatial arrangement rather than another for steric and electronic
reasons and must be corrected through an appropriate modulation of the ligands.
identification of the factors responsible for controlling selectivity in its
aspects of chemo-, regio-, stereo- and enantio-selectivity. The catalytic
system, in fact, may prefer a molecule or a position or a spatial arrangement
rather than another for steric and electronic reasons and must be corrected
through an appropriate modulation of the ligands. identification of the factors
responsible for controlling selectivity in its aspects of chemo-, regio-,
stereo- and enantio-selectivity. The catalytic system, in fact, may prefer a
molecule or a position or a spatial arrangement rather than another for steric
and electronic reasons and must be corrected through an appropriate modulation
of the ligands.
Asymmetric catalysis
The topic that arouses the greatest interest of researchers
in the field of organic synthesis concerns asymmetric catalysis. Selectively
obtaining only one of the two enantiomers, which make up a chemical substance
with asymmetrical carbon (for example, our two hands are equal but not
superimposable), is a long-pursued goal. Being equal chemical compounds, they
are not chemically separable but are detectable by their property of rotating
the plane of polarized light and are therefore designated as optically active
substances.
The traditional method, to obtain a pure enantiomer,
consists in the indirect separation, according to which the racemic mixture of
the two enantiomers is reacted with an enantiomerically pure substance.
Starting from a compound with an asymmetrical carbon, a compound with two
chiral centers is obtained for each of the two enantiomers. These two new
compounds, called diastereoisomers, constitute distinct and therefore separable
chemical individuals, for example by crystallization. To then obtain the two
pure enantiomers desired, it is possible to resort to a chemical operation
capable of eliminating the auxiliary substance used for the resolution and
therefore regenerating it.
Asymmetric catalysis is based on the formation of two
diastereomers, through the coordination of a substrate capable of being
transformed into a chiral compound, and therefore called prochiral, to an
organometallic complex containing an optically active ligand. The two
diastereomers thus formed are reacted in situ with a reagent that discriminates
them by forming a single enantiomer and at the same time eliminating the
original organometallic complex, whose catalytic activity can continue further.
In this way, an olefinic prochiral substrate can be transformed by catalytic
hydrogenation into an enantiomer of the corresponding saturated compound, as
indicated in:
[1] formula
where R 1 , R 2 = substituents; LM = organometallic complex
catalyst; L = binder; S = prochiral substrate which gives rise to stereoisomers
of opposite chirality (+ or -); * indicates optical activity; S * H 2 is one of
the two selectively produced enantiomers.
This method has found application in the targeted synthesis
of important fine chemicals. The problems that remain open are mainly related
to the realization of catalytic complexes capable of obtaining total (pure)
enantioselectivity by designing ligands with the correct geometry. Another
problem concerns the amplification of chirality: starting from a minimum
optical activity, very high values were reached by means of suitable
catalytic systems capable of favoring one enantiomeric form by inactivating the
other. The development of new and more suitable catalysts continues
intensively.
Synthesis of polymers
Symmetry considerations underpin the most recent
developments in the design of binders for catalytic polymerizations. It should
be remembered that the synthesis of polymers is based on the reiteration of
elementary acts such as the condensation of two groups (e.g. a carboxylic group
with an alcohol group), or the addition of reactive species (radicals, cations,
anions, coordinated groups , etc.) to an acceptor substrate (e.g., an olefin).
Ziegler-Natta catalysis operates in the coordination sphere of a complex
containing a metal-carbon bond. While important industrial achievements such as
the synthesis of polyethylene and polypropylene are in progress, the most
recent research developments have led to the development of a great variety of
catalytic systems,
The fig. 4 shows the initial growth process of a
polypropylene chain according to two different modalities of regiochemistry.
The attack of the metal occurs on the external and internal carbon, of the last
unit of propylene incorporated in the growing chain. At the end of the
polymerization the chain detaches from the metal, generally through the
elimination of hydrogen, which leads to the formation of a terminal double
bond.
The problem of stereochemistry is more complex as the side
groups (methyl in the case of propylene) can be arranged on the same side
(isotactic polymers) or on alternating opposite sides (syndiotactic polymers)
or in an irregular way (atactic polymers). Beyond these possibilities, however,
there are many others that lead to isotactic blocks alongside syndiotactic or
atactic blocks or to copolymerization with other olefinic monomers, etc.
Controlling stereoselectivity may depend on the type of polymer chain or the
type of symmetry of the binder used. The latter can make the two sites equal
where the attack of the polymer chain to the olefinic monomer generally takes
place (homotopic sites) or it can make them mirror images of each other (enantiotopic
sites). In both cases the resulting polymer will be isotactic or syndiotactic,
respectively, as in passing from one site to another the polymer chain will see
the same surrounding or its mirror image. The olefinic polymers generally
appear in helical form with a helix pitch dependent on the steric size of the
substituents.
The design of new catalysts includes metals and binders of
different nature and thanks to the practical application of the latest
developments in quantum mechanics, increasingly refined syntheses of polymers
will be achieved.
Reaction of metathesis
Among the catalytic reactions of greatest interest, the
metathesis reaction of olefins occupies a particular place. It allows the
breaking of a double bond into carbene fragments that can combine with others,
generated by breaking a second double bond, thus forming new olefins. A
metallocarbene is responsible for the initiation of the reaction, which
involves the formation of a metallocyclobutane, capable in turn of splitting
giving rise to a new olefin and a new metallocarbene. A very simple example is
shown in fig. 5 , which refers to a single type of olefin, but also different
olefins can be effectively subjected to cross metathesis.
Despite the complexity of the mechanism, the reaction lends
itself to the synthetic realization of a great variety of products. This
methodology is particularly interesting if applied to olefins substituted with
various functional groups, to obtain a preferential stereochemistry, to the
field of alkynes and polymers and to its realization in aqueous medium. Yves
Chauvin, Robert H. Grubbs and Richard R. Schrock received the 2005 Nobel Prize
in Chemistry for the discovery and identification of the mechanism of this
reaction.
Synthesis with organic catalysts
Alongside the syntheses with organometallic catalysts, which
dominate the field of catalytic reactions, there are also those in which the
catalyst is an organic compound. These reactions date back many years, but are
mentioned here because this sector is experiencing a new development following
the discovery of the catalytic activity of various neutral molecules. Among
these we mention, for example, the nitroxide radical, which catalyzes organic
oxidation reactions and radical polymerizations, or even trialkylphosphines
which favor Michael-like additions to olefins or alkynes.
Multi-stage reactions in sequence
Modern organic synthesis also allows the carrying out of
multiple reactions in sequence, in which certain molecules or groups are
transformed according to a well-defined order. Although some types of organic
molecules can be synthesized in this way in the absence of metal catalysts, the
most significant results come from the use of organometallic catalysts, mainly
of the VIII Group of the periodic system of elements. It is thus possible to
synthesize complex molecules which are selected from molecular pools consisting
of simple molecules in a chemo-, regio- and stereo-selective way. In this way,
the behavior of enzymes is simulated. This objective also requires the
development of synthetic methodologies in which reactions promoted by different
types of catalysts are coupled so as to use the product of the activity of one
catalyst as a substrate for the subsequent catalyst. Research in this sense
offers interesting perspectives.
Pericyclic reactions
Cycloaddition reactions, or, more generally, pericyclic
reactions, represent a traditional terrain of chemistry, which has however
undergone a strong revival from theoretical studies (Woodward-Hoffmann rules).
Even if catalysts are used which modify the acceptor or
donor character of the components (diene and dienophile) by charge transfer,
the acceleration of the reaction and its selectivity depend on the formation of
cyclic transition states deriving from the delocalization of the involved
electrons. Pericyclic reactions lend themselves well to quantum mechanical
studies aimed at establishing the conditions for the formation of cyclic
transition states. On the basis of these theoretical guides, studies aimed at
building complex molecules through intramolecular cycloaddition reactions are
multiplying.
Organic synthesis on solid matrices
An important synthesis technique of organic molecules, which
allows the automation of the various stages leading to the product, was
developed by Bruce Merrifield (Nobel laureate 1984). It involves anchoring the
compound to be transformed to a solid matrix. The steps required for the
synthesis are then carried out on the solid using protective groups of the
functional groups that are not to be reacted. The product, deprotected and
purified in the solid state, is finally released with appropriate reagents. In
this way it is possible to obtain polycondensations of amino acids to peptides
and numerous other reactions (polysaccharides, polynucleotides, and so on). The
system lends itself to complete automation and continues to be used in numerous
syntheses.
Synthesis of coordination or organometallic compounds
anchored to surfaces
A modern technique for the synthesis of coordination or organometallic
compounds, particularly suitable for compounds that can be easily altered in
solution, consists in anchoring metal precursors to surfaces (for example, to
the oxygen of silica) and then carrying out the desired transformation on the
anchored species. The final product is then detached from the surface through
appropriate reactions.
Synthesis of nanostructured compounds
Nanostructured compounds, ie with dimensions around 10 −6
-10 −7 cm, deriving from the aggregation of atoms or molecules, can be produced
by resorting to confined environments, capable of influencing the growth of the
compounds themselves in the desired dimensions. Just as a protein such as
ferritin can influence the formation of iron oxide clusters in biological
systems, it is possible to obtain similar syntheses by resorting to micelles or
vesicles capable of performing a similar function. Nano-structured carbon
compounds are also fullerenes (C-60, whose structure is similar to that of a
soccer ball, with an average diameter of about 7 × 10 −8cm, C-70, etc.) and
carbon nanotubes, all obtainable at the electric arc. Numerous nanocompounds,
derived from elements or from elementary combinations, are currently under
study.
Supramolecular synthesis by self-assembly
Supramolecular synthesis has developed over the past few
decades. It is based on weak interactions as an ordering criterion. Although
self-assembled systems are very common in nature (DNA double helix,
polypeptides, cell membranes, etc.), and also in synthetic products (fibers,
plastic substances, etc.), the self-assembly technique based on non-covalent
interactions (forces of van der Waals, electrostatic interactions, charge
transfer, coordination to metals, etc.) is still in its infancy, although
important results have already been achieved both as regards organic synthesis
as well as inorganic and metallorganic synthesis. It is a question of choosing
sites capable of non-covalent interactions at the points necessary for
self-assembly.
For instance, a
system containing polypyridine chains will bind to a cuprous salt through
nitrogen repeating along the chain and the type of coordination around the
copper will produce a helical structure. It is also possible to host a molecule
inside the cavity of another if complementary groups in one and the other are
able to recognize each other, for example through hydrogen bridges or
coordinative bonds..
Supramolecular systems are present in organometallic
complexes used as catalysts but also other types of supramolecular structures,
capable of exerting catalytic activity, are being studied. nitrogen repeating
along the chain and the type of coordination around the copper will produce a
helical structure. It is also possible to host a molecule inside the cavity of
another if complementary groups in one and the other are able to recognize each
other, for example through hydrogen bridges or coordinative bonds. In general,
the correct positioning of donor groups and receptors can ensure the
self-assembly of even complex molecules.
The synthesis of inorganic solids, such as oxides and
sulphides, constitutes an important area of solid state chemistry. The assembly
of these species into crystalline structures is one of the topics under
development in the field of supramolecular chemistry. What is called crystal
engineering is developing rapidly despite the difficulty of the synthesis being
kinetically controlled and therefore its outcome cannot be predicted based on
thermodynamic considerations.
Photochemical synthesis
The possibility of inducing chemical reactions using light
energy of a wavelength such as to produce the breaking of a covalent bond has
been recognized for a long time. More recently, the possibility of exciting an
electron, making it pass into the orbital of an excited state, has pushed
research towards increasingly effective systems for separating the electron
from the proton, based on trapping devices that allow the electron to be used
before it this rejoins the proton.
As in many other cases, chemical synthesis is inspired by
biological synthesis and in particular by the cycle of reducing carbon dioxide
to sugar. In this process the preliminary stage consists in conveying the
electron towards the reducing catalytic system through a complex system of
porphyrins.
Systems that develop hydrogen from water under the action of
light have already been described and titanium dioxide-based catalysts, doped
with suitable metal combinations, have shown a fair potential. The knowledge of
the electronic conduction system acquires a fundamental character for the
development of this type of synthesis.
Electrochemical synthesis
Electrochemistry offers a powerful tool for transmitting or
receiving electrons from a liquid or solid system to a suitable acceptor and
therefore generates possibilities for synthesis based on the use of the
electron. Traditionally, the need for an ionic liquid to conduct the electric current
in an electrochemical cell limited the scope of electrochemistry to aqueous
solvents, capable of dissolving inorganic (chlorine-soda synthesis) or organic
(Kolbe synthesis) salts.
The discovery of conductive organic salts, together with the
improvement of the electrodes and the more effective control of the reaction
conditions, has allowed the use of electrochemical synthesis in important
industrial achievements such as the synthesis of adiponitrile from
acrylonitrile at the cathode of an electrolytic cell that uses L' electron and
proton obtained from water.
From this discovery, organic electrochemistry has taken new
impetus and numerous syntheses have been carried out using reaction methods at
the cathode or anode of an electrolytic cell. Photoelectrochemical systems then
combine photochemical synthesis with electrochemical synthesis, in particular
for the development of hydrogen from water, as explained in the previous
section.
Transfer of the concepts of biology to chemical synthesis
A series of chemical syntheses of biological derivation, of
which an example is offered by the reactions related to photosynthesis, has
developed and is continuously increasing. The criteria governing biological
synthesis, in fact, can be imported for use in chemical synthesis. Significant
examples are offered by artificial enzymes, antibody- catalyzed reactions and
self-replication.
Artificial enzymes
As natural catalysts, enzymes perform extremely selective
activities in the biological environment. However, they can be transferred to
chemical environments that contain different substrates and reaction media.
Under these conditions, their activity can adapt to new substrates and equally
express themselves in a selective way.
Alternatively, the chemical transformation of the enzyme,
for example the replacement of an amino acid in a protein that is part of the
enzymatic structure itself, can generate different activities and other types
of synthesis. The enzymes that come from chemical transformations have been
given the name of artificial enzymes.
Synthesis with antibodies
It is well known how foreign substances to our organism
trigger a defense reaction in which substances called antibodies, which possess
high molecular recognition properties, recognize and neutralize foreign
substances by coordination. This coordinating capacity has been used to elicit
antibodies of molecules that have structures similar to those of the transition
state of organic reactions that are to be catalyzed. Stabilizing the transition
state of a reaction by means of coordination means to favor this reaction.
Although it is not possible to isolate a transition state, it is always
possible to hypothesize an analogous stable compound, with similar structural
and steric properties, and the antibodies it will elicit will also be able to
stabilize the transition state of the desired reaction.
Self-replication
The best-known example of a molecule copying itself is
offered by the self-replication of DNA chains, the bases of which establish
hydrogen bridges with other complementary bases. Therefore, if a chain capable
of molecular recognition is placed in contact with its complementary segments,
it is able to reconstitute itself through the use of reagents that cause the
various segments to be welded, thus reproducing the original molecule. This
criterion of self-replication underlies the origin of life. Chemical synthesis
is taking its first steps in this fascinating sector.
New means for chemical syntheses
The speed and selectivity of chemical syntheses are profoundly
influenced by the reaction medium in which they take place. The study of ionic
pairs present in solution has long conditioned the development of synthesis
through the use of dipolar aprotic solvents, such as dimethylformamide,
dimethylsulfoxide, tetramethylurea, etc., capable of coordinating cationic
species more strongly than anionic ones, thus favoring the reactivity of the
latter.
For example, the fluoride ion in cesium fluoride is so
weakly coordinated by dimethylformamide, used as a solvent, that it can exert
catalytic activity in place of traditional basic catalysts in many condensation
reactions. The rational design of the solvent, for a given type of reaction,
must take into account the mechanism in order to facilitate the determining stage
of the rate. For example, a polar stage consisting in the dissociation of an
anion from a cationic complex will be favored by a polar solvent. They have
recently been identified in ionic liquids,
The transfer of ion pairs to an immiscible aprotic liquid forms
the basis for the phase transfer technique. Reactions that do not occur in
water because an anionic species, soluble therein, does not react easily with a
hydrophobic substrate, are carried out by transferring the anion into the
immiscible solvent by associating it with water, by exchange in aqueous
solution, to a cation capable of easily transferring in the hydrophobic medium
(e.g., a quaternary ammonium or phosphonium cation with one or more long
hydrocarbon chains). Phase transfer is applicable to a large number of
reactions in which the transition from aqueous to hydrophobic solution and vice
versa can be taken advantage of, particularly in the case of catalytic
reactions.
A further development has been offered by the synthesis in
the fluorose phase, which consists in the use of a perfluorinated solvent in
which most of the organic solvents are insoluble. Perfluorinated catalysts are
soluble in the fluorinated phase, which allows easy recycling of the catalyst,
while the reaction product is separated or extracted from the organic phase.
However, several options are possible, for example it is possible to operate at
a sufficiently high temperature to allow the formation of a homogeneous phase
in which the reaction takes place and to separate the products at a low
temperature when the phases return to separate.
Another way, of using unconventional means to favor the
reactivity and / or selectivity of chemical syntheses, consists in carrying out
reactions in cavities offered by special natural or synthetic compounds such as
cyclodextrins or the aforementioned zeolites or intercalated inorganic
compounds such as montmorillonite, which allow to host reactants between the
layers that make up the lattice. The method consists in forcing the reactants
to approach at a distance that favors the reaction. In this way Diels-Alder
reactions and selective oxidation reactions were accelerated.
It should be remembered the use of supercritical liquids, in
particular carbon dioxide. In supercritical conditions, intermediate properties
occur between those of gases and those of liquids and this makes, for example,
possible the solubilization of metal salts and polymers with the consequent
realization of syntheses that would otherwise be impossible or very difficult.
Finally, it is worth mentioning the transfer of energy to
the reaction medium through microwaves or ultrasounds to accelerate the
chemical reactions.
2. TARGETED SYNTHESIS
The targeted syntheses are aimed at obtaining an objective
consisting of a defined product rather than a methodology. They can be
classified according to the type of product to be obtained, such a product may
already exist in nature, but it is also possible to develop advantageous ways
to obtain chemical compounds of various types, or products not yet existing
whose preparation is considered possible.
The former include basic industrial products, polymers,
commodities (eg sulfuric acid), fine chemicals, natural compounds, catalysts
and materials of all kinds. In all these cases, it is a question of finding a
new or better process as regards yield, selectivity, catalytic efficiency,
environmental compatibility, etc., and the choice between the various available
methodologies is guided by technical-economic criteria.
The latter include compounds and materials with properties
different from those existing or designed at the table. In these cases the
synthesis is guided by the knowledge of the relationship between structure and
properties of the product and by theoretical considerations.
Chemical syntheses aimed at existing products
The synthesis of industrial compounds (basic or commodities)
requires the use of the methodologies mentioned in the first part to be able to
carry out processes that are competitive with the existing ones. In particular,
the catalytic methods for organic synthesis allow the direct activation of the
most common bonds, such as HH, CH, OH, NH, CC, CO, CN, OO. Among the syntheses
of organic base products which can be replaced by more effective catalytic
processes are methanol from methane; ethyl alcohol and acetaldehyde from
methanol and carbon monoxide; acrylonitrile from propane, maleic anhydride from
butane; gasoline from methanol or from carbon monoxide and hydrogen.
The synthesis of products and materials in general can
benefit both from catalytic techniques (e.g., the synthesis of polymeric
materials by means of new catalytic systems is a field in great evolution) and
from techniques of assembling simple units in complex structures (such as
synthesis of zeolites from silicon and aluminum oxides).
When it comes to complex products, which require the
concurrence of various synthesis methodologies, then the targeted synthesis
requires specific strategies. In fact, it is a question of choosing among the
various possibilities the most suitable combination of methods to achieve the
desired objective. The logical procedure to follow is called retrosynthesis and
consists of the decomposition of the target molecule into many pieces or
precursors, called syntones, from which it is possible to reconstitute the same
molecule using proven synthesis methods.
Of course, according to the complexity of the molecule, each
primary synthon can be decomposed in turn into other simpler ones up to easily
available or accessible basic molecules. For example, adipic dinitrile,
intermediate for making nylon 6,6, it can be obtained through different methods
starting from different syntones. It is possible to imagine keeping the
skeleton of carbon atoms intact, transforming adipic acid as a synton with 6
carbon atoms, into dinitrile by treatment with ammonia at high temperature (via
A).
Adipic acid, in turn, can be obtained from cyclohexane which
also has 6 carbon atoms, by oxidation. Alternatively, it is possible to start
from a skeleton of 4 carbon atoms such as that of butadiene by catalytic
addition of hydrogen cyanide (via B). It is also possible to generate the
target molecule from 2 equal syntones of 3 carbon atoms such as acrylonitrile,
which in turn can be obtained by amoxidation of propylene (via C) (
Given the numerous possibilities offered by the
retrosynthesis process of molecules that are enormously more complex than the
one exemplified, which are generally biological compounds, the assistance of
suitable computer-assisted synthesis (CAS) is necessary in these cases.
Total syntheses are the most fascinating result of targeted
synthesis. Syntheses that have made history are those of vitamin B 12,
chlorophyll, penicillin, taxol and hepothylidone. Total syntheses not
infrequently require dozens of steps, which can be articulated in series
(linear syntheses) or in parallel with final reunion (convergent syntheses).
Many passages contemplate the presence of functional groups
that can negatively interfere and therefore must be protected for the time
necessary to complete a certain passage and subsequently deprotected. The
protective group technique has developed in parallel with the synthesis
methodologies and offers a huge number of possibilities. Currently, however,
there are compatible catalytic synthesis techniques, with a great variety of
functional groups, through which it is possible to arrive directly at the
desired compounds.
Synthesis of new compounds and materials
The synthesis of compounds and materials with new or
improved properties presents a challenge of ever greater proportions. The
entire field of specialty products, from food additives to detergents, from
materials for electronics chips to those for lasers, as well as the field of
polymers, from plastics to elastomers, and that of functional materials, from
conductors to liquid crystals, they feed on the continuous development of
synthesis methodologies, which are oriented towards obtaining the desired
product or artefact based on the increasingly precise knowledge of the relationship
between structure and properties (thermal, mechanical, and so on).
In many cases, once a base compound of promising activity
has been identified, rapid screening of a large number of variants or high
throughput screening (HTS) is required as is regularly the case for
pharmaceutical substances, pesticides, herbicides and numerous other categories
of compounds. For this reason, techniques for building libraries of binders
have been developed , for which thousands and millions of variations are produced
at the same time.
For example, a basic
structure X containing substituents R 1 , R 2 and R 3it can give rise to
variants with better properties according to the type of substituents and their
combination. The combinatorial technique allows to produce step by step all the
desired variants by simultaneously reacting a series of molecules X, containing
R 1 substituents , with a series of reagents capable of introducing the
R 2 group , and finally the R 3 group with all the their variants. These
combinatorial synthesis procedures can be carried out in solution or more
effectively in the solid state, using the Merrifield technique.
The materials can be organic or inorganic (remember, for
example, next to nylon fibers, glass fibers). Organic polymeric materials offer
a broad spectrum of application properties that depend on their structure. The
same can be said for inorganic materials, which often derive from the
repetition of simple units consisting of metal oxides or sulphides and
organic-inorganic hybrids.
The development of
techniques aimed at the synthesis of solids with certain properties (optical,
electrical, magnetic, etc.) for a wide variety of uses (optical fibers,
batteries, fuel cells, chips, etc.) represents a task of formidable complexity
.
The characteristics necessary for superconductivity have not
yet been clearly delineated and the synthesis of mixed oxides is still largely
empirical, while drawing inspiration from hypotheses on the
structure-superconductivity relationship.
Similar considerations can be made regarding the knowledge
of the structure-magnetism relationship, which proposes to guide the
construction of magnetic solids, resulting from the aggregation of many
elementary magnets made up of units with unpaired electrons.
The assembly carried out through the methods of
supramolecular chemistry (non-covalent interactions), is offering great
opportunities for development. Important application properties depend on
molecular orientation and packing, such as, for example, those of liquid crystals,
widely used for television screens, thermometers, and so on. The use of metals
or simple elements or compositions in an aggregate state such as clusters,
colloids, micelles and nanocompounds in general, it is establishing itself as a
topic of extraordinary interest both in the materials and in the biological
sector.
The synthesis of fullerenes and other carbon combinations
(nanotubes) offer opportunities for use, after appropriate functionalization,
in numerous application fields, such as those of conductive materials,
catalysts, materials for non-linear optics, adhesives, functional polymers, and
so on.
Similar considerations can be made for biological compounds
and materials, where, for example, the synthesis of species capable of
activating biological receptors is the basis of important developments in
pharmaceutical products. The phenomenon of biomineralization also takes place
in confined environments within biological structures and the chemical
synthesis of nanostructures therefore finds inspiration in a biological
phenomenon.
In this field, everything concerning DNA or RNA and the
proteins encoded by them is the subject of a very intense study. It should be
remembered that the PRC (Polymerase chain reaction) technique, which allows the
amplification of DNA through repetitive cycles of wrapping nucleotides around a
helix of the DNA itself, is a chemical procedure that applies the concept of
self-replication mentioned above.
Kary Mullis received the Nobel Prize in Chemistry in 1993
for finding a way to initiate the replication and wrapping process through the
use of primersoligonucleotides, capable of hooking single strands of DNA
obtained by heating it (denaturation). By supplying the system with nucleotide
substrates, replication of the stretch of DNA under examination is obtained by
DNA polymerase. The procedure is now routine for DNA recognition tests, but it
also lends itself to various other applications such as specific change of
nucleotides (direct mutagenesis).
However, very many organic molecules are capable of
determining behavioral variations of biological structures in general. Again,
the progress of knowledge of the structure-activity relationship offers a
valuable guide to synthesis. This knowledge becomes more and more detailed and
precise on the basis of structural X-ray determinations and theoretical
calculations.
Targeted synthesis of objects proposed by theoretical
considerations
Finally, it should be remembered that in addition to the
targeted syntheses of molecules, whose properties are predictable based on the
knowledge of the structure-property relationship, there is a series of
theoretically predictable object syntheses that pose as a challenge to the
intelligence and skill of the researcher. .
Some of these
syntheses were made as a satisfaction of a scientific curiosity and only later
was an application found. For example, the synthesis of Cuban (a cube-shaped
hydrocarbon molecule) first satisfied a theoretical interest only and later
demonstrated potential in the field of explosives, as the molecule is endowed
with high tension energy, which can be released by appropriate reactions . Even
dendrimers, tree-shaped branched molecules, they were first objects of
intellectual interest, and only more recently have practical applications been
proposed, for example in the deposition of molecular layers.
Many curious objects have been prepared by exploiting the
weak interactions of supramolecular chemistry, such as rotaxanes (linear
molecules that cross other donut-shaped ones), catenans (annular molecules that
intersect others), etc. For these compounds, uses in the field of molecular
electronics have been hypothesized. The latter aims to realize molecular
movements similar to those of macroscopic mechanics, which are found for example
in biological systems (contraction of muscles, rotator devices as in the
synthesis of ATP, described by Nobel laureate John Walker) and in those typical
of logic computer science (yes / no, logical gates, etc.).
A recent example of synthesis of two interpenetrating rings,
carried out by James F. Stoddart and Robert H. Grubbs (2005 Nobel Prize in
Chemistry) and collaborators, uses the methodology of metathesis. It starts
with the opening of a ring, consisting of a cyclic polyether containing a double
bond and electrostatic interactions, to make sure that the open molecule can
penetrate into the other ring arranging itself around a positive charge; at
this point the reversibility of the metathesis reaction allows the ring to be
closed again.
Thus, the concatenation of two rings was achieved, identical
to the starting ones, but arranged differently (topological isomerization).
