Essay: Organic Solid-State Reactions

1 Introduction

Organic solid-state reactions have gained much attention during the past few decades. The major reason is that organic solid-state reactions are highly selective and fast as compared with to solution-based reactions. Moreover, without the use of organic solvents, reactions can be less hazardous and are therefore environmentally benign. These reactions also have potential to aid the formation of molecular architectures that are difficult to form in solution-based chemistry. As a result, organic solid-state reactions are very interesting to organic synthetic chemists. It is necessity to broaden the area of research since it can lead to a more sustainable way to carry out organic reactions. It is also a challenging area to research in chemistry as many organic solid-state reactions still remain mechanistically unknown and problematic to anticipate the structure of crystal.
This review will introduce the reader to the basic concepts of organic solid-state reactions, lay out several examples and emphasise on the benefits of such reactions. Also, elaborate on the relationship between organic solid-state reactions and the environment.

Chapter 1 – What is Organic Solid-State Reactions?

1.1 What is Organic Solid?

Solid is one the basic state of matter alongside with liquid and gas. It has a permanent shape and volume whereas liquids change their shape according to its container and gases have the tendency to expand its volume to take up all available spaces. Solids exist in a variety of forms, such as non-crystalline, crystalline and amorphous. In crystals, atoms tightly packed together with a set of orientation, so that they form highly ordered and periodic three-dimensional arrays, known as crystal lattices. It is important to understand the structure of molecules within the crystal lattice and the nature of bonding between the molecules, as these determine reactivity of a molecule in the solid state.
Organic crystals are comprised of highly ordered three-dimensional molecular arrays and do not contain metals. Inside the crystals, the molecules are largely held together by weak non-covalent interactions such as van der Waals forces, hydrogen and halogen bonds. Therefore, molecular crystals are soft and exhibit relatively low melting points.

1.2 History of Organic Solid-State Reactions

The beginning of research of organic solid-state reactions can be trace back to 1828 when Friedrich W??hler discovered that ammonium cyanate can be converted to urea in solid-state. Unfortunately, since then there were no great developments in organic solid-state chemistry until the early 1900s. Riiber has found that cyclobutanes can be prepared in solid state using cynnamylidinemalonic acid and cynnamylidineacetic acid. , A few years later, Max von Laue discovered that crystal diffract X-rays. Based on his work, William Henry Bragg and his son, William Lawrence Bragg, had establish the Bragg’s law and suggested that planes of crystal can be observed through scattering of X-ray and marked the beginning of investigations of crystal structures. The area of solid-state chemistry had a great leap forward and hence became practical to identify atoms position in solid. This allowed studying the connection between the structure of a molecular crystals and their reactivity.
During the 1950s to 1970s, Gerhard M. J. Schmidt and his co-workers in the Weizmann Institute of Science used X-ray diffraction to investigate the structures of organic solids in order to understand their reactivity and properties. Schmidt’s group studies spent a considerable amount of time studying the solid-state photodimerisation of substituted trans-cinnamic acids and discovered why they react in a regioselective fashion and more efficient than in solution. This research marks the starting point of intense research activity in organic solid-state synthesis and Schmidt is thus considered to be a pioneer of modern organic solid-state chemistry. ,

1.3 Elements of Organic Solid-State Reactions

Cohen, Schmidt, Thomas, Singh and others have found out many interesting facts occur in organic solid-state reactions. , , , These features also distinguish truly what is organic solid-state reactions as these characteristics are not likely to be find in conventional organic reactions. These features are compiled below.

First of all, chemical properties and innate reactivity of molecules are less important in solid-state reactions. Packing pattern of atoms, the orientation of the reactants are far more important because they have more influence on the outcome of solid state reaction. Unimolecular reactions often occur easier than bimolecular or multimolecular reactions in solid state. This is because rate determining step for organic solid-state reactions are often depend on diffusion of reacting molecules to the site of reaction. When there are more different types of compounds reacting together, there will be more variation. The variation in here means that there will be greater variety of crystal geometry preference unless their shapes are complementary to each other. Otherwise these reactions are slower than melting them down or reacting in solution. Therefore, orientations of molecules are far more important than innate chemical reactivity in organic solid-state reactions. Second, some organic solid-state reactions happen more quickly than some reactions in solvent. However, the number of products in organic solid-state reaction is lower as in the same type of reaction that takes place in solution. Third, in some occasion under UV irradiation, molecules are able to react freely in solid-state but suffer isomerization in the melt. Fourth, molecules are not so flexible in crystalline organic solid. In other words, a crystal with a specific space group does not have much variety of conformation that can adapt. In a crystal, there are a well characterised space symmetries and geometries in molecules. Any intermolecular interactions are rigorously limited.

However, when the solids are dissolved in solution, all the weak intermolecular interactions will be destroyed and the reacting molecules will partner with each other randomly with respect to their chemical properties. This will take some time for the reactants to find their desired reactive site. However, a number of organic solid-state reactions do not involve much molecules movement and they occur very fast simply by grinding the solid chemicals together. It is said to be a diffusionless reaction. This is because the molecules are forced to react with their neighbours as no medium is provided to mediate the reaction. One of the classic examples has been shown below. (Figure 1)

Figure 1. Reaction of 1,1,6,6-tetraphenylhexa-2,4-diyne-1,6-diol and benzophenone.

Fifth, a vast amount of organic solid-state reactions are exothermic which means that they are heat releasing. Sixth, dislocations, defects and impurities play an important role in organic solid-state reactions. They generally provide empty spaces or new areas for molecular motion and act as a starting point of a reaction. Once a slight motion has occurred, it is easy for remaining molecules to follow up and accommodate themselves spontaneously. Seventh, a wide range of polymorphs can be found in molecular crystals. Polymorph refers to a particular solid material that has the capacity to exist in different formation of crystal structures. Molecules take up different spaces and arrange themselves in different fashion. There are number types of polymorphs such as conformational and tautomeric. N-acetyl-L-cysteine is one of the examples of conformational polymorph. (Figure 2) Red stands for oxygen, yellow stands for sulphur, cyan stands for hydrogen and blue stands for nitrogen. Hydrogen bonds are formed between different oxygen and hydrogen on different conformational polymorphs. For example, O from -OH of form I acts as hydrogen bond acceptor while O from ‘COOH of form II acts as hydrogen bond acceptor.

Figure 2. N-acetyl-L-cysteine Form I and Form II.
By reacting different polymorphs together, they react to give extraordinary product with 100% yield. For example, Polymorph A reacts with Polymorph A will give new product C. Polymorph B reacts with Polymorph B will give new product D and so on. Eighth, there is a balance between steric and electronic properties in crystal that affect reactivity. Despite when the crystals have similar chemical structure but different electronic properties or the other way round, only the one that has favourable topochemistry is considered as reactive. ‘Solvent effects’ are produced when the reactive sites in crystals are surrounded by molecules. Lastly, the reaction products in solid-state reactions can be different than in solution-base reactions. (Figure 3) Stereoselectivity can be enhanced in the solid-state. (Figure 4)

Figure 3. Photochemical reactions of acenaphthylene-1-carboxylic acid in different reaction state.

Figure 4. Photochemical reactions of 1-chloroanthracene in different reaction state.

1.4 Kinetics of Organic Solid-State Reactions

Morawetz illustrated that presence of dislocations and impurities has a direct impact on the mobility of molecules in the crystal lattices. In inorganic reactions, molecules can either insert themselves into interstitial positions or into available empty sites. However, that is not the case in organic solid-state reactions where molecules can only fill into free spaces due to the fact that the size of molecules are large and lattice are closely packed together. This is consistent with the idea suggested by Morawetz as extra spaces can be created by dislocations or impurities. The reasons behind will be cover in Chapter 4.

Rastogi, N. B. Singh and R. P. Singh had applied a capillary technique to study the kinetic pattern of solid-state reaction. Two interesting process can be observed and they are surface migration and penetration.

Figure 5. Surface migration of black and white species.

In Figure 5, there are two species of powdery solid indicated in black and white colour. If they are put very close to each other, black species will diffuse towards the white side through the boundary labelled as AB. This process is named as surface migration. A colour zone can be observed as time goes by and will stop growing after a certain period of time. Notably, the activation energy of this solid-solid reaction is low. Moreover, diffusion rates are different when they are kept in contact than when they are separated by an air gap. As the size air gap’s size increases, diffusion rate decreases. The reason behind is that involving an air gap means longer diffusion path and thus requires high activation energy to kick to start the reaction. The low activation energy of the reaction suggested that diffusion must occur through surface migration but not vapour-phase diffusion.
Another essential part of solid-state reaction is the penetration of black species into the lattice which involves two stages. The first stage is lattice contraction or expansion that creates gaps and tunnels in crystal grains. These features allow diffusion of species (i.e. molecule) in crystal. (Figure 6) Once the black species diffuse in and surround themselves with white species, the second stage of penetration will take place, which is penetration into lattice.

Figure 6. Diffusion of black species through gaps and tunnels in crystal.

Chapter 2 – Environmental Aspects of Organic Solid-State Reactions

Solvent has a long history in mediating and moderating chemical reactions. However, they are in top ranking of unsafe and damaging chemicals in respect to environmental protection. The reason is that highly toxic solvents are difficult to store safely due to their high volatility. It is therefore important to develop cleaner ways to conduct organic reactions. , Thus, in order to minimise the harmful effects, the interest in solvent-free reactions has significantly increased in recent years.

Loupy and Walsh have shown a number of advantages of solvent-free reactions. , A purification step can be removed as there are no solvents to extract from the obtained products. Moreover, solid-state reactions produce very few side products. The major side products are mainly water or inorganic salts that can be easily removed. Therefore, less waste and pollution are emitted to the environment. As stated before, solid-state reactions can proceed faster than those in solution. The reduced reaction time consequently contributes to lower energy consumption. Reactor size can be scale down to save handling cost and labour cost. Overall, capital investment has been reduced and that is important to the industry. ,

The concern of global warming and environmental protection has dramatically increased since the 1990s and led to the establishment of the twelve principles of green chemistry by Anastas and Warner in 1998, and the introduction of a new area of chemistry, namely ‘green chemistry’. Organic solid-state reactions have a strong connection with green chemistry since one of its main goals is to identify methodologies and technologies that will require minimal use of solvents in organic synthesis. This prevented the production of waste which fulfils the prevention criterion. Moreover, elimination of solvent has greatly reduced toxicity and harmful effect to human. This conforms to less hazardous chemical syntheses and designing safer chemicals criteria. Some organic solid-state reactions can achieve 100% yield without any form of loss, an example is shown in Figure 7. This satisfies the atom economy criterion as it refers to the effectiveness of conversion in chemical reaction in respect to all the atoms involved.

Figure 7. Reaction of 2-mercaptobenzothiazole and methylamine.
Organic solid-state reactions have high stereoselectivity so no protections or deprotections are required to produce a specific product. No stoichiometric reagents are required. This fulfils reduce derivatives and catalysis criterion. (Figure 4)

Chapter 3 – Criteria for Organic Solid-State Reactions

It is important that a clear boundary should be defining true solid-state reactions from other reactions to prevent any confusion so that researchers can truly focus on what they are doing and no information mislead the readers. Morawetz had defined four criteria for organic solid-state reactions in 1966.13 Paul and Curtin had further defined the five criteria in 1973.

The first criterion is that such reactions can only proceed in solid state ‘ they do not proceed in solutions and, if they do, they proceed very slowly. Secondly, the reactivity of closely relevant compounds has noticeable differences when reaction occurs in solid-state. Thirdly, the product outcomes of organic solid-state reactions are different from liquid state. Fourthly, different crystalline modification can result in same reactants which have different reactivity or formation of different product. Lastly, mixtures of products and starting materials have a specific eutectic point, and solid-state reactions occur in a temperature below this point. This is because the eutectic point is the lowest melting point of mixture and is a boundary between solid phase and liquid phase.

Chapter 4 – Organic Solid-State Reactivity Models

Reactivity models are used to explain how a solid-state reaction starts and provide insights on how molecules interact together during reaction. Before discussing the models, it is important to know where they generated from. Schmidt and co-workers in the Weizmann Institute have carried out a wide range of photochemical solid-state reactions and established the so-called topochemical postulates. The topochemical postulates stated that ‘reactions in crystals proceed with a minimum amount of atomic and molecular movement. Crystal packing of starting materials is the factor that controls the reactions.’ , , and suggested that centre-to-centre double bonds separation need to be smaller or equal to 4.2?? and lie parallel to each other. The postulates are very successful in predicting the outcome and more concern has been put on deriving other models in order to learn more about organic solid-state reactions.

4.1 Reaction Cavity

Reaction cavity was the first concept implied from the topochemical postulate and was introduced by Cohen in 1975. He defined the reaction cavity as the space in the crystal occupied by the molecules which directly participate in the reaction and surround with molecules. In favourable conditions, according to the topochemical postulate, reactions are under lattice control so that molecules have minimum amount of movement and no deformation of reaction cavity’s surface. On the contrary, formation of gaps may cause the cavity out of shape due to molecular movement. Thus, repulsion forces raise and attractive forces drop. This is said to be unfavourable. (Figure 8) Moreover, there is a chance that many different reactions are topochemically allowed at the same time. The one that does not involve much deformation of reaction cavity will take the priority first.

Figure 8. Difference between favourable and unfavourable conditions in reaction cavity.
Based on this idea, Gavezzotti introduced molecular volume and volume analysis. This analysis is useful in investigating steric effects based on vacant and occupied spaces within crystals, and therefore delivers quantitative information on steric effects. A few years later, he summarised different computational methods, using bis-(3, 3, 3-triphenylpropanoyl) peroxide as an example to suggest that elimination of small molecules are viable in crystals with low packing coefficient. Reaction cavities are important in many applications which are stated by Boldyreva in 1997. It emphasizes that ‘micro-reactors’, such as zeolites, can be used to synthesise chemicals. In addition, if the free spaces of cavity are large enough to prevent reacting with neighbour molecules, the cavity can be used as storage for drugs.

4.2 Steric Compression Control

Steric compression control was suggested by Ariel and co-workers as an extension to previous works. It illustrated that changes in reactivity are due to steric effects caused by molecules surrounding the reaction site in the crystal lattice. Steric compression control applies to both unimolecular and bimolecular reactions. An interesting example that illustrates the concept of steric compression control is that ene-dione photochemistry where the rate of formation of cyclobutanone is decreased in the case of compound 2 but not in 1. (Figure 9)

Figure 9. Structure of ene-dione.

3 is a three-dimensional representation of 2. Due to presence of an ethyl group in 2, it causes adverse interactions between methyl and ethyl groups as shown as dotted lines. This does not occur in compound 1, which only contains methyl substituents. Notably, molecules in the crystalline state do not have the capacity to freely change conformations and lack of the ability to minimise steric hindrances leads to lower reactivity.

4.3 Local Stress

The environment serves not as a passive cradle but as a press.

This new idea is opposite to the concept of reaction cavity and created as local stress which was suggested by McBride in 1983. Stresses are built up in the crystal continuously throughout the reaction and induced on molecules, so it is impossible that reaction follow the pathway with little atomic movement. Further, the molecular surrounding also has impacts on the reaction based on its mechanical properties. The study using dibenzoyl peroxide in a system with common stress but various reaction cavities proved the existence of stress. It also suggested that reaction cavity’s shape has smaller effect on the orientation of the product than stress. In addition, fourier transform infrared (FTIR) spectrometer is able to collect a wide spectral range of high resolution data for easy comparison. By comparing four FTIR spectra, they also show signs of stress as consecutive changes in certain IR stretches are found. As temperature increase, radical-pair transformations occur and rearranging their geometry by relieving the stress. Stresses are released as pressure. Therefore, absorptions of wavelength reduce. The drop of wavelength indicated the existence of stress and this will significantly affect reactivity of organic solid-state reactions.

4.4 Role of Defects

Crystal defects appear form of point, line and planar defects. In organic solids, point defects do not have great impact on reactivity whereas line and planar defects have more influence on reactivity. The reason is that sublimation enthalpy has the same order of magnitude as point defects formation. Therefore, they are too slight to have any effects. Williams and Thomas provided great insight into lattice imperfections in organic solids, and suggested that they have significant effects on photodimerisation of anthracenes in crystalline solids. Few years later, the relationship between dislocations and reactivity of organic solids had been investigated. It was reported that energetics, stereochemistry and catalytic impurities at dislocations may enhanced reactivity. The extra strain energy compensate by dislocations can reduce the kinetic barrier and hence change the reaction rate. Molecules in dislocations tend to orient themselves differently than those in dislocation-free regions and allow for the formation of unpredictable products with a distinct stereochemistry that could not be obtain under normal condition (more specifically, in perfect crystals). Catalytic impurities tend to accumulate in dislocations and speed up solid-state reactions. Moreover, it is known that X-ray diffraction is not able to identify any forms of defects. On contrary, chemical etching was the best method for identify and characterize dislocations in organic solids as pits will create after the process. Notably, dislocation pits are always pyramidal, thus easier for detection. An example of defect stimulated reaction has been reviewed. It was reported that 4-chlorocoumarin did not favour the topochemical postulate but still undergo photodimerisation. The centre-to-centre distance well greater than 4.2 ?? and double bonds do not lie parallel to each other. This suggested that external movement forced them to come close so that ?? orbitals can overlap and undergo reaction. This movement is due to dislocation.

Chapter 5 – Stages of Organic Solid-State Reactions

Paul and Curtin had defined four crucial steps in organic solid-state reactions in 1973.22 These stages are relative to thermodynamic controlled reactions which associate with intramolecular change, and allow diffusion of reagents in crystals. The four stages include are molecular loosening, molecular change, solid solution formation and separation of product phases. (Figure 10)

Figure 10. Four stages of organic solid-state reaction.

The solid-state reaction begins at rest, where molecules in a crystal are closely packed together and have no flexibility. At the initial stage, it was found that changes happen at sites of nucleation and continue to extend to the entire crystal. The direction of reaction extension is hardly predictable. However, it is known that the spread is quickly along the plane perpendicular to the long central axis of crystal and slower along this axis. This process can also be promoted by crystal defects or by injection of reactant’s products. In addition, mechanical stress tends to play an important role in nucleation which had been studied by McCullough, Paul and Curtin in 1972. When stress accumulates and exceeds the tension that the crystal can hold, cracks within the crystal are created and facilitate the formation of new nucleation sites. Therefore, the whole process of molecular loosening is finished.

The next step, namely molecular change is the stage that involves the breaking and forming of covalent bonds. It is important to have a quantitative understanding of how specific characteristics of organic solid-state reactions have an effect on reaction rates, so able to apply and accomplish results that are not able to do in solution. Nonetheless, it is still difficult to evaluate kinetic rate equation due the fact that crystallites vary greatly from each other. This had been proved by Pendergrass, Paul and Curtin using phenylazotribenzoylmethane. In order to overcome this difficulty, data from liquid-based reactions are used under the same assumption.

After a series of solid-state chemical reactions, first product is formed in a solid solution within the initial crystal. There are no great changes of structure. Thus, molecules from the daughter substance can still accommodate themselves in the starting crystal. The solid solution is stable and usually appears at the early stage of the reaction. This step is solid solution formation.

Finally, the last stage of the reaction is the separation of product phases. Newly formed products accumulate in the same position and once the optimal value for crystallization has reached, they will crystallise and separate themselves from starting crystal by forming new crystals. They are often micro-dimensional; they have random orientations and do not follow along the axis of the crystalline starting material. This stage has no effect on the rate of reaction whereas molecular loosening and molecular change majorly impact reaction kinetics.

Chapter 6 – Types of Organic Solid-State Reactions

Although organic solid-state reactions have not been studies for many years, the literature reports a fairely large number of examples involving a range from solid-solid to solid-gas reactions, as well as reactions involving single solid and multiple solids. Solid-solid reactions must have high contact frequency to increase the chance of molecules collide with each other to undergo a chemical reaction. It is therefore not surprising that milling is one of the preferred reaction methods. The fact is that grinding is a process of abrasion where involves shearing and rubbing only. On contrary, milling impacts the solids in all directions for effective collision between solids. Only assist with grinding and sonic when milling is not effective. Worth mentioning, there are a few types of milling available and used in different sectors. The first one is ball-milling which is used for small scale milling and often found in laboratories. The second one is swing-milling which is suitable for moderate scale syntheses and while rotor-milling that is used in industrial large scale milling. However, it is not in the case of solid-gas reactions. The molecules do not have to be thoroughly ground or milled, as reactions occur if gas is allowed to flow over the solid, while temperature and pressure are kept constant. Maintain required temperature and atmospheric pressure. If the solid is exposed to too much gas, excess amounts of heat and pressure will be generated and lead to the breakdown of the reaction vessel. Due to a great variety of organic solid-state reactions, the following two parts will describe several examples in thermodynamic and photochemical reactions separately in pure solid state only.

6.1 Thermodynamic Reactions

1) Methyl Migration

The history of rearrangement in organic chemistry is very long. Rearranged products are mostly due to thermodynamic stability and provide information to conduct thermodynamic specification of chemical reactions. It was known that rearrangements do occur in solid state and have high atom economy when compared to elimination and substitution. Therefore, it is worth to mention one of the rearrangement reactions, namely the methyl migration.

4H-1,2,4-triazoles have been investigated by Hakansson and co-workers. It was found that thermal rearrangement occurred for 4-methyl and ethyl substituted 4H-1,2,4-triazoles in the crystalline state. The lone pair of electrons in nitrogen atom initiates the reaction. A dialkyltriazolium tri-azolate salt is then formed via a SN2 reaction, which is concerted process. The salt becomes good electrophile and reacts with anion to form 1-alkyl substituted triazoles. The temperature for this rearrangement process is 270??C -300??C.

Figure 11. Rearrangement of 4H-1,2,4-triazoles.

The distance and orientation of the functional groups play the major role in this reaction. The distance between reacting centres for methyl derivative is 3.24?? and 4.61?? for the ethyl derivative. The data of activation energies is constant with that. The activation energy for the methyl derivative is 104kJ mol-1 and 173kJ mol-1 for the ethyl derivative. As the centers are further away from each other, more energy is required for the reaction. The angle, as shown in Figure 12, for both derivatives is around 160?? which is approximately a linear arrangement. Thus, favoring the formation of a SN2 transition state. Furthermore, the van der Waals radii between derivatives are 3.5??, as shown in Figure 12, which promotes group transfer in intermolecular fashion easily. With all these factors, process of rearrangement is feasible.

Figure 12. Distance between 1-N and ??-carbon. Angle between 1-N, ??-carbon and 4-N.

2) Baeyer-Villiger Oxidation

The Baeyer-Villiger oxidation was first discovered by Adolf Baeyer and Victor Villiger in 1899. It is used to produce esters from ketones and has a wide range of applications in modern day organic synthesis, such as the synthesis of lactones and steroids. Therefore, it is important to discover ways to carry out such reactions in solid state, that is, under more environmentally friendly conditions. Toda and his colleagues reported in 1988 that some ketones oxidised with m-chloroperbenzoic acid in crystalline state with much shorter reaction time. (Table 1)

Table 1. Yields of Baeyer-Villiger oxidation products in solid state and in CHCl3.43

Ketone Reaction Time Product Yield (%)

Solid State CHCl3

30mins

95 94

5 days

64 50

24h

97 46

24h

85 13

24h

50 12

4 days

39 6

The reaction does not require any solvent and proceed in room temperature. For every one mole of ketone used, two equivalent moles of m-chloroperbenzoic acid were used in the reaction. In 2002, this reaction was revised with cyclic and acyclic ketones with addition of NaHCO3. The two bulky steric hindrance TBDMSO groups cover both sides of carbonyl face. Thus, nucleophile has a hard time to attack the carbonyl.

Figure 13. Baeyer-Villiger Oxidation with cyclic ketones.

In solution, the use of NaHCO3 does not have any effect on product yield which is still around 75%. However, spreading NaHCO3 evenly on the surface of ketone and m-CPBA in the solid state, an unexpected product yield of 95% was observed. The high reaction yields prompted to more studies on Baeyer-Villiger oxidation reaction in the solid state.

3) Pechmann Condensation

The Pechmann condensation was discovered by Hans Von Pechmann in 1883, using phenol and ester that has a ??-carbonyl group. A year later, he applied his reaction to synthesise a new coumarin derivative, daphnetin.

Figure 14. Traditional Pechmann Condensation.

With the development of daphnetin, many other coumarin derivatives were eventually discovered using the Pechmann condensation. Until nowadays, coumarin has wide variety of applications such as perfumes, medicines and pesticides. Therefore, countless researches have focused on how to further improve this meaningful reaction. Nonetheless, it was discovered that coumarin was able to prepare in solid-state Pechmann condensation in 2001. The preparation steps are relatively simple and straightforward and involve grinding and subsequent heating of phenols, ??-keto esters and TsOH. The obtained solid is then recrystallized to yield the pure product. The efficiency of this solid-state reaction is exemplified by the reaction between resorcinol and ethyl acetoacetate yielding a condensation product in 98% yield.

Figure 15. Solid state Pechmann condensation.

6.2 Photochemical Reactions

1) Hydrogen Abstraction

Hydrogen abstraction reactions often occur within one single solid in an intramolecular fashion. For a unimolecular reaction, it is known that geometry and packing arrangement are the major factors that regulate reaction rates. The reason is that there are different chemicals in this world with different size and preferred orientation. When they act as substituents and bond to the main hydrogencarbon chain, they will hinder the reaction rate of hydrogen abstraction.

Scheffer and co-workers have investigated photochemical reactions of solid-state reactions of Diels-Alder adducts in 1979. The first adduct that has been investigated were formed between duroquinone and 1,3-dienes.

Figures 16. Photochemical reaction of 2,3-dimethylbutadiene adduct.

Photochemical reactions of 4 in either the solid state or solution produce the same products with 5 as the major product and 6 as the minor product in the ratio of 2:1. The conformation of 4 is unique where the cyclohexane ring adopts a half-chair arrangement and cis to a ene-dione ring which is nearly planar in geometry and confirmed with x-ray crystallography. The extraordinary shape of 4 allows hydrogen abstraction to occur selectively to obtain either 5 or 6 in the solid state. In Figure 17, abstraction of Ha in C-5 position by carbon generates a biradical species 7. The hydrogen is in C-2 position pointing away as shown in the figure. The two radicals join together via 3-5 bonding and obtain yield product 5. On the other hand, abstraction of Hb in the C-8 position by oxygen generates a biradical species 8. The hydrogen transfers on to ketone group of C-1 and reduce to alcohol group. The two radicals join together via 1,6 bonding and obtain final product 6.

Figure 17. Hydrogen abstraction of 2,3-dimethylbutadiene adduct.

This solid state photochemical reaction has shown that 4 has a perfect geometry undergo intermolecular hydrogen abstraction and to obtain biradical species. These can then react further to yield the desired product. Beside the factor of geometry, there are still other factors that need to be considered, such as the distance of abstraction, which is the dotted line in Figure 17. For oxygen abstraction, the distance ranges from 2.26?? to 2.58??. For carbon abstraction, the distance ranges from 2.66?? to 2.89??. The difference of distances is due to van der Waals’ forces. Oxygen has a smaller van der Waals’ radius than carbon. As a result, the distance of abstraction for oxygen is shorter. The important point is that as the distance of abstraction increases, van der Waals’ forces decrease and won’t be able to abstract hydrogen.

2) Cycloaddition Reactions

Another well-known organic solid-state reaction is the photoinduced cycloaddition reaction. The [2+2] photo reactions were heavily investigated heavily by Schmidt and co-workers in the 1960s using trans-cinnamic acid derivatives as model compounds.7

Figure 18. Photochemical reaction of two trans-cinnamic acids.

In solution, trans-cinnamic acid undergo isomerisation into cis-cinnamic acid. However, three polymorphic forms of dimeric products are obtained in solid state. This reaction is known as [2+2]-photodimerisation. The ??-form is composed of molecules that are aligned in a head-to-tail fashion in the crystal lattice whereby double bonds are separated by 3.6?? ‘ 4.1??. The ??-form displays cinnamic acid molecules being aligned in a head-to-head fashion whereby double bonds are separated by 3.9?? ‘ 4.1??. The ??-form is photostable due the fact that double bonds of the reactants are too far apart from each other at distances greater than 4.7??, while the double bonds are also not sufficiently aligned to support a photodimerisation reaction. These experimental observations led to the formulation of the topochemical postulates. It was stated that the solid-state reactivity of cinnamic acid derivatives depends on crystal packing and that atoms involved in this reaction undergo a little movement. There are other important conclusions derived from the cinnamic-acid study. First, the separation of double bonds between two centres of double bonds must be not larger than 4.2??. One of the rarest exceptions of this rule is p-formylcinnamic acids, which exhibits at 4.8?? distance between reacting double bonds. On the other hand, methyl 4-hydroxy-3-nitro-trans-cinnamate was reported to be photostable despite a separation distance of 3.2??. The legitimacy of the 4.2?? separation distance rule is therefore still being debated. Second, the reacting double bonds need to parallel to each other, so that their p-orbitals can effectively overlap to facilitate the formation of a cyclobutanyl moiety. It is known that [2.2]-(2,5)benzoquinonophanes form dimer at an angle of 53.3?? between reacting double bonds. Third, the reaction mode could be affected by the excitation state of the reactant. More specifically, Pfoertner, Englert and Schoenholzer had investigated photochemical reactions of retinoids. In Figure 19, the replacement of the ethyl ester group in 9 with a diethyl amide, isomerization results where only cis-isomer 10 was found due to the fact that the excitation energy has increased. This has changed the mode of how molecules react with each other.

Figure 19. Structure of retinoids.

Lastly, substitution of functional groups can promote the photodimerisation reaction. Gavuzzo and Mazza had investigated coumarin, 11, (Figure 20) extensively and found out that the two double bonds are 5.7?? apart, which is not sufficient for a photodimerisation to occur.

Figure 20. Structure of coumarin and ??-product.

Venugopalan, Rao and Venkatesan had modified coumarin through the addition of a bromine atom into C-6 or C-7 position (Figure 20). The bromine atoms drove the formation of coumarin stacks through the participation in Br”’Br halogen bonding. The coumarin molecules within the stacks are separated by 4.2??, so are therefore able to undergo the formation of the ??-photoproducts, 12. (Figure 20)

3) Polymerization Reactions

It was known that certain molecules can polymerize in the solid state while being exposed to UV irradiation. The obtained products are highly ordered and heavy in weight without many branches. Baughman has investigated solid-state polymerization in 1974 and identified three criteria for unimolecular solid-state polymerization.

1) Dimensional criteria. The reactivity could be affected by free-energy barrier to the motion of molecules. It is difficult to assess this barrier. To overcome this problem, the least-motion principle was applied. This is similar to what Schmidt stated in the topochemical principle. In particular, as molecules within crystals are very close to each other, only minimal amount of movement of atoms are involved. This principle also allows to compare the reactivity of various diacetylenes and to predict the solid-state reactivity of unexamined diacetylenes.

2) Phase stability criteria. It is reported that phase separation may not happen. There are two types of free energy identified, intramolecular and intermolecular. The first one is among atoms of assembling polymer which drop constantly over the time during reaction. The second one is between atoms on two different chains which can rise or decline. If the total amount of these two energies increases constantly during the reaction, crystals are formed. Otherwise, phase separation will not happen.

3) Symmetry and dimensional criteria for reaction uniqueness. Monomer molecules react depending on their respective crystal which based on their point-group symmetries. Besides, the relationship of symmetries between each reacting molecules also important to maintain uniqueness of reaction.

Figure 21. Diacetylene Polymerization.

One of the best examples is polymerization of diacetylenes which had been studied by Wegner. , , Monomers of diacetylene undergo a 1,4 addition reaction to form a polymer under light in the solid state upon UV irradiation. The whole reaction is propagated through radical mechanism. If the R group is polar, it will enhance reactivity. Monomers that are connected by hydrogen bond can promote reaction. Baughman proved that molecules are closed to each other to polymerize with minimum amount of motion which is the first criterion. This final product is a tempting material for the development of devices for data storage. The reason is that the long conjugated chain is an extended ??-system which lowers the excitation energy in optical absorption’s shift.

4) Fragmentation Reactions

There are many reactions that involve the elimination of small molecules such as decarbonylation, decarboxylation, removal of HCl etc. However, the benzoin ether photolysis is worth mentioning, as it is a good example to show how the reaction cavity applies in a reaction.
Figure 22. Reactions of benzoin ether in different conditions.63

Tomioka and Izawa investigated reactions of benzoin ether in 1980. In solution, ??-cleavage of benzoin ether produces two radicals. Solution acts as a medium and promotes free movement. Thus, allows them to partner up with different radicals and three distinct products are formed. Nothing has happened in solid state under vacuum condition. However, two products are formed in the solid state under atmospheric conditions due to the trapping effect by oxygen. The reason is that reaction cavity limits the movement of molecules while oxygen moves freely to trap the radicals in the reaction cavities to form the unique products, benzoic acid and alkyl benzoates. Without oxygen, radicals remain in the cavity and limit the movement of radicals, so no reaction occurs under vacuum.

Chapter 7 – Factors Affecting Reactivity of Organic Solid-State Reactions

There are a number of factors that will affect the reactivity of organic solid-state reactions. In no order of importance, they are impurity, imperfection, molecular geometry, molecular packing, particle size, polymorphism, radiation and electronic. As stated in previous chapters, these factors normally do not have any effect in solution-based reactions.

The presence of impurities can have an effect on reactions kinetics. They may block the site of defects so that the reaction rate is changed. On the other hand, if the impurities lower the eutectic point, a liquid might appear and could increase the reaction rate. If the eutectic point does not change with presence of impurities, kinetics will eventually remain the same. Thus, impurities do not contribute to the reactivity.

Dislocation defects will increase the energy of a particular region so that the total free energy will be higher in there than equilibrium. The extra energy trapped by dislocations can initiate reactions. They are the site for nucleation to happen. During excitation of photochemical reaction, if the energy transfers quickly enough to the crystal, this energy are trapped by defects on crystal. Therefore, crystals that have unusual geometry will get activated and form unforeseen products.

In 1968, Rastogi and Singh first suggested that size and geometry of molecules affect reactivity. Small and high symmetry molecules tend to diffuse fast. In 1986, Green, Arad-Yellin and Cohen also suggested that the importance of geometric factors and symmetry consideration. If the surface migration is faster, more molecules will be available for penetration into lattice for reaction occurs and hence higher reactivity. From a broader scope, the way that molecules pack also matters. The fact is that no liquid medium to promote agitation for reactions. Solids are required to put together closely with minimal air gap so that reactions will occur according to their orientation. A common example is the photochemical [2+2]-cycloaddition where molecules need to align properly for intermolecular reaction to happen. Moreover, particle size also has an impact on reactivity. Since reactions initiate at the surface of particles, the bigger the particle, the larger the contact surface area. Thus, greater contact between surfaces allow faster rate of reactions. Radiation by external source also influences the reactivity of organic solid-state reactions. In 1972, Hadjoudis and his colleagues investigated bromination of different trans-cinnamic acids. It was reported that radiation created defects which will affect reactivity. Furthermore, ??-phenylcinnamic acid was reported slower reactivity under light than in the dark. Consequently, radiation can either enhance or lessen reactivity. The last factor is polymorphism. When solids are reacting together, polymorphic change may take place. Thus, each lattice units loosen and rearrange. At transition temperature, mobility of lattice will be great.

Conclusion

Although organic solid-state reactions have been widely investigated in the last few decades, many of them are remain poorly understood from a mechanistic point of view. The fact is that many of the organic solid-state reactions are relatively serendipitous. It is undoubtedly that molecular size and arrangement have great influence on how they are going to react with each other. Therefore, making use of each distinct conformation, it is possible to engineer a specific product. This implies the idea of crystal engineering where a wide range of co-crystals, multiple units composed in a crystalline structure with precise stoichiometric ratio, are designed in order to obtain products that are hard to synthesise using conventional solution-based synthetic methods, such as ladderanes. If any other important chemicals can produce in the solid state rather than conventional solution-based method, the society could gain many social, economic and environmental benefits from it. In conclusion, it is crucial to discover more reactions in the solid state to replace traditional methods.

Source: Essay UK - https://www.essay.uk.com/essays/science/essay-organic-solid-state-reactions/


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