Cubane^[1]

Since the synthesis of the cubane-1,4-dicarboxylic acid has become shorter and easier, a new decarboxylation method has also devised to give increased yields of the final cubane product. This has allowed the scale of production reach multikilogram batches in places (Fluorochem in California and EniChem Synthesis in Milan) eventhough cubane and its derivatives remain expensive to purchase.

Cuneane may be produced from cubane by a metal-ion-catalyzed σ-bond rearrangement.^[4][5]

Cubanehas the highest strain energy (166kcal/mol) of any organiccompounds available in multi gram amount. It is a kineticallystable compound and only decomposite above 220 Celsius Degree.It is also one of the most dense hydrocarbons ever know.However, although many physical properties of cubane have been measured, in1980 and before, cubane was considered just a laboratory curiosity of interest only to academics.It changed, in early 1980s when Gilbert of U.S ArmyArmament and Development Command (now ARDEC) pointed out that cubane’svery high heat of formation and its exceptionally high density could make certain cubanederivatives important explosives. The effectiveness of an explosive is dependent on the energentics of the decomposition reaction, the number of moles and molecular weight of the gaseous products and also the density. The more mols of of an explosive that can be packed into the limited volume the better. . Highly nitrated cubanes can be predicted to be very dense and very powerful explosives. Octanitrocubane is calculated to be 15~30%more powerful than HMX.   Cubane, which CA index name is Pentacyclo[4.2.0.02,5.03,8.04,7]octane (7CI,8CI,9CI),has exceptional structure, strain and symmetry and it is a benchmark in organic chemistry.It has been studied extensively and much of its properties has been published.Some of the physical properties are given at right hand table.

The C-C bond length is a bit longer than obtained in the original X-ray structure determination by

Fleischer in 1964. There is not much difference between this bond length and the

C-C bond length in a simple cyclobutane.

 

SYNTHESIS

The cubane system was first synthesized over 35 years ago by Philip Eaton and Tom Cole.
It is a highly symmetric cubic cage structure having carbon atoms at the vertices of a cube.
The synthesis needs to go through brombromocyclopentadienone
dimer I and cubane-1,4,dicarboxylic acid. It is a marvel scheme of economy and simplicity.
With only minor modification, this procedure remains to this day the best available

method for large-scale synthesis of cubane-1,4,dicarboxylic acid.

 

 

 

The stereospecific in situ [4 + 2] (Diels-Alder) cyclodimerization of 4-bromocyclo-pentadienone
is the key in this kinetically controlled synthesis. However, it is still a tricky matter
and a few years later after this synthesis is published, N.B.Chapman et al in England following up
this work and improved this synthesis.

Why cubane is stable?

The reason for this, unappreciated at the time of the early predictions of instability,

 is that there are no kinetically viable paths along which cubane can rearrange thermally.

 On one hand, orbital symmetry considerations raise the energy of concerted two-bond ring

opening reactions. On the

other, there is little to be gained by breaking just one bond as there is concomitantly

only a small change in geometry, and the resulting biradical is still very strained.

Substitution on the cubane framework is fairly easy done by the cubyl radical.
However, the problem is such that a mixture of products are obtained.
Thus, to achieve controlled substitution on the cubane framework,
we need to carefully study the chemistry of the cubane system.

The improvement in synthesis of

cubane-1,4-dicarboxylic acid

Generally, for single-line proton magnetic resonance spectrum, the one

and only absorption appears at chemical shift=6.0ppm.

Originally there was doubt whether cubane does exist.

The geometry at each carbon atom is far from tetrahedral.

Only later, we found out that there is no kinetically viable paths exist for

the thermal rearrangement of cubane.

At same time, orbital symmetry considerations shows that

the energy of concerted two-bond ring-opening reactions is very high.

There will be very little gain in energy by breaking just one bond, as the

concomitant change in geometry is small, and the resulting biradical is still very strained

In 1964 Fleischer showed that cubane forms a stable solid at room temperature with a

crystalline structure composed of cubane molecules occupying corners of the rhombohedral

primitive unit cell (space group R3). The cubic molecular geometry gives the solid many unusual

electronic,structural, and dynamical properties compared to the other hydrocarbons.

For example, solid cubane has a relatively high melting point temperature about 405 K! and a

very high frequency for the lowest-lying intramolecular vibrational

mode (617 cm^-1). Recent work related to cubane has focused on solid cubane and cubane based

derivatives.Because of relatively weak intermolecular interaction the cohesive energy relative

to the constituent C₈H₈ is expected to be small, and most of the physical properties of

solid cubane are dominated by the properties of the C₈H₈molecule.

Pharmaceutical aspect of cubane

Because the cubane frame is rigid, substituent have precise spatial relationships to each another.

The distance across the cubane (the body diagonal) is almost the same as that between the para

positions of the benzene ring. On cubane, on can add substituents in the “benzene plane”, as

well as above and below it, so to speak. This offers fascinating position possibilities for

the synthesis of new pharmaceuticals. A number of cubane derivatives have already

been obtained which shows interesting activity in anti-AIDS and anti-tumor screens.

Although the activity or the toxicity balance of cubane is yet not know, the cubane

system is not inherently toxic. Most of cubanes are biologically innocuous.

The research of cubane pharmaceutical has just began. At least now,

cubane is a biologically stable, lipophilic platform on which the chemist

can install a wide range of substituents in a variety of well defined special relationships.

Developments in drug design programs should allow the judicious choice.

Dipivaloylcubane: a cubane derivatized with keto, cyano, and amide groups,

shown on the left- exhibits moderate activity against human immunodeficiency virus (HIV),

which causes AIDS, without impairing healthy cells.

Polymers of cubane:

Optically transparent cubanes and cubylcubanes have been proposed as building

blocks for rigid liquid-crystal compounds. UV active cubanes, for example cubyl ketones,

are readily transformed photochemically into coloured cyclooctatetraenes;this transformation

can be used to permanent information storage.

Another example of UV active cubane, which can be used to synthesis liquid crystals.

Polymers with cubane in the backbone or as a pendant group along a polymer chain is

focused now.

The cubane subunits in these polymers can be rearranged easily to cycloctatetraenes.

It is expected that polycyclooctatetra can be converted in to polyacetylenes by

the way of ring-opening metathesis polymerization. The polyacetylenes will have properties

which are enhanced by the chain being intrinsically part of another polymer.

These properties including stability and extrudability and etc. A example is shown below:

Cubane derivative could be the structural basis for a class of intrinsic small gap polymers.The small gap polymer could present intrinsic good conductivity without doping,good nonlinear optical and photoelectric properties.Investigation of oligamers with up to six units of a conjugated unsaturated cubane derivative,where all the hydrogen were removed, is carried out.The table below shows that the gap values in eV by EHT and PM3.These values suggest to us that these structures could be used to design a newclass of polymers with very small gap.

Explosive and fuels:

In the early 1980s Everett Gilbert of the U.S. Army Armament Research and Development

Command (now ARDEC) pointed out that the nitrocarbon octanitrocubane (ONC),

then unknown, has a perfect oxygen balance, and in light of the properties of the

parent hydrocarbon cubane should have a very high heat of formation per CNO₂ unit

and an exceptionally high density as well. His colleagues Jack Alster, Oscar Sandus

and Norman Slagg at ARDEC provided theoretical support for Gilbert’s

brilliant insight and estimated that ONC would have a detonation pressure

significantly greater than HMX. Later, both statistical and computational

approaches predicted a density of 2.1 ± 2.2 g /cm³ for octanitrocubane,

greater than any other C, N, O compound.

Is Cubane a really good explosives?

Quantitative evaluation of the potential of a candidate explosive before synthesis is very difficult.

Currently, estimation of energetic properties relies on the empirically derived Kamlet and Jacobs

equations:

In these equations the heat released by the decomposition, the number of moles of gas produced,

and the molecular

weight of these gases are all critical factors. Density too is crucial.

Obviously, the more molecules of a high-energy material that can be packed into the limited

volume of a shell or rocket the better. Less obvious, but more important, density affects the

detonation velocity of an explosive.

This is a specialized “linear” rate of reaction that ranges from 5 to 10 km/s in

explosives and affects the maximum detonation pressure, a direct measure of the

power of an explosive. For a given explosive, the detonation pressure is proportional

to the square of its density, so great effort is made to obtain the highest density form

of any particular explosive.

Quantitative evaluation of the potential of a candidate explosive before synthesis is very difficult.

Currently, estimation of energetic properties relies on the empirically derived Kamlet and Jacobs

equations:

In these equations the heat released by the decomposition, the number of moles of gas produced,

and the molecular

weight of these gases are all critical factors. Density too is crucial.

Obviously, the more molecules of a high-energy material that can be packed into the limited

volume of a shell or rocket the better. Less obvious, but more important, density affects the

detonation velocity of an explosive.

This is a specialized “linear” rate of reaction that ranges from 5 to 10 km/s in

explosives and affects the maximum detonation pressure, a direct measure of the

power of an explosive. For a given explosive, the detonation pressure is proportional

to the square of its density, so great effort is made to obtain the highest density form

of any particular explosive.

Numerous nitro compounds are employed commonly as military and commercial explosives.

There is a continuing search for more powerful and less shock-sensitive examples.

Such materials are also sought as potentially useful fuels and propellants.

Most interest is focused on high-density organic compounds that contain all of the

elements needed for combustion to gaseous products in the absence of air.

Nitrocubanes carrying five or more nitro groups contain enough oxygen to oxidize

all constituent carbon and hydrogen atoms to gaseous CO, CO₂, or H₂O.

Each of these, along with N₂, “explodes” from the solid to 12 gaseous molecules.

The expansion from the dense solid to a lot of gas (much expanded by the released heat)

produces the desired effect in propellants and explosives. ONC has a “perfect”

oxygen balance and would produce (were the detonation completely efficient)

eight molecules of carbon dioxide and four of dinitrogen. As ONC has no

hydrogen, no water forms when it burns; when used as propellants such zero-hydrogen

compounds leave little or no visible smoke (steam) in the plume behind the rocket;

such “low-signature” rockets are difficult to track.

On application of the Kamlet and Jacobs equations led ARDEC to predict that

octanitrocubane would be a very much better explosive (Table 1) than the classic

C-nitro compound trinitrotoluene (TNT), perhaps 15±30% better than the nitramine

HMX (the most powerful, commonly used military explosive), and at least competitive

with (and perhaps less shock-sensitive than) the newest experimental explosive CL-20

SYNTHESIS:(1)

The high strain that the cubane framework is under has already been highlighted. The researchers had to very cautiously attach a nitro group to each of the corners of the cube in order to make the desired product. The insertion of the first four nitro groups could be done by manipulating functional groups:

The key intermediate, cubane-1,3,5,7- tetracarboxylic acid (TNC), was obtained by clever application of the Brown-Kharasch photochlorocarbonylation to cubane mono-acid.

The addition of four further nitro groups proved far more difficult and new methodologies had to be developed, specifically the process of interfacial nitration. This method was used successfully to convert the sodium salt of TNC to pentanitrocubane (PNC) and then hexanitrocubane (HNC), both are stable materials.

Interfacial nitration, however, proved deficient for further nitration of HNC and again new experimental methodology had to be developed for its successful conversion to heptanitrocubane (HpNC):

Addition of excess NOCl to a solution of the lithium salt of HpNC in dichloromethane at -78°C gave the long-sought ONC:

 DIFF TYPES

For the last planned post in my Unnatural Products series, I’m going to write about Eaton’s 1981 synthesis of pentaprismane.[A] At the time, unnatural hydrocarbons were hot targets, and as the next largest prismane on the list this target was the subject of much research by groups around the world. Perhaps Eaton’s biggest rivals were the groups of Paquette and Petit, and in fact all three had, at various times, synthesised hypostrophene as an intended precursor to the target.

Unfortunately, the ‘obvious’ [2 + 2] disconnection from pentaprismane turned out to be a dead end and the photochemical ring closure was unsuccessful. The 1970s and early 1980s saw the publication of a number of other similarly creative, but sadly ill-fated, approaches based on various ring contractions, and the compound gained a well-earned reputation for extraordinary synthetic inaccessibility.

Eaton’s route began, as with the cubane and dodecahedrane syntheses previously covered in this series, with a Diels-Alder reaction. The diene used was the known tetrachlorocyclopentadienone acetal shown that upon heating neat with benzoquinone produced the endo adduct shown in excellent yield. Next, an even higher yielding photochemical [2 + 2] reaction was used to close the cage-like structure by cyclobutane formation. Treatment with lithium in liquid ammonia simultaneously reduced both ketones and removed all four chlorine atoms. The resulting diol was converted to the ditosylate, which, under carefully controlled conditions with sodium iodide in HMPA, underwent a mono-Finkelstein reaction to give the iodotosylate shown. When this was treated with t-BuLi halogen-lithium exchange, followed by an extraordinary fragmentation, gave a diene reminiscent of hypostrophene shown above. However, the extra carbon atom in the skeleton made all the difference, and unlike the parent compound, this did undergo a [2 + 2] cycloaddition when exposed to UV light. Finally, acetal hydrolysis gave homopentaprismane in 34% yield from benzoquinone, putting the group a single ring contraction from victory.[B]

With significant amounts of homopentaprismanone in hand, the group now intended to employ the transformation that had been the cornerstone of their cubane synthesis – the Favorskii rearrangement. Unfortunately, this required the introduction of a leaving group in the ketone α-position, a transformation made incredibly difficult due to the strained system and Bredt’s rule, which prevented enolisation.[C] Eventually a six-step sequence (!) to introduce a tosyloxy group was devised, beginning with a Baeyer-Villiger reaction using m-CPBA. A remarkable CH oxidation with RuO4, generated in situ, then gave the hydroxylactone. Treatment of this with diazomethane gave the corresponding δ-ketoester in almost quantitative yield. The group then reformed the starting norbornane-like bridge through use of an unusual acyloin type reaction effected by treatment with sodium in liquid ammonia. Finally, oxidation of the secondary alcohol and tosylation gave the Favorskii precursor, apparently preparable in muti-gram quantities.

Treatment with aqueous potassium hydroxide solution effected Favorskii rearrangement in excellent yield, especially considering that this was the first time the elusive pentaprimane ring system had been prepared. Finally, Eaton used the three-step decarboxylation he had developed for cubane to remove the extraneous acid and give pentaprismane in 18 steps. Awesome.[D]

References and suchlike

1. A    J. Am. Chem. Soc., 1981, 103, 2134. Much like Eaton’s seminal cubane paper, the title is a single word, ‘Pentaprismane’. I love the lack of hype.
2.  B   Although Petit had prepared this compound a full decade earlier, his approach relied on a cycloaddition of the difficult to prepare cyclobutadieneiron tricarbonyl with the acetal of tropone, and proved difficult to scale  up. In fact, in his own paper Eaton rather directly described it as ‘conceptually fascinating [but] useless synthetically’.
3. C   Eaton uses the phrase ‘invasion at the bridgehead’, which I find delightfully evocative. Makes it sound like a second world war campaign. Apparently the group initially planned, in spite of Bredt’s rule, to deprotonate the bridgehead position, relying on inductive stabilisation of the anion rather than enolate formation, but were unable to do so.
4. D  Pentaprismane is the most recent of three prismanes synthesised to date, the other two being cubane, and triprismane. Although I think triprismane looks quite silly, it was actually synthesised some 8 years previouslyby T. J. Katz in far fewer steps. Go figure.
   

The Amide Activating Group

Transmetalation is the basis of a complete synthetic methodology for the preparation

of a great variety of the substituted cubanes.

In order to make the substitution productively, a way must be found to

make use of the small amount of anion in the equilibrium with the starting material.

Mercury salt is used here as an effective anion trap and very little starting material remain unreacted.

The mercury for lithium transmetalation resulted in nearly complete conversion of the

starting material by drawing the lithiation equilibrium to the right.

1,3,5 trinitrocubane and 1,3,5,7 tetranitrocubane(TNC)

As we mention early, addition of nitro groups cannot be done through direct transmetalation. Thus, we need found some indirect route.

This is done by introducing a substituent on each of 3 ortho carbons and remove the ortho-activating group in the end.

By adding a electron-withdrawing group such as a cyano group will help the case here. This choice of original substituent is important here and when cyano group is chosen, it activates the cubane nucleus without affecting the ortho directing by the diamide (for details please refer to electron-withdrawing group-cyanite).

When the dicyano amide was treated with TMPMgBr in THF and quenched with CO₂. The ortho (to amide) carboxylic acid was the only product.

Even when the much activated tricyanoamide is treated with TMPMgBr and CO₂ ,again, the ortho position ( to amide) carboxylic acid was formed.

The removal of the carboxamido group is done through a smart yet tedious process. The cyano group is converted to acid group first. Then, it is reduced to alcohol by lithium aluminium hydride. At same time, the carboxamido is reduced to aminotetrol. The alcohols are protected as acetates and amino tetrol is converted to carboxylic acid. The carboxylic is then removed through Barton Decarboxylatio. A detail mechanism is provided below.

The cubane-1,3,5,7-teracarboxylic acid is converted to TNC on the mechanism as follow:

The whole process is very clever, but it is very long. Thus, in 1997, a improved synthesis method for TNC was proposed by making use of the photochemsitry.

Improved synthesis for TNC

In 1993, Bashir-Hashemi showed the cubane-1,3,5,7-tetracarboxylic acid chloride can be formed by applying photochemically induced chlorocarbonyl cation( the Kharasch_Brown Reaction).

For a fast reaction, a high power Hanovia of 450 watts, medium pressure Hg was used. The favoured products are cubane tetraacid chloride shown on the right hand side. The first one, cubane-1,3,5,7-tetracarboxylic acid, made up 30% overall. This reaction conveniently prepare us the important versatile intermediate .

A detail conversion process is provided below:

A catalyst TMSN₃ is used in converting tetraacid chloride to tetracylazide. The rest is the same as the orginal reaction.

TNC is a thermodynamic powerhouse but remarkly stable kinetically. Figure 1 shows that rapid thermal decomposition doesnot start until over 250°C.

The literature was unsupportive of this optimistic view. Poor results were also obtained initially with nitrating agent such as NO₂BF₄, acetyl nitrate, amyl nitrate etc.

Tetranitrocubylsodium can be formed directly on treatment of TNC with sodium bis(trimethylsilyl) amide in THF at -75°C. It can react with electrophiles to provide a useful and convenient way to achieve further functionalization of cubane nucleus.

More substituted nitrocubanes-

Pentanitrocubane(PNC) and Hexanitrocubane(HNC)

PNC

Base on the property of tetranitrocubylsodium, nitryl chloride(NO₂Cl) was used to further nitrate the cubane nucleus. Treatment of NO₂Cl with tetranitrocubylsodium in THF at -75°C works out 10-15% yield of pentanitrocubane(PNC). The yield increased to 30% when the solution was frozen to-180°C and allowed to warm slowly. This is called the interfacial nitration process. It is suggested that NO₂Cl oxidized tetranitrocubylsodium to a radical, which made the whole reaction worked.

Base on the property of NO₂Cl , N₂O₄ should be a better choice. The results showed that it is actually a better with 60:40 PNC to TNC ratio. The reaction is extremely clean.

PNC is colourless and highly crystalline. It is the first nitrated cubane to contain adjacent nitro groups. It behaves just TNC and other nitrocubanes, remarkly stable kinetically.

HNC

Although HNC can be prepared the same way as PNC, but the separation between PNC and HNC is extremely difficult.

However, if TIPS-substituted PNC( by N₂O₄ nitration from TIPS-sub TNC) react with potassium base (K(TMSN)₂and the nitration with N₂O₄ gave a mixture of (triisopropyl) HNC and PNC in 60:40 ratio. This step is important and crucial. The separation is now possible by column chromatography on silica gel. 30% isolated yield of PURE HNC could be obtained when further treated with SiO₂.

Synthesis for the last two nitro cubanes- heptanitrocubane and octanitrocubane

Interfacial nitration is not sufficient to further nitration for heptanitrocubane. Al though it is very good in deed, we need to find something which can successfully convert heptanitrocubane (HpNC).

HpNC

In this procedure TNC was treated with at least 4 equivalents of the base NaN(TMS)₂ (where TMS = trimethylsilyl) at ±78 C in 1:1 THF/MeTHF. After the mono sodium salt had formed, the solution was cooled to between ±125 and ±130°C giving a clear, but very viscous fluid. This was stirred vigorously as excess N₂O₄ in cold isopentane was added. After one minute, the base was quenched, and the whole mixture was added to water. This resulted reproducibly in almost complete conversion of TNC (1 g scale) to HpNC (95% by NMR), isolated crystalline in 74% yield!

ONC

However, even in the presence of excess nitrating agent (N₂O₄ or many others) no indication
of any formation of ONC was ever seen. It is suspected that anion nitration with N₂O₄ proceeds by oxidation of the carbanion to the corresponding radical.Perhaps the anion of HpNC is too stabilized for this to occur. (HpNC is significantly ionized in neutral methanol.) This concept led to the use of the more powerful oxidant nitrosyl chloride. Addition of excess NOCl to a solution of the lithium salt of HpNC in dichloromethane at 78° C followed by ozonation at 78° C gave the long-sought ONC in 45±55% isolated yield on millimole scale. The intermediate product prior to oxidation is thought to be nitrosoheptanitrocubane.

Finally, the magic molecule, the so called the impossible molecule, octanitrocubane was synthesised. But, how good are they and how useful are they? Let us discuss about it in the following section.

Properties of nitrocubane:

Neither HpNC nor ONC is detonated by hammer blows!
Both have decomposition points well above 200 C. Octanitrocubane
sublimes unchanged at atmospheric pressure at 200 C. HpNC forms beautiful, colorless, solvent-free crystals when
its solution in fuming nitric acid is diluted with sulphuric acid. Single-
crystal X-ray analysis confirmed the assigned structure and
provided an accurate density at 21 C of 2.028 g cm±3, impressively
high for a C, H, N, O compound. Although octanitrocubane
catches the imagination with its symmetry, heptanitrocubane
currently is significantly easier to make than ONC. It is
denser, and it may be a more powerful, shock-insensitive explosive
than any now in use. According to page 41 of a 2004 IUPAC guide, cubane is the “preferred IUPAC name.”

• Eaton Cubane Synthesis @ SynArchive.com
• Cubane chemistry at Imperial College London

• Basketane
• Octaazacubane
• Octanitrocubane

http://cst-www.nrl.navy.mil/lattice/struk/c8h8.html.

http://www.ch.ic.ac.uk/local/projects/b_muir/Enter.html.

http://www.sciencedirect.com.

http://www.sciencenews.org/.

http://www.winbmdo.com/.

Bashir-Hashemi, A., New developments in cubane chemistry: phenylcubanes.

J. Am. Chem. Soc.;1988;110(21);7234-7235, 110(21), 7234-7235.

D.S.Calvao, p. m. v. b. B. A. C. J. a., Theooretical Characterization of oligocubane.

Synthetic Metals 102 (1999) 1410.

E. W. Della, E. F. M., H. K. Patney,Gerald L. Jones,; Miller, a. F. A.,

Vibrational Spectra of Cubane and Four

of Its Deuterated Derivatives.

Journal of the American Chemical Society / 101.25 / December 5, I979,7441-7457.

Galasso, V., Theoretical study of spectroscopic properties of cubane.

Chemical Physics 184 (1994) 107-114.

Kirill A. Lukin, J. L., Philip E. Eaton,*,Nobuhiro Kanomata,Juirgen Hain,Eric Punzalan,and

Richard Gilardi, Synthesis and Chemistry of 1,3,5,7-Tetranitrocubane Including

Measurement of Its Acidity, Formation of o-Nitro Anions, and

the First Preparations of Pentanitrocubane and Hexanitrocubane.

J. Am. Chem. Soc., Vol. 119, No. 41, 1997,9592-9602.

P.E.Eaton, Cubanes: starting Materials For the chemistry of 1990s and the New Century.

J. Am. Chem. Soc.;1992;31;1421-1436, 31, 1421-1436.

Philip E. Eaton, t. Y. X., t and Richard Gilardi*, Systematic Substitution on the Cubane Nucleus.

Synthesis and

Properties of 1,3,5-Trinitrocubane and 1,3,5,7-Tetranitrocubane

. J. Am. Chem. SOC.1993,115, 10195-10202.

Philip E. Eaton, R. L. G.; Zhang, a. M.-X., Polynitrocubanes: Advanced High-Density,

High-Energy Materials**. Adv. Mater. 2000, 12, No. 15, August 2.

Philip E. Eaton, Cubane: Starting Materials for the chemistry of the 1990s and the new century.

Angew.Chem.Int.Ed.Engl.1992,31,1421-1436.

Philip E. Eaton, t. Y. X., t and Richard Gilardi*, Systematic Substitution on the Cubane Nucleus.

Synthesis and

Properties of 1,3,5-Trinitrocubane and 1,3,5,7-Tetranitrocubane.

J. Am. Chem. SOC., Vol. 115, No. 22, 1993,10196-10202.

T. YILDIRIM, P. M. G., D. A. NEUMANN, P. E. EATONC and ‘T. EMRICK’, SOLID

CUBANE: A BRIEF REVIEW. Carbon Vol. 36, No. 5-6, pp. 809-815,1998.

Zhang, P. E. E. a. M.-X., Octanitrocubane: A New Nitrocarbon.

Propellants, Explosives, Pyrotechnics 27, 1 – 6 (2002).

Azadirachtin

11141-17-6  cas no

Azadirachtin, a chemical compound belonging to the limonoid group, is asecondary metabolite present in neem seeds. It is a highly oxidizedtetranortriterpenoid which boasts a plethora of oxygen functionality, comprising an enol ether, acetal, hemiacetal, and tetra-substituted oxirane as well as a variety of carboxylic esters.

This compound is a tetraterpenoid characteristic of the Meliaceae family but particularly from the Neem tree (A. indica), indigenous to India. The compound is found in bark, leaves and fruits of the tree but seeds have the highest concentration. This compound has not yet been synthesized in the laboratory, but when isolated and tested pure the results have been less than when extracts are used.  In the extract 18 compounds have been identified among which salanine, meliantrol and azadiractin are most prominent, the latter being in the highest concentration. Azadirachtin shows antifeedant activity, is a growth regulator, inhibits oviposition and is also a sterilizing compound. Today, commercial formulations of neem may be found with names like Neem Gold, Neemazal, Econeem, Neemark, Neemcure and Azatin among others, in many countries including the United States, India, Germany and several Latin American countries.

Azadirachtin has a complex molecular structure, and as a result the first synthesis was not published for over 22 years after the compound’s discovery. The first total synthesis was completed by Steven Ley in 2007.^[1][2] Both secondary and tertiary hydroxyl groups and tetrahydrofuran ether are present and the molecular structure reveals 16 stereogenic centres, 7 of which are tetrasubstituted. These characteristics explain the great difficulty encountered when trying to produce it by a synthetic approach. The described synthesis was actually a relay approach, with the heavily functionalized decalin being made by total synthesis in a small scale but also being derived from the natural product itself for the purpose of obtaining gram amounts of the material to complete the synthesis.

“I would rank this as being one of the very toughest syntheses so far reported.”
– Steven Ley, University of Cambridge, UK, 1 G E Veitch et al, Angewandte Chemie, 2007, DOIs: 10.1002/anie.200703027 and 10.1002/anie.200703028
2 M L Maddess et al, Angewandte Chemie, 2006, 46, 591 (DOI: 10.1002/anie.200604053)

IT TOOK 22 YEARS and the efforts of more than 40 chemists, but Steven V. Ley‘s group has finally managed to complete a 64-step synthesis of azadirachtin, a naturally occurring insecticide (Angew. Chem. Int. Ed., DOI:10.1002/anie.200703027 and 10.1002/anie.200703028).

Isolated from the Indian neem tree Azadirachta indica, azadirachtin possesses a small but densely functionalized architecture. It has 16 stereogenic centers, seven of which are tetrasubstituted, and a diverse array of oxygenated functionalities.

“This has been a tough project from start to finish, as the molecule is so prone to rearrangement under acidic, basic, or photolytic conditions,” says Ley, a chemistry professor at England’s Cambridge University. “It has forced us to be inventive.”

Of the many hurdles the researchers had to overcome, Ley reckons the most challenging was coupling the molecule’s two main fragments. After years of attempts at this convergent approach, the group was finally able to marry these two fragments by means of a propargylic enol ether Claisen reaction. The next step, a radical-induced cyclization, elegantly constructed one sterically dense portion of the molecule.

“Making a molecule such as this is not an Everest-climbing exercise; it’s about what you learn from the experience,” Ley says. “We can be proud of the new methods and solutions to the tough problems we have encountered, and now we have the tools and procedures to really work out how this molecule functions biologically.”

Amos B. Smith III, a chemistry professor at the University of Pennsylvania, calls the work “an outstanding achievement, further demonstrating Ley and colleagues as superb tacticians in the art of complex-molecule total synthesis.”

Smith adds: “More important than the actual conquest is the exciting new chemistry that has emanated over the past 22 years from the Ley and other laboratories who have participated in this monumental challenge. Clearly, the science of synthesis is the winner.”

It was initially found to be active as a feeding inhibitor towards the desert locust(Schistocerca gregaria),^[3] it is now known to affect over 200 species of insect, by acting mainly as an antifeedant and growth disruptor, and as such it possesses considerable toxicity toward insects (LD₅₀(S. littoralis): 15 μg/g). It fulfills many of the criteria needed for a natural insecticide if it is to replace synthetic compounds. Azadirachtin is biodegradable (it degrades within 100 hours when exposed to light and water) and shows very low toxicity to mammals(the LD₅₀ in rats is > 3,540 mg/kg making it practically non-toxic).

This compound is found in the seeds (0.2 to 0.8 percent by weight) of the neemtree, Azadirachta indica (hence the prefix aza does not imply an aza compound, but refers to the scientific species name). Many more compounds, related to azadirachtin, are present in the seeds as well as in the leaves and the bark of the neem tree which also show strong biological activities among various pest insects ^[4][5] Effects of these preparations on beneficial arthropods are generally considered to be minimal. Some laboratory and field studies have found neem extracts to be compatible with biological control. Because pure neem oil contains other insecticidal and fungicidal compounds in additional to azadirachtin, it is generally mixed at a rate of 1 ounce per gallon (7.8 ml/l) of water when used as a pesticide.

Azadirachtin is formed via an elaborate biosynthetic pathway, but is believed that the steroid tirucallol is the precursor to the neem triterpenoid secondary metabolites. Tirucallol is formed from two units of farnesyl diphosphate (FPP) to form a C₃₀ triterpene, but then loses three methyl groups to become a C₂₇steroid. Tirucallol undergoes an allylic isomerization to form butyrospermol, which is then oxidized. The oxidized butyrospermol subsequently rearranges via a Wagner-Meerwein 1,2-methyl shift to form apotirucallol.

Apotirucallol becomes a tetranortriterpenoid when the four terminal carbons from the side chain are cleaved off. The remaining carbons on the side chain cyclize to form a furan ring and the molecule is oxidized further to form azadirone and azadiradione. The third ring is then opened and oxidized to form the C-seco-limonoids such as nimbin, nimbidinin and salannin, which has been esterified with a molecule of tiglic acid, which is derived from L-isoleucine. It is currently proposed that the target molecule is arrived at by biosynthetically converting azadirone into salanin, which is then heavily oxidized and cyclized to reach azadirachtin.

Azadirachtin ball and stick view

• Extoxnet
• Neem: The wonder tree

Extracts of the neem tree (Azadirachta indica) , the chinaberry tree (Melia azedarach) , and other plants in the family Meliaceae (e.g. Azadirachta excelsa) have long been known to have insectici al activity (Natural Pesticides from the Neem Tree, Proc. 1st Int’l Neem Conf. 1980 [H. Schmutterer et al. eds. 1982]; Natural Pesticides from the Neem Tree and Other Tropical Plants, Proc. 2nd Int’l Neem Conf. 1983 [H. Schmutterer and K.R.S. Asher eds. 1984]; Natural Pesticides from the Neem Tree and Other Tropical Plants, Proc. 3rd Int’l Neem Conf. 1986 [H. Schmutterer and K.R.S. Asher eds. 1987]). Azadirachtin, a major active ingredient in many of these extracts, is a limonoid of the tetranortriterpenoid type. Azadirachtin has been shown to be a potent insect growth regulator and feeding deterrent with value as an active ingredient in commercial insecticides (R.B. Yamasaki et al. (1987) J. Agric. Food Che . 3_5:467-471) .

The use of azadirachtin in commercial insecticides requires that the compound be extracted from the plant material and concentrated in a convenient form. Suitableazadirachtin concentrates are solid in form, have high levels of azadirachtin

(typically greater than 1-3% by weight) , and contain little or no plant oils and water. These characteristics facilitate handling, storage, distribution, and formulation.

Various methods of extracting azadirachtin from neem seeds are known in the art. J.H. Butterworth and E.D. Morgan, (1971) J. Insect. Physiol. Y]_ 969-911, describe the extraction of azadirachtin and neem oil from neem seeds using ethanol, a common solvent for azadirachtin isolation. Further separation steps (including filtration, partition of the soluble portion between light petroleum and methanol, and chromatography of the methanol extract on Floridin earth) are used to concentrate the azadirachtin to obtain a solid. Larson (U.S. Patent No. 4,556,562) discloses a similar method whereby neem seeds are first reduced in size to that of a regular grind of coffee. Azadirachtin is then extracted at elevated temperatures, again using ethanol. No further concentration steps are used, however, and the final extract is a liquid containing only 0.5-1% azadirachtin. Walter (U.S. Patent No. 4,946,681) describes a related process for extractingazadirachtin from ground de-oiled neem seeds with aprotic solvents or alcohols. The liquid extract is further treated with molecular sieves to remove water. Carter et al. (U.S. Patent No. 5,001,146) describes a two-step extraction process comprising a “cleanup” extraction with a non- polar aprotic solvent to remove the neem oil from the seeds, followed by a second extraction of the defatted neem seeds using a more polar, azadirachtin-soluble solvent. The final extract from this process is a solution containing about 4.5 g/1 azadirachtin. Kleeberg (WO 92/16109) also describes a multi-step procedure whereby the azadirachtin is first extracted from neem oil and plant material using water. The aqueous fraction is then extracted with an organic solvent to remove the azadirachtin from the water. A solid azadirachtin concentrate is ultimately obtained using a slow and inefficient phase separation followed by concentration of the organic phase and crystallization.

Inefficiencies and limitations associated with the processes described above illustrate the need for more practical and versatile methods for obtainingazadirachtin concentrates. Specifically, current methods that produce extracts containing suitably high azadirachtin content (>l-3% by weight) all involve expensive steps to remove neem oil, water, and other impurities. Such steps include decantation, phase separation, chromatography, crystallization, treatment with molecular sieves, and other purification steps. None of the known methods provides a suitably efficient, economical, or practical means for recoveringazadirachtin in a concentrated solid form that contains little or no neem oil or water.

It is known that the seeds and other parts of the neem tree [Azaderachta indicia and related species) contain natural pesticidal compositions. The main active pesticidal composition is azadirachtin which is a tetranortriterpenoid that causes feeding inhibition and growth inhibition in a variety of organisms including insects, mites and nematodes. It is possible that there are a number of similar insecticidal compounds present in neem extracts that partition with the azadirachtin. As used in this specification, the term azadirachtin is taken to include all insecticidal terpenoids present in neem extracts that partition with azadirachtin. In recoveringazadirachtin from neem seeds it is necessary to separate the active constituent from other materials including the other triterpenes, the oil. fibre and other insoluble materials, and water soluble constituents such as sugars and water soluble proteins. These separation procedures are complicated by the fact thatazadirachtin is susceptible to hydrolysis in water and to heat degradation.

One conventional method for extracting azadirachtin from neem seeds involves the use of three organic solvents and two liquid/liquid partition steps. Firstly, the neem seeds are pressed to remove the majority of the neem oil. The resulting expeller cake is then extracted with methanol. The methanol extracts a wide range of substances including azadirachtin and the other triterpenes, diterpenes. the residual oil, and some polysaccharides and proteins. To produce a powder from the methanolic supernatant, the extract must undergo a number of clean-up steps.

In the first clean-up step, the supernatant is concentrated and partitioned against hexane, or a similar non-polar solvent, to remove the oils and diterpenes. The hexane is then driven off in a still and the resulting oil is collected. The second clean-up step involves taking the de-oiled supernatant and driving off the methanol. The resulting tar is then resolved in ethyl acetate, or a similar solvent, and partitioned against water to remove the polysaccharides and water soluble proteins. The ethyl acetate which contains the azadirachtin and other triterpenes is then evaporated to produce an azadirachtin rich powder.

There are a number of problems associated with this conventional method, with the major problem being cross-contamination of the solvents used in the process and the resulting variation in product quality. While good quality azadirachtinpowder can be produced when first using the process with fresh solvents, after a number of cycles problems with cross- contamination do arise. While hexane and methanol are normally considered essentially immiscible, in a multi-component system, such as is created during the extraction of azadirachtin described above, the hexane and methanol do demonstrate some miscibility. The change in the polarity of the solvents allows oils to be carried through the hexane partition and so creates difficulties in producing a non-oily or flowable powder. A more serious problem is any occurrence of cross-contamination between the methanol and ethyl acetate. If the methanol is not removed in the drying step after the hexane partition, cross-contamination with ethyl acetate occurs. This contamination of the ethyl acetate with methanol causes azadirachtin to be carried over into the water in the ethyl acetate/water partition or in the worst case prevents a partition forming at all. A further problem with the conventional method for extractingazadirachtin is the production of waste water with a high biological oxygen demand (BOD). In many countries, the release of waste water with high BOD is not permitted and requires the installation of a relatively expensive water treatment facility. An alternative azadirachtin extraction process is described in Australian patent no 661482 to Trifolio-M GmbH, Herstellung Und Vertrieb Hochreiner Biosubstanzen. In this alternative process, the neem seed is pressed or crushed to remove the majority of the oil and the expeller cake is extracted with warm water. The warm water extraction removes the azadirachtin. some of the more polar triterpenes. the majority of the polysaccharides and water soluble proteins, and a slight amount of the more polar oily compounds. The aqueous supernatant is partitioned against a solvent of intermediate polarity, such as ethyl acetate or dichloro me thane. with the azadirachtin partitioning into the organic layer. The organic layer can then be concentrated under vacuum and theazadirachtin precipitated through the addition of a non-polar solvent, such as hexane or petroleum ether. While high yields of azadirachtin powder are produced using this alternative process, the process still results in the discharge of an aqueous solution loaded with polysaccharides and proteins which, in some countries, will require treatment to meet environmental standards. Further, the precipitation step where a non-polar solvent is added to the concentrated supernatant results in cross-contamination with its attendant problems and expense of requiring purification of the solvents prior to their re-use in the extraction process.

Azadirachtin is an insect antifeedant. A major challenge in this 22-year odyssey was the construction of 16 contiguous stereogenic centers seven of which are quaternary. The excerpt depicted here focuses on the Claisen rearrangment used to construct the congested C8-C14 bond.

Compounds A and G were obtained by total synthesis and by degradation of azadirachtin. The degradation route enabled exploration of the difficult closing stages of the synthesis. Note the harsh conditions required to effect the difficult epoxidation F→G.

 

………………………………..

The basic skeleton of the decalin fragment, intramolecularDiels-Alder reaction and aldol type cyclization and is building well using. Together is important for the selectivity of the Diels-Alder reaction, a silyl group in the after Tamao-Fleming oxidationhas become a stepping stone for introducing a hydroxyl group by.

　Subsequently, a fragment coupling. An attempt was made to make the binding by alkylation, but what has been obtained, It was a compound the reaction is going on in the oxygen atom of the enol.

Anyway Since make a bond between the fragments, was a stepping stone to this Claisen rearrangement by carbon – and is trying to build a carbon bond. Reaction seems to have gone even heat, but has been developed by Toste et al (I) catalyst Au Claisen rearrangement using that seems to have been effective. 
　Conversion fairly high hurdle is followed thereafter. Barton-McCombie conditions and it has succeeded in building carbon skeleton of the right half be subjected to a radical cyclization reaction by. At a position that is crowded Then epoxidation and we have been. Becomes the conditions investigated thoroughly that (7 days) radical scavenger addition temperature (100 ℃ or more) time, it’s easy to imagine that even just one step here, consider mind-boggling are stacked . Same compound obtained in Degradation Studies This is obtained, advances the synthesized according to the reverse route later, we have completed the synthesis of azadirachtin.

　Total synthesis route of the 64 steps that have been achieved 

　

Synthesis of Azadirachtin: A Long but Successful Journey Veitch, GE; Beckmann, E.; Burke, BJ; Boyer, A.; Maslen, SL; Ley, SV …. Angew Chem Int Ed 2007 , 46 ., 7629 DOI:10.1002/Anie.200703027
A Relay Route for the Synthesis of Azadirachtin Veitch, GE; Beckmann, E.; Burke, B. j;. Boyer, A.; Ayats, C.; Ley, SV … Angew Chem Int Ed. 2007 , 46 ., 7633 DOI: 10.1002/Anie.200703027\

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THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

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http://www.chemistryviews.org/details/ezine/5392681/Amide_Hydrogenation_in_Flow_Reactor.html

Amide Hydrogenation in Flow Reactor (wiley)

Amines are produced by amide hydrogenation over a bimetallic platinum–rhenium catalyst in a high-throughput vertical flow reactor

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Carbon dioxide is an important carbon source in the atmosphere and is “problematic” toward the activities of human beings. Although carbon dioxide is a cheap, abundant and relatively nontoxic C1 source, its chemical transformations have not been widely developed so far and are still far from synthetic applications, especially in the construction of the C–C bond. This critical review summarizes the recent advances on transition-metal-catalyzed C–C bond formation through the fixation of carbon dioxide and their synthetic applications (124 references).

http://pubs.rsc.org/en/content/articlelanding/2011/cs/c0cs00129e#!divAbstract

Once the heteronuclear seeds had been used in the lab, the cocrystal formed regardless of whether or not the seeds were used

The caffeine•benzoic acid cocrystal that has eluded scientists for 60 years has finally been crystallised

Cocrystals are crystalline materials composed of two or more molecules held together within the same crystal lattice. Cocrystallisation is significant in the pharmaceutical industry, where drug molecules are screened for cocrystal formation in order to improve their solubility, stability and bioavailability. This has the added advantage of increasing the number of crystal forms that can be considered for drug formulation while simultaneously maximising patent protection.