Bond, Pi Bond

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Reactor materials

The material of chose for the chemical reactor is crucial. In the lab, most of time we perform the reactions in glass reactors. Also during the scale up the most common choice is glass. There are several reasons for that choice: glass has excellent chemical resistance, smooth so allows easy stirring and it is also easy to clean.

For large systems, glass-lined steel units are common. The inner glass layer of a steel vessel is mecanically resistant and incorpores the advantages of the lab glass reactor (with the exception of visibility).

In spite of its advantages, it has obvious limitations. It's relativelly fragile, has low thermal conductivity, which can make it less safe than metallic reactors in large scale exothermic reactions. It is also advisable not to expose it at large temperature differentials (with the exception of borosicilated glasses). A rule may be de 50ºC rule for glass-lined steel, ie., not expose it to 50ºC variation in relativelly a short period of time so to preserve it from cracking or separation from its metal substrate.

Metal reactor vessels are often emploed. Several metallic materials are available, being the choice dependent on the use intended. 316 stainless steel is possibly the most common. Is durable, has excellent heat transfer characteristics and meets any temperature or pressure requirement.

Where acid are employed, Hastelloy is usually the choice. Is a more expensive, highly chemically resistant nickel alloy.

A very interesting general lecture on the topic of scale up, including reactor materials: www.pprbook.com

Seryne-Hydrolase mechanism

The so far commonly accepted seryne-hydrolase mechanism for hydrolitic reactions is an exemple of how enzymes works.

During the course of the reaction, any type of chirality in the substrate is recognized by the enzyme, which causes a stereochemical preferent pathway. The value of this discrimination is a crucial parameter since it stands for selectivity.



Being the nucleophile of the scheme water (hydrolysis), alcohol (acyl transfer), amine (ester aminolysis) or hydrogen peroxide (peracid formation).

Jacobsen-katsuki epoxidation

In this interesting paper (Helvetica chimica acta, 2009, 92, 623-628), the difficulty of the epoxidation of terminal olefins by the Jacobsen-Katsuki epoxidation is discussed and slightly improved by slight modifications in the procedure. The modifications are basically on the promoter of the reaction. The dependence on the solvent is also clear. Although it is interesting, a lot of things remain unclear on this reaction and further improvements are needed for difficult (terminal) olefins as styrene.

Cu effect on Fe catalyst

The use of Fe based catalyst in reactions that tipically are in the field of Pd chemisty has been logically subject of a great interest in recent years. Potencial toxicity and higher costs are obvious drawbacks for the use of Pd instead of Fe, so the idea is very interesting. I first conscienciously heard of this in last june in ChemSpecEurope Barcelona, in a lecture by Bedford, at Bristol, and had it in mind to check it next time I’ll face a catalytic coupling or a Heck reaction.

A few days ago, however, a very interesting comment appeared in OPRD quoting a paper from Buchwald and Bolm (Angew.Chem.Internat.Ed.,2009,48,5586) where Fe was used as catalyst in a coupling reaction. Interestingly, the reaction performance negatively correlated with the purity of iron (the impurities are meant to be other metals, such as Cu). In the same Angewandte number (Angew.Chem.Internat.Ed.,2009,48,5691) Bolm showed that coupling reactions can behave quite well in the presence of Cu, even at ppm levels, indicating that the actual active species could very well be Cu-based instead of Fe-based.

The Nerve Growth Factor

"Above all, don't fear difficult moments. The best comes from them."

Said Rita Levi Montalcini, in a interview last weekend. Montalcini is a jewish-italian scientist, guardoned with the Nobel price in Physiology/Medicine in 1986 for her discoveries about Nerve Growth Factor, she's celebrating her 100 birthday on April 22nd.

Eutomer, distomer and eudismic ratio

Enantiomers of an Active Pharmacological Ingredient must be regarded as two distinct species. Most of times, one of them has a higher activity than the other. The isomer with the highest activity is denoted as the eutomer, whereas its enantiomeric counterpart, possessing less or even undesired activities, is termed the distomer. The ratio of the activities of both enantiomers is known as the eudismic ratio.

What is organic chemistry?

Here's a beautiful introduction what Modern Organic Chemistry is, including a historical perspective and a modern approach including pharmaceuticals and neurochemicals. You can downlad it for free here: http://www.oup.com/uk/orc/bin/9780198503460/ch01.pdf

The book: http://www.oup.com/uk/orc/bin/9780198503460/

Chapters on isomerism and Nucleophilic substitution at saturated carbon are also available to download for free in the link above.

Basics on Weinreb Amides

For an updated review, including applications and examples see Synthesis 2008, 23, 3707.

Weinreb amides (N-alkoxy-N-methylamides), WA hereafter, provide a very convenient synthesis to aldehydes and ketones.

The collapse of the intermediate usually requires aqueous work up, which avoids over-addition despite the use of a large excess of reagents.

WA are very attrractive since they are easy to prepare, are very effective, reactions are scalable and provide stability-storability. The facile reduction to aldehydes with hydride reduction agents makes them serve as precursor to sensitive aldehyde in the masked form.

When treated with reagents as Lithium DiisoprPropylAmine at low temperatures results in demethoxylation with concomitant release of formaldehyde. This undesired competitive pathway can be overcame by using a t-butoxy group instead of a methoxy.

2008 Nobel Prize in Chemistry

Has been awarded to Osamu Shimomura, Martin Chalfie and Roger Y. Tsien for their discovery and development of the green fluorescent protein, GFP.

Enantioselective Organocatalytic Transfer Hydrogenation

Molecular H or an hydride donor, in conjunction with a chiral metal catalyst system, is the usual strategy for asymmetric catalysis. in nature, however, C-H stereogenic centers are not created this way but by biochemical processes controlled by enzymes (NADH type) and hydride reduction cofactors. This review discusses the advent of a transfer hydrogenation alternative in which small molecule oranocatalysts are used instead of enzymes/cofactor or metall/ligand systems. They call it EOTH (Enantioselective Organocatalytic Transfer Hydrogenation) and it seems to be very promising in some cases. Acc.Chem.Res., 2007, 40, 1327

A reminder on the basicity of enaminates

An alkyl side-chain on an alfa or gamma-carbon of a N-heterocycle is subject to varying degrees of stabilisation by interaction with the ring. The resulting aninon (an enaminate) is stabilized in much the same way as a conjugated enolate. The most favourable situation is the alfa or gamma-carbon of a pyridine. The pKa data available ( 34 for a 2-methylpyridine, 27.5 for a 4-methylquinoline) show that the acidity is not so far from typical ketone alfa-deprotonation (pKa about 20).

A very attractive reactivity option consist on a prior electrophilic addition to the nitrogen, which acidifies further the side-chain H and enhances formation of enaminate and its nucleophilia. For a nice example see Chem.Lett., 1984, 1591.

Some Lithium metallation generalities on 5- and 6-membered heterocycles

5-membered heterocycles

Due to the inductive effect of the heteroatom (which makes alfa-H more acidic), most of five-membered heterocycles undergo alfa-lithiation. In general, H-acidity determines selectivity. The exception is the 5 member S-heterocycle: one should expect alfa position of a furan would be more prevalent when competing for the same position in a thiophene analogue. But this is not the case. This “anomaly” is often explained in part because of the higher polarisability of sulphur, which allows a more efficient charge distribution.

In pyrroles, lithiation is complicated by the presence of a much more acidic H on N. As a consequence, a protecting group is often required (tipically Boc, which allows alfa-lithiation while easily hidrolized. Boc also withdraws electron density, thus acidifying the alfa-nitrogen further, and also provides chelation assistance for the alfa-lithiation).

Llithiation at hetero-ring positions other than alfa-position is challenging. It can be achieved via halogen exchange, but at very low temperatures to prevent equilibration with the more stable 2-lithiated heterocycle.

1,3-azoles lithiate very readily at C2.

For imidazoles, the usual protecting group is SEM (trimethylsilylethoxymethyl).

1,2-azoles (pyrazoles) lithiate at C5 (the pyrrole-like alfa-position).

If the temperature is allowed to rise, hetero-ring cleavage can occur, especially in beta-lithiated five-membered systems. The heteroatom can act as a leaving group.

Other effects:

When strong bases are used, as TMEDA (N,N,N’,N’-tetramehylethylenediamine) can result in dimetallation.

The impact of directing grups can be dramatic and there’re two general categories according to the effect: (1) Those which able coordination to lithium, and (2) electronic effects. In the first case, the thiophene-2-carboxylic acid reaction with n-BuLi in THF at -78ºC doesn’t yield the normal alfa-lithiation but beta-lithiation due to the effect of the nucleophilic carboxylate moiety, but if the reaction is performed with a lithium amide, as LDA, which is more weakly coordinating, the main product is the alfa-substituted.

6-membered heterocycles

In contrast with the selective lithiation of 5-membered heterocycles, the direct metallation of pyridine is difficult and complex. In general, the main problem with 6-membered heterocycles is to overcome the nucleophilic addition/substitution by the lithium reagent. Then, they need using strong base combination, as n-butillithium/potassium t-butoxide.

In non-polar solvents kinetic 2-metallation predominates, but in more polar solvents or under equilibrated conditions 4-isomer is the major product (alfa and gamma position are more acidic than beta). Of these two options, the anion in gamma position is the most stable (since in the alfa position there is a more unfavourable repulsion between the coplanar nitrogen lone pair and the charge). Accordingly, pyridine can be selectively lithiated at C2 when the lone pair is tied up as a complex with boron trifluoride.

Pure lithio-pyridines can be prepared by halogen exchange at low temperature.

Quinolines react like pyridines, but are more susceptible to nucleophilic addition. This also happens with pyrimidines. In this later case, susbtituents at 2 and 4 positions add some stability.

Amination of Aryl Halides

Electron rich halo-substituted aromatics do not often undergo alkylation of amines only in presence of a base and without a catalyst. A set of strategies, however, already exist. Apparently, these strategies to easy the C-N bond formation, has been transported from the toolbox of catalytic C-C bond formation. The set includes Cu-mediated(Ullmann-type reactions)and Pd-catalyzed (Buchwald-Hartwig methods) as the main basic methodologies.

Lately, a very interesting Kumada Cross-Coupling between aryl-amines and aryl-halides has been published (Org.Lett. 2005, 7, 2209-2211). The use of EtMgBr activates the amine enhancing its reactivity and a simple and cheap Nickel triphenylphosphine based catalyst does the job. This paper opens the possibility to transmetallation with Zn, Sn and boron derivatives (Negishi, Stille and Suzuki couplings) which I’d guess are also possible and potentially very useful in particular cases.

On the other hand, Buchwald-Hartwig aminations showed a much better performance with secondary amines than the Ullmann-type coupling (Tetrahedron, 2006, 62, 9010-9016) in piperazine arylations. The role of the Pd catalyst, once more, is unclear, since there is no much difference using BINAP or the simpler and cheaper triphenylphosphine. The role of the base is key, but the role of the Cessium cation on the arylation of secondary amines under Pd catalytic conditions is also unclear to me.

In the aminoalcohols particular cases (J.Am.Chem.Soc., 2007, 129, 3490-3491), the N-arylation is preferred over O-arylation under Buchwald-Hartwig conditions. In the Ullmann-type reactions, however, C-O coupling can undergo preferently one way or another depending on the reaction conditions in this very interesting study.

A Bite on Catalytic Enantioselective Oxidation of Sulphides with H2O2 in Water

Selectivity in chemical transformation is one of the keys that guide us to green chemistry. As ecological sustainability of a reaction depends on the reagents, solvents and work up, intense work focused on the development of methodologies. This is particularly challenging for asymmetric reactions, and in particular, for oxidation reactions. The use of water and molecular oxygen or hydroxide peroxide as oxidizing agent has been studied so far. However, few highly enantioselective oxidations with molecular oxygen or hydrogen peroxide have been reported: The asymmetric reaction using a chiral catalyst in water without a surfactant is a challenge.

Optically active sulfoxides are subunits of many bioactive compounds, and they also serve as chiral auxiliaries, so there’re methods in the literature for asymmetric sulfoxidation, some of them using aqueous hydrogen peroxide as the oxidant of alkyl aryl sulfides and with good yield and high enantioselectivity. The reaction with Fe(salan) complex (JACS, 2007, 29, 8940) or the one with Al(salalen)Cl (Chem. Commun., 2008, 1704) are very nice examples.

I guess this possibility is depending on the availability of the ligand, and the choose of the proper metal (Fe, Al, Mn…) and solvent for the particular substrate. Although probably the ligands depicted in the quoted papers above are not commercial, other perhaps would suit.

On the other hand, there are other options for catalytic enantioselective oxidation, although perhaps not in pure water.

Among the well know methodologies:

VO(acac)2 + chiral Shiff bases and a peroxide, usually in a two phase system (often the organic solvent which works better is dichloromethane)

Ti(OiPr)4 a ligand (chiral inductor), a base and a peroxide.

Good results with monooxigenases have been also publised.

A much less evolved strategy is the kinetic resolution of the racemic sulphide and further separation of the corresponding sulphone, although there are remarkable examples and can be useful for particular substrates.

C-H bond functionalization. Some strategies.

As creating a new covalent bond usually requires the presence of either an heteroatom or a unsaturation in the carbon backbone, H attached to C is not considered a functional group. However, selective introduction of new functionalities directly through transformation of C-H bonds unlocks opportunities for different synthetic strategies. Let's focus on three of them that are real alternatives to longer and/or less mild classical procedures.

Intramolecular Radical Reactions

Over unactivated alkyl C-H bonds in complex substrates, regioselectivity is classically achieved by exploiting structural proximity between the high energy radical (transiently generated), and the alkyl group, resulting in intramolecular H abstraction. May be amazing to notice that, in this field, the earlier work by Hoffman started in the 1800 on the hydrolysis of haloamines to functionalise methyl groups. This reaction is know today as the Hoffman-Loffler-Freitag reaction.

Another (not so) earlier work is the photolysis of a nitrite ester as a means for converting an isolated methyl group into an oxime in one step. Although with a low yield, is a demonstration of the potential of C-H functionalization.

Intramolecular Transition Metal-Catalyzed Carbene and Nitrene Insertion

Carbenes can also serve as reactive intermediates for C-H functionalization. In contrast to carbenes, the corresponding transition metals carbenoids readily available by decomposition of diazocarbonyl substrates offer more control over the reaction course. In particular, the introduction of Rh dimeric catalysts has became a powerful tool, in which, for instance, diazocarbonyl substrates can be converted in one step to cyclic ketones, lactones and lactams by means of regioselective C-C bond formation at the alkyl site. These strategies provide a unique and straightforward strategy for preparation of valuable cyclic products.

C-N bond formation at an isolated alkyl site, achieved by transition metal-catalyzed nitrene insertion, can be formally viewed as a nitrene insertion, a process analogous to the carbene derivative. Cyclization of carbamate or sulfamate substrates is achieved with dimeric Rh, an oxidant and a base in a mild, regio and stereoselective process.

Both, carbene and nitrene insertion reactions may be an elegant synthesis for natural products or advanced intermediates.

Directed Metallation

Directed metallation entails the use of a suitable heteroatomic function to direct a metal complex. The resulting metallacycle serves as intermediate to C-C or C-X bond formation. Palladium metallacycles (palladacycles) are versatile catalyst to choice, as well as its Pt, Ru and Rh analogs. Other examples include the almost classical ortho-lithiation of arenes (stoichiometric in this case), and the Friedel-Crafts alkylation, which can have its catalytic alternative and perhaps with reversed regioselectivity, depending on the case.

Science, 312, 2006, 67

Radical Substitution at Carbon in Heterocycles (a pocketful of key basic concepts)

Both electron-rich and electron-poor heterocyclic rings are susceptible to substitution of H by radicals. The electronic properties, which are a consequence of the interaction between the SOMO of the radical and either the HOMO or the LUMO of the substrate, depending on their relative energies, are key factors. In fact, the Radical Substitution at Carbon (RSC) is understood by classifying the radicals as nucleophilic or elecrophilic.

Nucleophilic radicals (e.g., ·CH2OH, ·alkyl and ·acyl) react with electron-poor heterocycles (and will not attack electron-rich systems), allowing electron density drift away from the radical to the electron-deficient heterocycle.

Electrophilic radicals (e.g., ·CF3, ·CH(CO2Et)2) would form stabilised anions on gaining an electron, therefore react readily with electron-rich systems.

Aryl radicals can show both types of reactivity at about the same rate.

The Minisci Reaction

The reaction of nucleophilic radicals, under acidic conditions, with heterocycles containing a C=N unit is a very spread synthetic tool. They react selectively at alfa and gamma to the nitrogen. Acidic conditions are essential since it enhances reactivity and also promotes regioselectivity. The Minisci methodology is particularly useful to introduce acyl groups (equivalent to the Friedel-Crafts, impossible under normal conditions for such systems).

Regarding to the Minisci reaction, it is worthy to have in mind the following tips:

1.- Tertiary radicals are more stable, and also have more nucleophilic character and then are more reactive than methyl radicals in Minisci reactions.

2.- Many times this reaction is carried out in aqueous or partially aqueous conditions.

3.- Several methods have been employed to generate the needed radical, most of them employing sulphuric acid and a peroxide or a peroxide derivative (oxidative path), or a mixture of an alkyl iodide with tris(trimethylsilyl)silane, or a carboxylic acid precursor for alkyl and acyl radicals via silver-catalysed peroxide oxidation, etc. (reductive path).

Doesn’t surprise that, when more than one reactive position is available in a heterocycle, there are regioselectivity or/and disubstitution issues to consider. Although regioselectivity is partially dependent on the nature of the attacking radical and solvent, it can be difficult to control.

Key factors influencing nucleophilic substitution on heteroaromatics

Nucleophilic substitution of aromatic compounds proceeds via addition of nucleophile and then elimination of the leaving group, in a two steps sequence. The former step is often the rate determining one and the stabilisation of the charged intermediate (Meisenheimer complex) the key factor for such processes to succeed. As many times in organic chemistry the product distribution is controlled by the kinetics of the slowest step (kinetic control).

In heteroaromatic compounds, the same general rules apply. In this case, the difference between 5 or 6-membered rings is noticeable, as in electrophilic aromatics substitution (the yesterday's post) there's a big difference between 5 and 6-membered rings. In the former case, the displacement of a good leaving group is more difficult, so the displacement of good leaving groups by a nucleophile is specially important in six-membered pi-electron-poor systems while in their five-membered pi-electron-rich systems such processes only come into play in special situations (i.e., in azoles when the leaving group is attached to an azomethine link).

In general, and as a rule of thumbs, positions alfa and gamma of an azomethine N are activated for the initial addition of a nucleophile by 2 factors:
1.- Inductive (electronegativity based) and mesomeric (resonance based) withdrawal of electrons by the nitrogen,
2.- Inductive withdrawal of electrons by the leaving group,
The sigma-adduct intermediate is stabilised when the attack is at alfa and gamma positions. In these situations the negative charge resides largely on the nitrogen, meaning that beta position is usually much less reactive in nucleophilic displacements. For instance, in Cl-pyridines the displacement of chloride by methoxide in methanol undergo with these approximate rates 10^8, 10^4 and 10^9 (alfa, beta and gamma, resp.).

Other effects:

The presence of a formal positive charge on the nitrogen, as in N-oxides and N-alkylpyridinium salts, enhances the rate of nucleophilic substitutions (more in quaternisation than in oxidation). All positions are enhanced, especially the alfa position, meaning that as in neutral pyridines the gamma position is a little bit more enhanced than the alfa position, in positively charged pyridines the order is the other way around.

In bicyclic systems, a certain increase on rate is observed in quinolines derivatives than in their monocyclic counterparts. Quaternisation again greatly increase the rate of substitution having a larger effect at the alfa position than in the gamma position.

Diazines with halogen at alfa and gamma positions are much more reactive than similar pyridines.

Electrophilic Substitution in Five-Membered Heterocycles: A briefing of key concepts

The nitrogen lone pair in pyrrole forms part of the aromatic 6-electron system. In this structure, the charge distribution in the resonance canonical structures (responsibles of the mesomeric effect) makes that electron density drifts away from the nitrogen. On the other hand, the inductive effect of the nitrogen is towards the hetero atom and away from carbon, meaning that electronic distribution in pyrrole is a balance of two opposing effects, of which the mesomeric effect is often the most significant. As a consequence, de dipolar moment of the pyrrol is solvent dependent and away from the N towards the carbon. For this reason, five-membered heterocycles of the pyrrole type are referred as electron-rich or, better, pi-electron-rich.

For thiophene and furane, however, the heteroatom's higher electronegativity means that positive charges on the hetero atom in canonical resonance make a smaller influence. The decreased mesomeric electron drift away is insufficient, in these cases, to overcome inductive polarisation and the dipolar moment is practically not dependent on the solvent and and away from the N and away from carbon.

Due to their higher pi-electron richness, heterocycles such as pyrrole, thiophene and furan undergo electrophilic substitution much easier than their 6-membered counterparts. And although either carbon on the ring is possible, the preference is the attack to the adjacent hetero atom (alfa position). As this preference is facilitated by the electron-release from the hetero atom, pyrroles are more reactive than furans which are in turn more reactive than thiophenes. Indoles are only slightly less reactive than pyrroles, electrophilic substitution taking place preferably in the heterocyclic ring.

The reactivity of an indole is very comparable to that of a phenol: depending on pH, indoles can undergo coupling reaction at the heteroatom with certain easiness.

Halogen/Metal exchange reaction, a mechanistical insight

Although the halogen/metal exchange reaction (R1-X + R2-M = R1-M + R2-X) is a cornerstone in the methodology of organometallic chemistry, its mechanism is far from being settled.

3 structures have been postulated as possible transition state/intermediate for this reaction: (1) A four-centres, rhomboid [R1MXR2] transition state, (2) Ate-complexes [(R1-X-R2)M], and (3) radicalary.

When R1 and R2 are such that the ate-complex can enjoy substantial thermodynamic stability, it can be a detectable intermediate. The structural and kinetic stability of the ate-complexes permits them to be present as solvent separated ion pairs (SSIP) or even as dissociated ions.
In this cases, C-X bond formation precedes the C-M bond formation, and the TS may be approximated by the contact ion pair (CIP), in which a linear dialkyl-halogenate anion is distorted by coulombic attraction between the metal cation and the negatively charged carbon atoms.

In addition, the preferred pathway for a quite stable ate-complex is not one based on a SET mechanism. However, ate complexes are highly sensitive to enter into a SET-inititiated radical processes (even a small amount of radical may trigger the SET pathway). In the competence cases, lowering the temperature can be a way to favour the polar mechanism, as can be the use of additives as Mg(OTf)2 (by adding a common ion).

For an indeeper discussion see Org.Lett.2003, 5, 313

Opening a broader window, and as a law of thumbs:

1. Aryl bromides and iodides react through an ate-complex
2. Primary alkyl iodides react via polar mechanism
3. Secondary alkyl iodides undergo polar/radical competition
4. Alkyl iodides react via radical mechanism
5. I-Mg exchange is via ate-complex

For a rationale with examples