Mechanism (LAH reduction nitrile to amine)

Below is the mechanism of the reduction of an nitrile to amine using LiAlH4 (LAH).  I have kept it simple by not going into much details.

 Transfer of a hydride ion from lithium aluminum hydride to the carbon atom of the nitrile generates an imine intermediate, which is in equilibrium with the corresponding imino alanate.

 The imino alanate converts to the amino alanate after adddition of an additional hydride ion.

Hydrolysis yields the primary amine.

Mechanism (LAH reduction ester to alcohol)

Below is the mechanism of the reduction of an ester to alcohol using LiAlH₄ (LAH).  I have kept it simple by not going into details.

Step 1: The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl group of the ester. Electrons from the C=O move to the electronegative O creating the tetrahedral intermediate a metal alkoxide complex.

Step 2: The tetrahedral intermediate collapses and displaces the alcohol portion of the ester as a leaving group, in the form of the alkoxide, RO^-. This produces an aldehyde as an intermediate.

Step 3: Now we are reducing an aldehyde.  The nucleophilic H from the hydride reagent adds to the electrophilic C in the polar carbonyl group of the aldehyde. Electrons from the C=O move to the electronegative O creating an intermediate metal alkoxide complex.

Step 4: This is the work-up step, a simple acid/base reaction. Protonation of the alkoxide oxygen creates the primary alcohol product from the intermediate complex. 

Chromium Reagents (Chromate)

All forms of Cr(VI) are powerful oxidizing agents, and oxidize any CH bonds on a carbon with an oxygen as far as possible without breaking any carbon-carbon bonds; for example, secondary alcohols are converted to ketones, and aldehydes to carboxylic acids. The most common reagents are: H₂CrO₄; K₂Cr₂O₇ + H₂SO₄; CrO₃ + H₂SO₄; they are approximately equivalent. They oxidize the activated CH bonds next to an aromatic ring, the "benzyl" hydrogens, so completely that they usually convert any alkyl benzene to a benzoic acid. Cr(VI) reagents are so powerful that they can also oxidize alkenes and alkynes, breaking the carbon-carbon bond as ozone does, but this reaction is not synthetically useful.

In non-aqueous solutions, oxidation by Cr(VI) does not go to completion (the intermediate partially oxidized material containing Cr must be hydrolyzed for oxidation to continue); thus, under these conditions, primary alcohols may be oxidized to aldehydes without forming carboxylic acid. The most common reagents for this partial oxidation are: PCC, or pyridinium chlorochromate (formed by dissolving CrO₃ and HCl in pyridine); Collins reagent (CrO₃ in CH₂Cl₂); chromyl chloride (CrO₂Cl₂).

Some of the oxidizing reagents containing Cr(VI) are listed below:

Sarett reagent: CrO₃.2C₅H₅N     (where C₅H₅N = pyridine): The highly exothermic reaction of chromium trioxide when added to an excess of pyridine leads to the formation the CrO₃ • 2 Py complex (Sarett Reagent). Compared to the Jones Reagent, Sarett Reagent allows the oxidation of various primary alcohols to aldehydes due to the non-aqueous conditions (see  Jones Oxidation for an explanation). Unfortunately, the complex is highly hygroscopic and the preparation of the reagent is not without risk because the solvent occasionally catches fire during preparation. In addition, the use of pyridine as solvent does not permit the oxidation of base-sensitive substrates.

The reagent is named after the American chemist Lewis Hastings Sarett (1917– 1999).

Collins reagent: CrO₃.2C₅H₅N diluted in CH₂Cl₂ : A solution of CrO₃ • 2 Py (Sarett Reagent) in methylene chloride is called the "Collins Reagent". One advantage over the Sarett Reagent is that the addition of one equivalent chromium trioxide to a stirred solution of two equivalents of pyridine in methylene chloride allows the convenient and safe preparation of the oxidant. In addition, the use of methylene chloride as solvent and stoichiometric amounts of pyridine makes the Collins Reagent less basic than the Sarett Reagent. Thus, most acid and base-sensitive substrates can be oxidized with Collins Reagent, unlike both the Sarett and Jones Reagent.

As the Collins Reagent does not contain water (compared to the Jones Reagent) and is not as hygroscopic as is the Sarett Reagent, the oxidant is especially useful for the oxidation of primary alcohols to aldehydes where traces of water can lead to overoxidation.

This complex is both difficult and dangerous to prepare, as it is very hygroscopic and can inflame during preparation. It is typically used in a sixfold excess in order to complete the reaction. Nowadays, PCC or PDC oxidation have largely supplanted Collins oxidation for these very reasons.

Cornforth reagent: CrO₃/ Pyridine / H₂O: The Cornforth reagent or pyridinium dichromate (PDC) is a pyridinium salt of dichromate with the chemical formula [C₅H₅NH]2[Cr₂O₇]. This compound is named after the Australian-British chemist Sir John Warcup Cornforth (born. 1917) who introduced it in 1962. The Cornforth reagent is a strong oxidizing agent which can convert primary and secondary alcohols to aldehydes and ketones respectively. In its chemical structure and functions it is closely related to other compounds made from hexavalent chromium oxide, such as pyridinium chlorochromate and Collins reagent. Because of their toxicity, these reagents are rarely used nowadays.

The Cornforth reagent is prepared by slow addition of a concentrated aqueous solution of chromium trioxide to pyridine. The reaction may cause explosion, which is avoided by thoroughly dissolving the trioxide in water and cooling the solution by ice. The product is filtered, washed with acetone and dried, yielding an orange powder. The powder is stable in air, not particularly hygroscopic and has an almost neutral pH that facilitates its handling; it is only slightly acidic owing to the presence of pyridinium cations. The Cornforth reagent is readily soluble in water, dimethylformamide and dimethyl sulfoxide (DMSO). It is poorly soluble in acetone and chlorinated organic solvents, such as dichloromethane, and forms suspensions.

The oxidation is usually carried out at ambient conditions, in nearly neutral pH conditions, in dimethylformamide or dichloromethane or their mixture. The choice of solvent or their ratio affects the reaction rate; in particular, higher content of dimethylformamide results in stronger oxidation. The slow oxidation rate for some alcohols can be accelerated by the addition of molecular sieves, organic acids or acetic anhydride or of their combinations. The acceleration by molecular sieves works best when their pore diameter is about 0.3 nm, and it is apparently unrelated to their water absorption capability. Among organic acids, acetic acid, pyridinium trifluoroacetate or pyridinium tosylate can be added, the first one being most efficient and easiest to remove. The achieved acceleration is remarkable, but the reaction inevitably turns from neutral (pH) to acidic. Comparable acceleration is achieved with acetic anhydride, which is used in sugar and nucleoside chemistry. Reaction acceleration depends not only on the additives but also on their form, so all reagents are preferred dry and freshly prepared, and PDC and molecular sieves should be finely ground. The disadvantange of the accelerators is that they may simultaneously promote several oxidation routes thereby reducing the selectivity of the reaction.

Fieser reagent: CrO₃ in acetic acid: Fieser's reagent is a mixture of chromium trioxide in acetic acid.

Jones reagent: CrO₃ + H₂SO₄ : The Jones Reagent is a solution of chromium trioxide in diluted sulfuric acid that can be used safely for oxidations of organic substrates in acetone. The reagent can also be prepared from sodium dichromate and potassium dichromate. Jones Reagent is especially suitable for the oxidation of secondary alcohols to ketones and of primary alcohols to carboxylic acids and in a few cases to aldehydes (Jones Oxidation). Some alternative chromium reagents allow the selective preparation of aldehydes, such as PCC and PDC.

Although the reagent is very acidic, the substrate in acetone is essentially titrated with the oxidant solution and only very acid-sensitive groups are incompatible. For example esters, even tert-butyl esters, remain unchanged. The concentration of sulfuric acid can be decreased to minimize side reactions, although the oxidation power increases too.

Depending on the reaction conditions, the aldehydes may then be converted to carboxylic acids. For oxidations to the aldehydes and ketones, two equivalents of chromic acid oxidize three equivalents of the alcohol:

2 HCrO₄^– + 3 RR'C(OH)H + 8 H⁺ + 4 H₂O → 2 [Cr(H₂O)₆]³⁺ + 3 RR'CO

For oxidation of primary alcohols to carboxylic acids, one equivalent of Jones reagent is required for each substrate. The aldehyde is an intermediate.

4 HCrO₄^– + 3 RCH₂OH + 16 H⁺ + 11 H₂O → 4 [Cr(H₂O)₆]³⁺ + 3 RCOOH

The inorganic products are green, characteristic of chromium(III) aquo complexes.  Although the reagent is very acidic, the substrate in acetone is essentially titrated with the oxidant solution and only very acid-sensitive groups are incompatible. For example esters, even tert-butyl esters, remain unchanged. The concentration of sulfuric acid can be decreased to minimize side reactions, although the oxidation power increases too.

Thiele reagent: CrO₃ + acetic anhydride + H₂SO₄

Corey-Suggs reagent (Pyridinium Chlorochromate (PCC) in CH₂Cl₂): [C₅H₅NH]+[CrO₃Cl]^-

Corey-Schmidt reagent (Pyridinium Dichromate (PDC) in CH₂Cl₂ or DMF):(C₅H₅NH)₂Cr₂O₇

Brown-Garg H2CrO4/(ether or benzene)/water

Kiliani Reagent H2CrO4 /H2SO4/ water/ acetic acid

Chromic anhydride CrO3/ water/ acetic acid

Snatze Reagent CrO3/ DMF

CrO3/ acetic anhydride/ acetic acid

CrO3 /HMPT

All the above reagents can be used with co-catalysts like mercuric acetate, ceric ammonium nitrate, manganous nitrate, oxalic acid and special effects come with controlled amounts of water in the reagent.

ATTENTION: Cr(VI) reagents have been shown to be carcinogenic, upon ingestion either through the stomach or the lungs. Not many years ago chromic acid solutions were the way to clean glassware (they remove organic compounds very well and leave the glass sparkling). They have been shown to leave traces of Cr(VI) on the glass, which can be death to a Grignard reagent, for example. The cancer-causing properties have resulted in strict regulations for disposal (you can't!), and thus these reagents are no longer used routinely. Interestingly, the chromate (CrO4-) looks like sulfate to cells, and is readily incorporated. Once in the cell, it oxidizes something and is converted to Cr(III); the Cr(III) looks a lot like Zn(II) and other biologically important ions. It is the Cr(III) that actually causes the damage that leads to cancer but the Cr(III) itself cannot get into the cells - it has to enter as Cr(VI).

Jones Oxidation (CrO3 + H2SO4)

The Jones Oxidation allows a relatively inexpensive conversion of secondary alcohols to ketones and of most primary alcohols to carboxylic acids.  The Jones reagent is a mixture of chromic anhydride and dilute sulfuric acid (CrO₃ + H₂SO₄ + H₂O) in acetone. It is used in the oxidation of secondary alcohols, that do not contain acid sensitive groups, to corresponding ketones and also the oxidation of primary allylic and benzylic alcohols gives aldehydes.

Jones described for the first time a conveniently and safe procedure for a chromium (VI)-based oxidation, that paved the way for some further developments such as Collins Reaction and pyridinium dichromate, which also enabled the oxidation of primary alcohols to aldehydes.

How does it work:

The Jones Reagent is a mixture of chromic trioxide or sodium dichromate in diluted sulfuric acid, which forms chromic acid in situ.

The alcohol and chromic acid form a chromate ester that either reacts intramolecularly or intermolecularly in the presence of a base (water) to yield the corresponding carbonyl compound.

Aldehydes that can form hydrates in the presence of water are further oxidized to carboxylic acids.

Some alcohols such as benzylic and allylic alcohols give aldehydes that do not form hydrates in significant amounts; these can therefore be selectively oxidized with unmodified Jones Reagent to yield aldehydes. Although the reagent is very acidic, the substrate in acetone is essentially titrated with the oxidant solution and only very acid-sensitive groups are incompatible. For example esters, even tert-butyl esters, remain unchanged. The concentration of sulfuric acid can be decreased to minimize side reactions, although the oxidation power increases too.

Procedures:

The oxidation reagent is prepared by dissolving 70 g. (0.70 mole) of chromium trioxide in 100 ml. of water in a 500-ml. beaker. The beaker is immersed in an ice bath, and 112 g. (61 ml., 1.10 moles) of concentrated (18M) sulfuric acid followed by 200 ml. of water is added cautiously with manual stirring. The solution is cooled to 0–5°C. 

A solution of 110 g. (1.00 mole) of nortricyclanol (Note 1) in 600 ml. of acetone (AR grade) is cooled to 0–5°C in a flask immersed in an ice bath and equipped with an efficient mechanical stirrer, a thermometer, and a dropping funnel with a pressure-equalizing arm. The cooled oxidation reagent prepared above is poured into the dropping funnel, and the reagent is added with vigorous stirring, at a rate to maintain the temperature of the reaction mixture at about 20°. The stirring is continued for 3 hours after the addition is completed.

Work-up: Sodium bisulfite is added in small portions until the brown color of chromic acid is gone from the upper layer of the two-phase mixture. The top layer is decanted, and the dense, green, lower layer is extracted with 200 ml. of 30–60°C petroleum ether. Combination of this extract with the original upper layer causes a separation into two phases. The lower phase is drawn off and added to the original lower phase, which is then extracted with there 200-ml. portions of 30–60°C petroleum ether. The extracts are combined, washed successively with two 50-ml. portions of saturated sodium chloride, two 50-ml. portions of saturated sodium bicarbonate solution, and 50 ml. of saturated sodium chloride solution, and dried over magnesium sulfate. The solvent is removed by distillation through a short column containing glass helices, and the residue is distilled under reduced pressure to give 85–95 g. (79–88%) of nortricyclanone, b.p. 103–105° (77 mm).

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The chromic acid oxidizing reagent is prepared by dissolving 67 g. of chromium trioxide in 125 ml. of distilled water. To this solution was added 58 ml of conc sulfuric acid (sp. gr. 1.84), and the salts which precipitate are dissolved by addition of a minimum quantity of distilled water; the total volume of the solution usually does not exceed 225 ml.

A solution of 64 g. (0.5 mole) of cycloöctanol in 1.25 l. of acetone is added to a 2-l. three-necked flask fitted with a long-stem dropping funnel, a thermometer, and a powerful mechanical stirrer (Note 2). The vigorously agitated solution is cooled in a water bath to about 20°C. The chromic acid oxidizing reagent is added from the dropping funnel as a slow stream, and the rate of addition is adjusted so that the temperature of the reaction mixture does not rise above 35°. The addition is continued until the characteristic orange color of the reagent persists for about 20 minutes. The volume of reagent added is about 120 ml.  The stirrer is removed, the mixture is decanted into a 2-l. round-bottomed flask, and the residual green salts are rinsed with two 70-ml. portions of acetone. The rinsings are added to the main acetone solution and additional oxidizing agent is added, if necessary, to ensure complete reaction. The stirrer is replaced and isopropyl alcohol is added drop wise until the excess chromic acid is destroyed. In small portions and with caution was added 63 g. of sodium bicarbonate, and the suspension is stirred vigorously until the pH of the reaction mixture tests neutral. The suspension is filtered and the filter cake is washed with 25 ml. of acetone. The filtrate is concentrated by distillation through a 75-cm. length of Vigreux column until the pot temperature rises to 80° and a water film begins to develop in the lower portions of the distillation column. The cooled pot residue (about 110 ml.) is transferred to a 1-l. separatory funnel, 500 ml. of saturated sodium chloride solution is added, and the mixture is extracted with two 150-ml. portions of ether. The ether extracts are combined, washed with a total of 25 ml. water in several portions, dried over anhydrous magnesium sulfate, filtered, and the ether distilled at atmospheric pressure. The pot residue is distilled under reduced pressure, b.p. 76–77° (10 mm.). The yield of cycloöctanone is 58–60 g. (92–96%), m.p. 40–42°.

An additional 2.2 g. (4%) of cycloöctanone may be obtained by addition of 250 ml. of water to the green salts formed during the reaction, extraction of the mixture with ether, distillation of the ether, and addition of 12 ml. of acetone. To the acetone solution there is added sufficient chromic acid oxidizing reagent to permit the orange color of the reagent to persist , and the mixture is processed as above.

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1.06 grams  CrO3 are added to .92ml H2SO4, and distilled water is added to bring the total volume to 4ml. 2 grams of pseudoephedrine are dissolved in 20ml acetone, and cooled in an ice bath. The Jones reagent is slowly added to the pseudoephedrine, dropwise and with stirring. The mixture becomes a reddish brown.

The reaction will proceed slowly, but very smoothly as exact moles were added (mild conditions). Stir the solution warm over night.  About 12-18 hours later the reaction is complete, the color is now a very dark green. Add about 20mL of water, and chill in an ice bath. Drop wise and with stirring add about 1 gram of NaOH in a solution with as little water as possible (highly concentrated). Check the pH regularly, and stop at pH=12. The now basic solution is extracted with toluene (3 x 50ml), filter if any emulsions form.  Combine the three toluene extractions and evaporate to result in a impure ketone of pseudoephedrine, also know as methcathinione or ephedrone.

Purification: It is purified by adding just enough toluene to redissolve it.  The toluene is filtered to remove any additional particles, poured back into the separation funnel and shaken with an equal amount of distilled water. This removes any small amount of water solubles. The toluene is put into a clean RB flask and distilled again. The impurities are more soluble in acetone than the ephedrone, so a very small amount of acetone is added, and sloshed around. Filter this and the solids resulting are a little over 1 gram (about 60% yield) of relatively pure, slightly off-white methcathinone.

Note: The example given - Pseudoephedrine or Ephedrine to Methcatinone - is for illustrative purposes only. Oxidizing cold pills is illegal, and makes a lousy drug anyway.

Reactions to remember with Jones Reagent:

The secondary alcohols are oxidized to corresponding ketones in Jones reaction.

The primary alcohols are oxidized to carboxylic acids via aldehydes with Jones reagent.

Benzyl alcohol can be oxidized to benzaldehyde. Further oxidation to benzoic acid is not possible as the benzaldehyde cannot form stable hydrates in water.

In Jones reaction, the allylic alcohols are also selectively oxidized to aldehydes. The double bonds are intact in this reaction.

Tips:

• Disproportionations and single electron transfers lead to chromium (V) acid and stable Cr(III) hydroxide. The chromium (V) acid promotes a two-electron oxidation of an alcohol and becomes Cr(III). Any residues of toxic Cr(V) and Cr(VI) compounds can be destroyed by the addition of an excess of 2-propanol once the intended reaction is complete. The formation of Cr(III) is indicated by a color change to green.
• For the synthesis of aldehydes, the Collins Reaction or use of more modern - although more expensive - chromium (VI) reagents such as PCC and PDC can be an appropriate choice.
• Some newer protocols are available in which a catalytic amount of CrO3 in aqueous solution is used in tandem with a strong stoichiometric oxidant, which is able to reoxidize Cr(IV) but does not interfere with the organic compounds.
• The Jones reagent is prepared by adding chromic anhydride to dilute sulfuric acid in acetone and is added to the alcohol at 0-25C.
• The orange or yellow colored Cr(VI) is reduced to blue green Cr(III) species during the oxidation.
• Make sure the reaction mass is slightly acidic for it to progress.

Pyridinium Chlorochromate (PCC) Corey-Suggs Reagent

Pyridinium chlorochromate is a reddish orange solid reagent used to oxidize primary alcohols to aldehydes and secondary alcohols to ketones. Pyridinium chlorochromate, or PCC, will not fully oxidize a primary alcohol to the carboxylic acid as does the Jones reagent. A disadvantage to using PCC is its toxicity. PCC was developed by Elias James Corey and William Suggs in 1975.  Pyridinium dichromate has the advantage of being less acidic than its class of oxidizing agents.

Preparation:

First chlorochromic acid is prepared by the dissolution of chromium trioxide in 6M aq. hydrochloric acid. Addition of pyridine gives pyridinium chlorochromate as orange crystals.

The properties of PCC can be compared with those of PDC: it is not particularly hygroscopic, is stable, commercial available and can be stored. PCC is soluble in many organic solvents, and especially dichloromethane at room temperature has been used in most cases, whereas DMF promotes the over-oxidation of primary alcohols into carboxylic acids.

PCC is more acidic than PDC, but acid-labile compounds can be oxidized in the presence of sodium acetate or other buffers such as carbonates. Another drawback is the formation of viscous materials that complicate product isolation. Addition of Celite, powdered molecular sieves or magnesium sulfate to PCC oxidation reaction mixtures can simplify the work-up, because the reduced chromium salts and other reagent-derived byproducts are deposited onto these solids, which can then be readily removed by filtration.

How does it work?

Oxidation reactions of this sort are actually a kind of elimination reaction. We’re going from a carbon-oxygen single bond to a carbon-oxygen double bond. The elimination reaction can occur because we’re putting a good leaving group on the oxygen, namely the chromium, which will be displaced when the neighboring C-H bond is broken with a base.

Attention: Chromium (VI) compounds are toxic and must be handled with care as it is a known carcinogen. Other methods for oxidizing alcohols using less toxic reagents have been introduced and are more preferred by green chemists:

• DMSO-based oxidations (Swern oxidation, Moffatt oxidation)
• hypervalent iodine based oxidation (such as the Dess-Martin periodinane)

Procedures:

A 500-mL, round-bottomed flask equipped with a 4.5-cm, egg-shaped Teflon-coated magnetic stir bar is charged with 130 mL of CH₂Cl₂, the alcohol (10.4 g, 40.0 mmol), and 15 g of freshly powdered 3 Å molecular sieves. Pyridinium chlorochromate (21.5 g, 100 mmol) is added portionwise over 10 min and the resulting mixture is stirred at room temperature for 15 hr. Ether (200 mL) is added slowly with vigorous stirring and the solution is filtered under vacuum through a pad of 35 g of Celite. The solids remaining in the reaction flask are transferred to the Celite pad by scraping with a spatula and washing with three 50-mL portions of ether. The resulting cloudy brown filtrate is concentrated by rotary evaporation at room temperature to give a brown solid. To this solid is added 25 mL of 1:1 ether:hexane and the solids are scraped with a spatula. The mixture is then poured onto 60 g of Whatman 60 Å (230-400 mesh) silica gel packed in a 4-cm diameter chromatography column and the liquid is adsorbed onto the silica gel by gravity. The material remaining in the flask is further washed with 1:1 ether:hexane and transferred onto the silica gel; this process is repeated until all the material has been loaded onto the silica gel. The ketone is eluted using 500 mL of 1:1 ether:hexane and the eluent is concentrated by rotary evaporation to afford the crude ketone as a white solid. This material is dissolved in 40-45 mL of boiling hexane. Upon cooling the solution to room temperature, the ketone begins to crystallize. The flask is then cooled to −25°C for 2 hr. The resulting solids are collected by filtration, washed with three 25-mL portions of cold (−25°C) hexane, and dried to afford 8.84-9.08 g, (86-88%) of the ketone as a white solid.

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A flame-dried, 250-mL, three-necked, round-bottomed flask is equipped with a magnetic stir bar, rubber septum, glass stopper, and an argon inlet. The flask is charged with pyridinium chlorochromate (16.4 g, 76 mmol) and 75 mL of dichloromethane. A solution of crude (6R)-(+)-1,6-dimethylcyclohex-2-en-1-ol (4.79 g, 38 mmol) prepared as described above in 25 mL of dichloromethane  is transferred into the reaction mixture via cannula over 5 min, and the resulting mixture is stirred at ambient temperature for 3 hr. The reaction mixture is then diluted with 120 mL of diethyl ether, the solution is decanted, and the remaining black resinous polymer is thoroughly washed with three 50-mL portions of diethyl ether. The combined dark brown/black ether solution is washed successively with two 100-mL portions of 5% aqueous sodium hydroxide solution, 100 mL of 5% aqueous hydrochloric acid, and two 50-mL portions of saturated aqueous NaHCO3 solution, dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation at room temperature (50 mmHg) to give 4.42 g of the crude product as a yellow oil. Purification by column chromatography  yields 3.71-3.85 g (79-82% overall from 1) of (R)-(+)-3,4-dimethylcyclohex-2-en-1-one (3) as a colorless oil.

Tips:

In practice the chromium byproduct deposits with pyridine as a sticky black tar, which can complicate matters. Addition of an inert adsorbent such as crushed molecular sieves or silica gel allows the sticky byproduct to adsorb to the surface, and makes workup much easier.