常見的金屬氫化物還原劑

金屬氫化物還原具有反應條件溫和，副反應少以及產率高的優點，特別是某些烴基取代的金屬化合物，顯示了對官能團的高度選擇性和較好的立體選擇性。在複雜的天然產物的合成中，較之其他還原法顯示出更多的優點。最常用的為氫化鋁鋰(LiAlH₄)、硼氫化鉀（鈉、鋰）[K(Na,Li)BH₄]，以及發展了化學和立體選擇性好的試劑，例如硫代硼氫化鈉(NaBH₂S₃)、三仲丁基硼氫化鋰LiBH (CH₃CH₂CH(CH₃))₃等。

 

機理

金屬複氫化物具有四氫鋁離子(AlH₄^-)或四氫硼離子(BH₄^-)的複鹽結構，這種複合負離子具有親核性，可向極性不飽和鍵中帶正電的碳原子進攻，繼而發生負離子轉移而進行還原。There are, however, some differences depending on the reagent and to address those, let’s start with the mechanism of LiAlH4 Reduction:

 

The hydride addition to the carbonyl is also catalyzed by the lithium ion which serves as a Lewis acid by coordinating to the carbonyl oxygen. This decreases the electron density on the oxygen thus making the C=O bond more susceptible to a nucleophilic attack.

The resulting alkoxide salt can react with the AlH3 and convert it to another source of hydride. However, for simplicity, most often we show only one addition to the carbonyl followed by a protonation of the alkoxide with water or aqueous acidic solutions which gives the final product alcohol.

四氫鋁鋰是相當強的還原劑。還原酮，醛不在話下，羧酸和酯也能被還原到對應的醇。腈和酰胺也能被還原，得到胺。鹵化物和碸也能被還原，它們原位置上變成氫。它也能使能使環氧化合物發生開環反應。反應一般用到本身不與氫化鋁鋰發生反應同時有良好的溶解性的THF，乙醚等溶劑。氫化鋁鋰會與水或質子溶劑發生劇烈反應，放出氫氣。由於反應劇烈和容易飛散，不可避免發生火災。取用時要十分的注意。

NaBH4 是另外常用的一種還原劑，對水分穩定，空氣中也能使用，最適合工業生產。溶解性是它的一大問題，通常用甲醇或乙醇作溶劑。酯，酰胺，羧酸不能被還原，但是酯的羰基α位若被雜原子取代的情況下是例外（可能是由於相鄰的定位作用）。對於α，β-不飽和羰基化合物，優先發生1,4-還原，加入鈰鹽的情況下則會優先發生1,2-還原（luche還原）。

Sodium borohydride reduces aldehydes and ketones by a similar mechanism with some important differences that we need to mention.

First, NaBH4 is not so reactive and the reaction is usually carried out in protic solvents such as ethanol or methanol. The solvent has two functions here:

1) It serves as the source of a proton (H+) once the reduction is complete

2) The sodium ion is a weaker Lewis acid than the lithium ion and, in this case, the hydrogen bonding between the alcohol and the carbonyl group serves as a catalysis to activate the carbonyl group:

由於這類還原劑的反應活性和穩定性的不同，使用時反應條件也有所不同，氫化鋁鋰遇水，酸或含羥基，巰基化合物，可分解放出氫而形成相應的鋁鹽。因而反應需在無水條件下進行，且不能使用帶有羥基或巰基的質子溶劑及可被還原的溶劑（DMF, DMSO, CH2Cl2）等。一般用醚類溶劑，主要是無水四氫呋喃或乙醚，其在乙醚中的溶解度為20-30%，四氫呋喃為17%。

氫化硼鉀（鈉）與上述鋰鹽有所不同，在常溫下，遇水，醇都較穩定，不溶於乙醚及四氫呋喃，能溶於水，甲醇，乙醇而分解甚微，因而常選用醇類作為溶劑。如反應須在較高的溫度下進行，則可選用異丙醇，二甲氧基乙醚等作溶劑。在反應液中，加入少量的堿，有促進反應的作用。硼氫化鈉比其鉀鹽更具引濕性，易於潮解，故工業上多采用鉀鹽。采用氫化硼鉀（鈉）還原劑反應結束後，可加稀酸分解還原物並使剩餘的氫化硼鉀生成硼酸，便於分離。

用氫化鋁鋰還原劑反應結束後，可加入乙醇，含水乙醚或10%氯化銨水溶液以分解未反應的用氫化鋁鋰和還原物。用含水溶劑分解時，其水量應近於計算量，使生成顆粒狀沉澱的偏鋁鋰而便於分離。如加水過多，則偏鋁酸鋰進而水解成膠狀的氫氧化鋁，並與水和有機溶劑形成乳化層，致使分離困難，產物損失較大。

因而，氫硼化物類還原劑，不能在酸性條件下反應，對於含有羧基的化合物的還原，通常應先中和成鹽後再反應。

 

除了常用的 LITHIUM ALUMINIUM HYDRIDE AND SODIUM BOROHYDRIDE, OTHER HYDRIDE REDUCING REAGENTS INCLUDING:

二異丁基氫化鋁 (i-Bu)2AlH (Diisobutyl Alminium Hydride; DIBAL)

DIBAL (Di-isobutyl Aluminum Hydride) is A Bulky Reducing Agent For The Partial Reduction Of Esters.

DIBAL is a strong, bulky reducing agent. It’s most useful for the reduction of esters to aldehydes. Unlike lithium aluminum hydride, it will not reduce the aldehyde further if only one equivalent is added. It will also reduce other carbonyl compounds such as amides, aldehydes, ketones, and nitriles.

Keeping the temperature low (–70°C) tends to keep a lid on the reactivity here. So long as the temperature is kept here for the duration of the experiment and only one equivalent of DIBAL is added, the aldehyde is obtained.

In addition, DIBAL can do all the reductions that NaBH4 does, so ketones and aldehydes are reduced to secondary and primary alcohols, respectively.

Finally, DIBAL will also do partial reductions of nitriles to imines. The imines are then hydrolyzed to aldehydes upon addition of water. In this respect DIBAL again differs from LiAlH4, which will reduce nitriles all the way to amines.

The mechanism for reduction by DIBAL is a little bit unusual compared to NaBH4. Whereas NaBH4 is considered a “nucleophilic” reductant – that is, it delivers hydride (H-) directly to a carbonyl carbon, DIBAL is an “electrophilic” reductant. That is, the first step in the reaction is coordination of a lone pair from the carbonyl oxygen (a nucleophile) to the aluminum (electrophile). It is only after coordinating to its carbonyl host that DIBAL delivers its hydride to the carbonyl carbon, resulting in formation of a neutral hemiacetal intermediate that is stable at low temperatures. Quenching of the reaction then breaks down the hemiacetal, resulting in isolation of the aldehyde. (“real life” disclaimer: this reaction looks great on paper but can sometimes be difficult to achieve in practice).

The same mechanism is in effect in the reduction of nitriles to imines (and then on to aldehydes). Coordination of the nitrile nitrogen to aluminum is followed by delivery of hydride, and from there, addition of water leads to hydrolysis of the imine and subsequent isolation of the aldehyde.

Lithium Tri-tert-butoxyaluminum Hydride (LiAlH(Ot-Bu)3)

Lithium tri tert-butoxy aluminum hydride is lot like lithium aluminum hydride, but with a difference. Like lithium aluminum hydride, it’s a reducing agent. As a source of hydride, it will form carbon-hydrogen bonds.

Unlike lithium aluminum hydride, which is kind of a raging beast,  reducing everything in sight, LiAlH[OC(CH3)3]3 is a lot more controlled. First of all, it only has one hydride to give, unlike LiAlH4, so it’s a lot easier to control the reaction using stoichiometry. Secondly, those big bulky tert-butoxy groups (that’s -OC(CH3)3) help to modulate (i.e. slow down) the reactivity of the reagent. They’re kind of like a fat suit around aluminum that ensure that the hydride can’t fit into tight spaces.It will reduce acid chlorides to aldehydes, and stop there. This is a big deal, because aldehydes are very reactive species themselves, easily reduced to alcohols. So if you use just 1 equivalent of the reagent, you’ll end up with one equivalent of the aldehyde. And aldehydes can themselves be used in all kinds of useful applications.This serves as a way to indirectly reduce carboxylic acids to aldehydes: you can convert the carboxylic acid to an acid chloride using something like SOCl2 or PCl3, and then reduce the acid chloride to the aldehyde with LiAlH[OC(CH3)3)]3.

the mechanism is pretty straightforward actually. Just like with NaBH4, the hydride from Al–H adds to the carbonyl carbon of the acid chloride, breaking the C–O π bond and forming a tetrahedral intermediate. If you’ve covered carbonyl chemistry at all, you should recognize this step as The Most Important Mechanistic Step in Carbonyl Chemistry – the 1,2-addition. Then, we’ve got this negatively charged oxygen which can then come down and re-form the C-O π bond, expelling the chloride ion (Cl-) in the process. This is the 2nd Most Important Mechanistic Step in Carbonyl Chemistry, called the 1,2-elimination. And that’s it.

氰基硼氫化鈉 NaBH3CN (Sodium Cyanoborohydride)

Sodium cyanoborohydride (NaBH3CN) is a mild reducing agent that is commonly used in reductive aminations. The presence of the electron-withdrawing cyano (CN) group makes it less reactive than sodium borohydride (NaBH4). This reduced reactivity allows NaBH3CN to be employed at neutral or slightly acidic conditions for the selective reduction of iminium ions in the presence of ketones and aldehydes.

Reductive amination by NaBH3CN is sometimes done in the presence of certain Lewis acids (ex. Ti(OiPr)4, TiCl4, or ZnCl2). The aldehyde or ketone is typically prestirred with the amine in the presence of the Lewis acid, then treated with NaBH3CN. This procedure is useful in cases where imine formation is poor, when the use of excess amine isn't possible, or acidic conditions aren't well tolerated.

NaBH3CN can effectively be used in H2O and protic solvents (ex. MeOH or EtOH), unlike sodium triacetoxyborohydride (STAB) which is quickly degraded by H2O and protic solvents.

To a solution of 10% AcOH in MeOH was added the SM (1 equiv) and dry acetone (5 equiv). The solution was stirred at RT 1 h, after which time it was cooled to 0 C and treated with NaCNBH3 (1.5 equiv). The reaction was stirred at RT for 5 h. The mixture was concentrated and the residue brought to pH = 10 using Na2CO3. The mixture was extracted with EtOAc and the org layer was washed with H2O, brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified by silica gel column chromatography (2% MeOH/DCM) to provide the pdt as a yellow solid. (ref. 1  WO2007084786, page 112).

A mixture of the SM (260 mg, 0.79 mmol), PMB-NH2 (162 mg, 1.18 mmol), and Ti(iPrO)4 (168 mg, 1.58 mmol) in THF (10 mL) was stirred in a microwave reactor at 100 C for 2 h. After cooling to RT, NaBH3CN (98 mg, 1.58 mmol) was added to the mixture. The reaction mixture was stirred at 50 C for 1 h. The mixture was poured into H2O (10 mL) and extracted with EtOAc (20 mL). The org phase was concentrated and the residue was purified by silica gel column chromatography (6:1 PE/EtOAc) to provide the product as a yellow solid. [180 mg, 50%] [Patent Reference: WO2016011390, page 104]

To a solution of the SM (1.10 g, 4.61 mmol) in MeOH (15 mL) was successively added oxetan-3-one (1.66 g, 23.01 mmol), 4A molecular sieves (0.5 g), and ZnCl2 (3.14 g, 23.01 mmol). After stirring 2 h, the reaction mixture was treated with NaBH3CN at 0 C, and stirring was continued for another 4 h. The mixture was diluted with H2O (20 mL), EtOAc (25 mL), and sat aq NaHCO3 (10 mL). The layers were separated and the aq layer was further extracted with EtOAc (3 x 25 mL). The combined organics were washed with brine (50 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel column chromatography (50% EtOAc/hexane) to provide the product as a colorless syrup. [1.1 g, 81%][Patent Reference: WO2015088045, page 108]

Lithium borohydride

Lithium borohydride (LiBH₄) is a borohydride and known in organic synthesis as a reducing agent for esters. Although less common than the related sodium borohydride, the lithium salt offers some advantages, being a stronger reducing agent and highly soluble in ethers, whilst remaining safer to handle than lithium aluminium hydride.

LiBHEt3(Lithium Triethylborohydride: Super-Hydride)

Lithium triethylborohydride (LiEt₃BH), commonly abbreviated to LiTEBH or Superhydride, is a powerful and selective reducing agent used in inorganic and organic chemistry. The structure of LiTEBH causes the compound to be a very strong hydride source. Hydrogen is more electronegative than boron which causes the B-H bond to be strongly polarized with boron having a partial positive charge and hydrogen having a partial negative charge. The ethyl groups on the boron also aids to this abnormal polarizability by removing additional electron density from the boron making it even more electropositive. This polarization of the B-Et and B-H bonds causes the hydrogen to be in the (-I) oxidation state instead of its usual (+I) oxidation state which leads to its high reactivity with atoms that can accept electrons to allow the hydrogen to go to its (+I) oxidation state.LiTEBH is far more powerful than lithium borohydride and more powerful than lithium aluminum hydride (LAH) in many cases. One of the main advantages of LiTEBH is that it is safer than LAH.

LiTEBH rapidly reduces:

1. Aldehydes, ketones, acid chlorides and esters to alcohols

2. Lactones to diols

3. Acid anhydrides to alcohols

4. α,β-enones by 1,4-addition to give lithium enolates

5. Disulfides to thiols

6. Tertiary amides to an alcohol

LiTEBH reacts violently and exothermically with water, alcohols, or acids releasing flammable hydrogen gas which can ignite explosively and the pyrophoric triethylborane vapor can ignite spontaneously. It can cause severe eye, skin, and respiratory tract burns.

Sodium bis(2-methoxyethoxy)aluminium hydride

Sodium bis(2-methoxyethoxy)aluminium hydride ( trade names Red-Al) is a complex hydride reductant with the formula NaAlH₂(OCH₂CH₂OCH₃)₂. The trade name Red-Al refers to its being a reducing aluminium compound. It is used predominantly as a reducing agent in organic synthesis. The compound features a tetrahedral aluminium center attached to two hydride and two alkoxide groups, the latter derived from 2-methoxyethanol. Commercial solutions are colorless/pale yellow and viscous. At low temperatures (<-60°C), the solution solidifies to a glassy pulverizable substance with no sharp melting point.

RED-AL is a versatile hydride reducing agent. It readily converts epoxides, aldehydes, ketones, carboxylic acids, esters, acyl halides, and anhydrides to the corresponding alcohols. Nitrogen derivates such as amides, nitriles, imines, and most other organonitrogen compounds are reduced to the corresponding amines. Nitroarenes can be converted to azoxyarenes, azoarenes, or hydroazoarenes, depending on the reaction conditions.

Some common functional group reductions using SMEAH can be found below:

As a reagent, RED-AL is comparable with lithium aluminium hydride (LAH, LiAlH₄).

It is a safer alternative to LAH and related hydrides. RED-AL is exhibits similar reducing effects, but does not have the inconvenient pyrophoric nature, short shelf-life, or limited solubility of LAH. Upon contact with air and moisture, it reacts exothermically but does not ignite, and tolerates temperatures up to 200 °C. Under dry conditions it has unlimited shelf life. It is soluble in aromatic solvents, whereas LAH is only soluble in ethers. For example, a solution greater than 70 wt.% concentration in toluene is commercially available. The reagent can be modified to effect partial reductions.^[1]

RED-AL in toluene under reflux has been used to reduce aliphatic p-toluenesulfonamides (TsNR₂) to the corresponding free amines and is one of the few reagents that can carry out this challenging reduction in general settings. Notably, LiAlH₄ does not reduce this functional group unless forcing conditions are used.

Sodium triacetoxyborohydride

 

Sodium triacetoxyborohydride, also known as sodium triacetoxyhydroborate, commonly abbreviated STAB, is a chemical compound with the formula Na(CH₃COO)₃BH. Like other borohydrides, it is used as a reducing agent in organic synthesis.

Sodium triacetoxyborohydride is a milder reducing agent than sodium borohydride or even sodium cyanoborohydride. It reduces aldehydes but not most ketones. It is especially suitable for reductive aminations of aldehydes and ketones.

However, unlike sodium cyanoborohydride, the triacetoxyborohydride hydrolyzes readily, nor is it compatible with methanol. It reacts only slowly with ethanol and isopropanol and can be used with these.

This colourless salt is prepared by protonolysis of sodium borohydride with acetic acid:

NaBH₄ + 3 HO₂CCH₃ → NaBH(O₂CCH₃)₃ + 3 H₂

 Zn(BH4)2(Zinc    Borohydride)

利用鋅的螯合能，能發生syn-非對映選擇性還原

Zinc can chelate to the two heteroatoms with lone pairs, sulfur and the carbonyl group, and here it changes the conformation of the starting material. No longer does the most reactive or most populated conformation place the electronegative S atom perpendicular to the C=O; instead it prefers SR to lie as close to the carbonyl oxygen as possible so that Zn can bridge between S and O. Attack of borohydride from the less hindered side (next to H rather than Et) leads to the anti diastereoisomer.

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Lithium Tri(sec-butyl)borohydride;  L-Selectride)

L-selectride is an organoborane. It is used in organic chemistry as a reducing agent, for example in the reduction of a ketone, as part of Overman's synthesis of strychnine.

Under certain conditions, L-selectride can selectively reduce enones by conjugate addition of hydride, owing to the greater steric hindrance the bulky hydride reagent experiences at the carbonyl carbon relative to the (also-electrophilic) β-position. L-Selectride can also stereoselectively reduce carbonyl groups in a 1,2-fashion, again due to the steric nature of the hydride reagent.

N-selectride and K-selectride are related compounds, but instead of lithium as cation they have sodium and potassium cations respectively. These reagents can sometimes be used as alternatives to, for instance, sodium amalgam reductions in inorganic chemistry.