羧酸的合成——水解法

1.   前言

利用縮水的方法可以將羧酸轉變為各種羧酸的衍生物，如醯氯、酸酐、酯、醯胺和腈等，反過來通過水解反應各種羧酸衍生物也可以轉變為羧酸，除醯氯和酸酐外，酯、醯胺和腈的水解一般都可以在酸或鹼的催化下進行。

羧酸衍生物水解的速度與羰基碳原子的正電性有關，一般來說正電性越大，水解速度越快。

 

2.   醯氯的水解

把羧酸製成醯氯，再通過醯氯去進行各種反應是有機合成中常用的方法，較少有用醯氯來製備羧酸的例子，但在有些條件下利用醯氯來制羧酸也是較為有效的。例如芳環通過佛克反應與草醯氯反應得到相應的醯氯。一般來講脂肪醯氯的水解是相當快的，不用加任何催化劑即可反應。但芳香醯氯的反應要相對慢了很多，有時為了促進其水解需要加入鹼和酸。

2.1 醯氯的水解示例

Aluminum chloride (160 g, 1.2 mol) was added to astirred solution of the 4-n-pentylbiphenyl (224 g, 1 mol) in methylene chloride(1000 mL) at approximately -20°C. Then Oxalyl chloride (96 mL) was added to thesolution at a temperature below -10°C. After addition, the reaction temperaturewas allowed to rise to approximately 0°C. Stirring continued at approximately 0°Cuntill the evolution of hydrogen chloride was ceased. The resulting reactionmixture was poured into ice water forming two nonmiscible fluid layers. Theorganic layer was seperated from the aqueous layer, washed with water, anddried over anhydrous sodium sulfate. The solvent was removed by distillation toyield a crude 4-n-pentylbiphenyl-4』-carboxy chloride (213 g, 75%) which wasused directly in the next step.

The 4-n-pentylbiphenyl-4』-carboxy chloride (142 g, 0.5mol) was reacted with a hot, stirred solution of sodium hydroxide (60 g, 0.75mol) in water (50 mL) and acetone (500 mL) for about three hours. The coldreaction mixture was then acidified with concentrated hydrochloric acidsolution. The acid was filtered and washed with water untill the filtrate wasneutralized. The product of the reaction was purified from ethanol to yield4-n-pentylbiphenyl-4』-carboxylic acid (102.4 g, 80%).

Reference: US4424371

 

1.   酸酐的水解

酸酐也並不常用於製備酸，由於酸酐的活性比酸強，多數情況下直接室溫水解就可以轉變為羧酸，在有些情況下對反應加加熱可以促進反應的進行。

3.1 酸酐的水解示例

To citraconic anhydride (22.4 g, 0.2 mol) was added from apipet exactly 4 mL (0.22 mole) of distilled water. The mixture was stirred on ahot plate until a homogeneous solution was formed, then covered with a watch glass and allowed to stand for forty-eight hours.At the end of this time the mixture would solidified completely. For furtherpurification it was finely ground in a mortar, washedwith 50 mL of cold benzene,dried in the air, and then dried for twenty-four hours in a vacuum desiccator over phosphoruspentoxide to give citraconic acid (24.4 g, 94%)which melts at 92~93°C.

Reference:  Organic Syntheses. Coll. Vol. 2, 140

 

4.   酯的水解

在有機合成中，羧酸和酯可以很方便地相互轉換，因此酯化反應是保護羧基的一種常用方法，酯水解也成為水解法制羧酸的重要方法。

4.1    酯的鹼水解

水解反應是酯化反應的逆反應，酯化反應要在酸性條件下進行的，因此多數情況下酯的水解在鹼性條件下進行是有利的。一般來說非位阻酯的水解主要通過LiOH-MeOH-H2O體系於室溫下進行反應，正常條件是氫氧化鋰的當量為2-5 當量，甲醇與水的比例為5:1~3:1。如果反應仍不能水解，可適當加熱直至回流。對於有些位阻大、惰性的酯，需要用更強的反應條件，一般可使用NaOH、KOH的水溶液或水甲醇的混合溶液進行水解，其中最強烈的條件是用KOH的水甲醇的混合溶液回流水解，KOH的濃度越大、溶劑甲醇的比例越高，水解條件越強，很少有在這種條件下水解不了的酯。對於該類水解反應的後處理一般先濃縮去處醇類溶劑，然後用有機溶劑提取可能未反應完的非酸類副產物，再酸化，許多酸在此時可以析出沉澱，過濾即可得到，若為油則用有機溶劑提取。

有時當一個分子同時存在甲酯和叔丁酯時，用以上條件很難較好的選擇性的水解甲酯，有時需要控制鹼的當量數和反應溫度。

4.1.1      LiOH-MeOH-H2O水解體系的標準操作

Toa solution of ester (10 mmol) in MeOH-H2O (30 mL, MeOH:H2O=3:1~5:1,甲醇濃度越高，水解能力越強) at 0°C was slowly added LiOH.H2O (800 mg ~ 2 g, 20-50 mmol). Thereaction mixture was allowed to warm to room temperature overnight (若水解不完全就加熱至反應完全). Methanol was removed invacuo and the residual aqueous solution was partitioned with Et2Oor AcOEt (~20 mL), then the organic phase was extracted with H2O (5-10 mL, two times). The combined aqueous extracts was acidified to pH 2 with 1N HCl. The aqueous phase was extractedwith CHCl3 (three times) (注意若有固體析出則過濾得到相應的酸). The combined organicextract was dried over MgSO4 and concentrated to afford the desired acid(normal yield >95%).

 

4.1.2      LiOH-MeOH-H2O體系的選擇性水解甲酯和叔丁酯示例

Toa solution of compound 1 (14.15 g, 48.1mmol) in MeOH (250 ml) at 0°C was slowly added aqueous LiOH (1M, 48 ml, 48mmol) over 15 min. Thereaction mixture was allowed to warm to room temperature overnight withstirring.

Theorganic solvent was removed in vacuo and the residual aqueous solutionwas partitioned with Et2O, then the organic phase was extracted withH2O (two times). The combined aqueous extract was acidified to pH 2with 1N HCl. The aqueous phase was extracted with CHCl3 (three times).The combined organic extract was dried over MgSO4 and concentratedto afford the desired acid (11.4 g, 85%).

Reference:  Publ.: US2004/6065 A1 (2004/01/08); Appl.:US2003-465426 (2003/06/19)

4.1.3      KOH-H2O體系的水解示例

A mixture of ethyl 3-methylcoumarilate (70g, 0.34mol) and 10% aqueous potassium hydroxide solution (500 mL) was refluxedfor 1 hour. The clear yellowish solution was acidified while hot with a slightexcess of concentrated hydrochloric acid to precipitate 3-methylcoumarilicacid. The suspension was cooled to room temperature, and thecolorless solid was filtered with suction. The filter cake was resuspended in500 mL of cold water, stirred vigorously for several minutes, and filteredagain with suction. The colorless powder The filter cake was dried in adesiccator under reduced pressure to give a colorless powder (54~57 g, 90~95%)which melts at 192~193°C.

Reference:  Organic Syntheses: Coll.Vol. 4, 590

 

4.2   酯的酸水解

某些情況下對於一些特定結構的酯需要在酸性條件下進行水解，例如叔丁酯和一些對鹼不穩定的酯。有些胺基酸酯在1 N鹽酸回流條件下水解（一般回流1~2小時即可），蒸乾溶劑後可直接以鹽的形式進行下面的反應，而無需進一步提純，此時也可以考慮用酸進行水解。叔丁酯一般比Boc難脫，一般要用50-100%TFA或4NHCl/Dioxane （注意：在用HCl/dioxane來脫除叔丁酯時，千萬不能在溶劑處理時中引入甲醇，乙醇或其他小位阻的醇，否則叔丁酯會轉變為相應的酯。

 

4.2.1      叔丁酸酯的酸水解示例

1-(4-Methoxycarbonyl-2-methylbutanoyl)-L-proline t-butylester (3.4 g, 10.8 mmol) was dissolved in trifluoroacetic acid (25 mL) and the resultingsolution was kept at room temperature for one hour. The trifluoroacetic acid wasremoved in vacuo and the residue was used to the next reaction directly.

Reference:  US4154937

 

4.2.2      對鹼不穩定的酯的酸水解示例

A solution of ethylα-chlorophenylacetate (119 g, 0.6 mol) in glacial acetic acid(238 mL) and concentrated hydrochloricacid (119 mL) was heated under reflux in a hood for 1.5hours. At the end of the heating period the solution was concentrated byheating in an oil bathat 100°C at reduced pressure (15~20 mmHg) until no further material wasdistilled. The residue was allowed to cool to room temperature and pouredslowly with stirring into 1 L of ice-cold saturated sodium bicarbonate solution. Solid sodium bicarbonatewas added in small portions until the solution became neutral to universalindicator paper. The solution was then extracted with two 200 mL portions of ether. The aqueousphase was acidified cautiously with ice-cold 12N sulfuric acid until the mixture was acid to Congo red paper. The oilysuspension was extracted with two 200 mL portionsof ether. The ether extracts were washed with two100 mL portions of water and dried over 45g of anhydrous sodium sulfate. The dried ether extract was concentrated on a steambath until etherwas no longer distilled. To the residue there was added 500 mL of warm (50~60°C) concentrated hydrochloric acid (in a hood) and the suspension was allowed to cool with occasionalswirling. Crystallization was completed by chilling in ice and the product wascollected on a sintered-glass funnel. After the product was dried as much as possible on the funnel itwas dried to constant weight in a vacuum desiccator over solid potassium hydroxide to give the dry acid (82~84 g, 80~82%) which melts at 77.5~79.5°C.

Reference:  Organic Syntheses. Coll. Vol. 4, 169

 

4.3    丙二酸二乙酯合成法

丙二酸二乙酯合成法是把滷代烴轉變為多兩個碳原子的酸的經典而有效方法，它藉助丙二酸二乙酯這一特定試劑，實際包括了α-H的取代、水解和脫羧三步反應。

4.3.1      丙二酸二乙酯合成法示例

To anhydrous butyl alcohol (2.5 L) was added clean,bright sodium (115 g, 5mol) cut in smallpieces at one time. After the sodium was dissolvedcompletely, the solution was allowed to cool to 70~80°C and then redistilled ethyl malonate (800g,5mol) was added rapidly with stirring. After heating the reactionsolution to 80~90°C, pure heptylbromide (913 g, 5.1 mol) was added. The bromide should be added ratherslowly at first, until precipitation of sodium bromidebegan; it might then be added at such a rate that the butylalcohol refluxed gently. Usually about one hour was required for theintroduction of the heptyl bromide. The mixture wasrefluxed gently until it was neutral to litmus (about one hour).

Tothe entire mixture, including the precipitated sodiumbromide, was added a solution of 90 per cent potassium hydroxide (775 g, 12.5 mol) in an equal weightof water. The mixture was heated cautiously, with occasional shaking, untilrefluxing started, and refluxing was continued until saponification wascomplete (about four or five hours). The flask was fitted at once for steamdistillation, and the mixture was distilled until no more butylalcohol passes over. To the residue was addedconcentrated hydrochloric acid (1350 mL, 15.5 mol) carefully, with shaking, and themixture was refluxed for about one hour. After cooling, the water layer wassiphoned off and discarded.

Theoil obtained in the preceding step was heated under an air-cooledreflux condenser in an oil bath at about180°C. When the evolution of carbon dioxide ceased(about two hours), the oil was decanted from a small amount of solid material.The solid residue on treatment with 200~300 mL ofconcentrated hydrochloric acid gave anadditional small quantity of oil which was added to the main portion.

Thecrude pelargonic acid was distilled in a modified Claisen flask having a fractionating side arm,and the material boiling at 140~142°C/12 mmHg (or 188~190°/100mmHg) was collected to give an oil (525~590 g,66~75% of the theoretical amount). The meltingpoint of the pure acid was 12~12.5°C.

Reference:  Organic Syntheses Coll. Vol. 2, 474

 

 

5.   醯胺的水解

醯胺的活性比羧酸差，因此醯胺的水解一般需要強酸或強鹼參與並在加熱的條件下進行。醯胺水解也有鹼水解和酸水解兩種情況，在有些情況下，加入亞硝酸鈉可以促進醯胺水解。

由於醯胺直接水解較為強烈，對於一些複雜的分子無法使用，因此對氮上有活潑氫的醯胺可將其衍生化後水解，一般衍生化的方法是用引入Boc，其反應如下：

5.1     醯胺直接酸水解示例

A suspension of2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten-2-yl)propionamide (15 g, 53.7mmol) in a mixture of sulphuric acid (d = 1.36, 50 mL) and water (60 mL) washeated with vigorous stirring for 3 hours at 110°C. After cooling, the product whichprecipitated was filtered off and then added to 2 N sodium hydroxide solution(55 mL). The alkaline solution, clarified by filtration, was acidified byadding 2 N hydrochloric acid (60 mL). The product which precipitated was filtered off, driedand then recrystallized from CCl4 (170 mL) to give2-(5-oxo-10,11-dihydrodibenzo[a,d]cyclohepten2-yl)propionic acid (7.4 g, 49.2%)melting at 122°C.

Reference:  US3933905

5.2    醯胺直接鹼水解示例

A solution of 4-(1,1-diphenylpropyl)-picolinamide (3.8 g,0.012 mol) in ethanol (50 mL) was added 10% aqueous potassium hydroxide (100mL) and the resulting mixture was heated at reflux overnight。 The solvent was removed under reduced pressure and theresidue was added water then adjusted to about pH 5 with 10% aqueoushydrochloric acid. The resulting solid was filtered and recrystallized fromethanol to obtain the desired compound of this example (1.6 g, 42.0%) melting at 191~193°C.

Reference:  US4138488

 

5.3     亞硝酸鈉促進的醯胺酸水解法示例

To a solution of 4-carbamoyl-3-methoxyisothiazole (7.9 g, 0.05 mole)in 90 mL of 80% sulfuric acid at 10~15°C was added slowly beneath the surface of the liquid a solution ofsodium nitrite (9.5 g, 0.137 mol) in water (13 mL). When the addition wascomplete the solution was allowed to come to 25°C and then was heated to 60°C for several minutes. After cooling to 25°C the reaction solution waspoured onto ice to afford 4-carboxy-3-methoxyisothiazole (3.64 g, 46%) as awhite solid melting at 182~185°C.

Reference:  US3957808

 

5.4    醯胺的間接水解法示例

To a 0.5 M solution of (R)-N-Methyl-3-phenylbutanamide(194 mg, 1.09 mmol) in methylene chloride was added triethylamine (0.15 ml,1.09mmol), di-tert-butyl dicarbonate (0.5 ml, 2.18 mmol) and4-(dimethylamino)pyridine (150 mg, 1.11 mmol). The solution was stirred for 8 hat room temperature. The volatiles were removed and the residue was purified byflash chromatogramphy (1/20 (v/v) EtOAc/hexane) to afford the desired (R)-N-Boc-N-Methyl-3-phenylbutanamide(210 mg, 70%).

A 0.2 M solution of (R)-N-Boc-N-Methyl-3-phenylbutanamide(175 mg, 0.63 mmol) in THF (4 ml), under N2 atmosphere, was cooledto 0°C. To this solutionwas added 1 N lithium hydroxide (2.0 ml, 2.0 mmol). The reaction mixture wasallowed to stir for 6 h. After removal of THF in vacuo, the basicresidue was acidified with 5% HCl and extracted with ether (3× 15 ml). The combined ether layers weredried over anhydrous MgSO4, filtered and concentrated under reducedpressure. The residue was purified by bulb-to-bulb distillation (110~120°C/1.2mmHg) to give the desired (R)-3-phenylbutyricacid (85 mg, 85%).

Reference:  J. Org. Chem.; 61; 14; 1996; 4542~4554.

 

6.   腈的水解

由於氰基很容易由滷代烴或重氮鹽與無機氰化物反應引入，因此腈水解是製備羧酸的很重要的方法。腈水解也有酸水解和鹼水解兩種情況。腈的酸水解一般都是用濃硫酸在水或水-乙醇的溶劑中進行，若用濃鹽酸，經常會停留在醯胺一步。在某些特殊情況下，腈水解也會停留在醯胺這一步，此時為了水解完全，可以加入亞硝酸鈉促進水解反應的進行。直接將腈水解為酸的反應條件相當苛刻，因此並不是一個很好的辦法，一般來說，是將腈在HCl/MeOH中轉化為甲脂，而後再水解，這樣條件就要溫和了很多。

6.1 腈的酸水解示例

A mixture ofwater (1150mL), commercial sulfuricacid (840 mL) and benzyl cyanide (700 g, 6mol) was heated under a reflux condenser and stirred for three hours, cooledslightly, and then poured into 2 L of cold water. The mixture should be stirredso that a solid cake was not formed; the phenylacetic acidwas then filtered off. The crude material was melted under water and washed bydecantation several times with hot water. These washings, on cooling, depositeda small amount of phenylacetic acid which wasfiltered off and added to the main portion of material. The last of the hotwater was poured off from the material while it was still molten, and it wasthen transferred to a Claisen distilling flask anddistilled under reduced pressure. A small amount of water came over first and wasrejected; about 20 mL, containing an appreciable amount of benzyl cyanide, then distils. This fraction was used inthe next run. The distillate boiling at 176–189°/50 mmHgwas collected separately and solidified on standing to give the product (630 g, 77.5%) which melts at 76~76.5°C. 

Reference: Organic Syntheses Coll. Vol. 1,436

 

 

6.2 腈的鹼水解示例

A mixture of 2-phenylpropanenitrile (13.2g, 0.1 mol) and an aqueous solution of sodium hydroxide (10%, 60 mL) was heated with magnetic stirring in an oil bath at reflux temperature for 4.5 hr. The course ofthe reaction was monitored by gas-chromatographic analysis. After the solution wascooled to room temperature, it was extracted with diethylether to remove nonacidic material (primarily traces of amide). Anaqueous solution of hydrochloric acid (15%, 50 mL) was added portionwise. The suspension thatformed was poured into a separatory funnel and extracted with diethyl ether (3 × 50 mL).The combined organic extracts were washed with water (60 mL) and dried over sodium sulfate (25 g). Afterfiltration, the solvent was removed by rotary evaporation, and the yellowliquid residue was distilled under reduced pressure to afford 2-phenylpropionic acid(14.3 g, 93%) as a pale-yellowliquid.

Reference: OrganicSyntheses Coll. Vol. 10, 640

 

6.3亞硝酸鈉促進的腈的酸水解示例

A mixture of compound 1 (6.6 g, 35 mmol), conc.H2SO4 (29 ml), AcOH ( 58 ml) and water (115 ml) was heated at 120°C for 1h,then a solution of NaNO2 (4.0 g), in water (30 ml) was added at 90~100°C. Afterthe mixture had been heated for 1 h, NaCl (40 g) was added to the hot mixtureand the whole was cooled in an ice-bath. The precipitate was collected to givethe crude free acid (6.2 g, 62%).

Reference: Chem. Pharm. Bull.;EN; 33; 8; 1985; 3336-3348.

本文內容來源於網絡，版權歸原作者所有