磺酰氯合成法-060303.doc

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1、【精品文档】如有侵权，请联系网站删除，仅供学习与交流磺酰氯合成法-060303.精品文档.经典化学合成反应标准操作磺酰氯合成法编者： 张国柱药明康德新药开发有限公司化学合成部目 录1. 前言22. 芳香磺酰氯的制备22. 1直接氯磺化法制备芳香磺酰氯22. 2芳香磺酸或盐氯化制备芳香磺酰氯32. 3芳香硫醇及相关衍生物氯代、氧化合成芳香磺酰氯82. 4. 芳香硫醇的制备112. 5 Sandermeyer 反应由芳胺合成芳香磺酰氯133. 脂肪磺酰氯的制备3. 1 烷基硫醇的合成及通过烷基硫醇合成脂肪磺酰氯143. 2 通过烷基硫脲合成脂肪磺酰氯163. 3 通过烷基异硫氰酸酯合成芳香磺酰氯1

2、73. 4 通过羧酸硫醇酯合成芳香磺酰氯173. 5 脂肪磺酰氯合成反应示例18参考文献：201. 前言磺酰氯是有机化学中非常重要的一类化合物，它们可以作为重要的中间体进行修饰。比如，同胺类化合物作用生成的磺胺类药物是优良的化学治疗剂，开始应用于20世纪30年代。它们能抑制多种细菌，如链球菌、葡萄球菌、肺炎球菌、脑膜炎球菌、痢疾杆菌等的生长和繁殖，因此常用以治疗由上述细菌所引起的疾病。高碳烷基磺酸钠类化合物则是优良的合成洗涤剂。磺酰氯主要分为脂肪族磺酰氯和芳香族磺酰氯。芳香磺酰氯的来源有以下几类：1）由硫酚，各种硫醚在酸性溶剂中导入氯气制得；2)芳香磺酸类化合物在氯化试剂作用下形成；3）磺化反

3、应。脂肪族磺酰氯的来源主要是硫醇或相关衍生物氯代或氧化。因此，作为磺酰氯的重要前体，磺酸和硫醇类化合物的引入，也是合成磺酰氯基团的重要手段。2. 芳香磺酰氯的制备芳香磺酰氯的制备一般分为以下几种方法， 直接用氯磺化法制备芳香磺酰氯。 芳香磺酸或盐经氯化制备芳香磺酰氯。 芳香硫醇及相关衍生物氯化，氧化合成芳香磺酰氯。 Sandermeyer反应由芳胺合成芳香磺酰氯。2. 1直接氯磺化法制备芳香磺酰氯氯磺酸是一类比较常用的直接氯磺化试剂，氯磺酸的活性比浓硫酸大，反应温度较低，同时可以直接得磺酰氯。氯磺化也是亲电反应，选择性也遵循芳环取代基定位效应及其规则。有规律可循。如果希望反应比较缓和，可以用氯

4、仿或其它卤代烷烃作为稀释剂。反应温度一般都控制在0至20。如果芳环上存在至钝基团，像羧基等，直接氯磺化的温度要提的比较高，要达到100多度。1当体系因为位阻，取代基定位效应劣势等等不能直接完成氯磺化时，就可以选择分两步走，先引入磺酸基团。再转变为磺酰氯。2. 1. 1芳香环磺化反应示例：In a three necked 500 mL round flask equipped with mechanical stirring, was placed with ClSO3H (290 g, 2.49 mol). The system was cooled to 1215 using ice wa

5、ter. N-Phenyl-acetamide (67.5 g, 0.5 mol) was added dropwise. The temperature was maintained at 15 oC. After addition, the reaction mixture was heated at 60oC for two hours. The reaction was cooled down to room temperature and poured slowly into 1000 mL of water under finely stirring. The precipitat

6、e was collected by filtration, washed with water, dried to afford desired 4-Acetylamino-benzenesulfonyl chloride (90 g, 77% yield). This sample could be used in next step without further purification.2. 2芳香磺酸或盐氯化制备芳香磺酰氯芳香磺酸或盐可以用氯气或者某些氯化试剂比如五氯化磷，三氯氧磷，二氯化砜等处理得到芳香磺酰氯。这几种氯磺化试剂各有优缺点，五氯化磷，三氯氧磷反应效果较好，但是后处理

7、比较繁琐，反应温度要求较高。而二氯化砜后处理方便，往往蒸掉溶剂就可以直接投入下一步反应。因此，芳香磺酸作为引入芳香磺酰氯基团重要的前体得到非常大的重视。2. 2. 1芳香磺酸的制备芳香磺酸的制备有几种办法，磺化，有机金属试剂同三氧化硫加成，Sandermeyer法合成芳香磺酸。这几种合成芳香磺酸的方法也是各有特色，针对不同的底物也可有不同的选择。磺化是对芳环体系直接的引入磺酸基团。想把芳卤转变成芳香磺酰基团时，就可以考虑用有机金属试剂置换卤素后用三氧化硫处理即可以得到芳香磺酸。Sandermeyer法则提供了由芳胺基团转变为芳香磺酸的一条途径。2. 2. 1. 1磺化芳烃的磺化通常采用浓硫酸或

8、含有5%-20%三氧化硫的发烟硫酸。磺化反应是一可逆反应，欲得良好产率的磺酸，必须使用过量的磺化剂或者不断移去生成的水。 对于较难磺化的芳烃可采用三氟化硼，锰盐，汞盐，矾盐做催化剂。苯在室温下可用浓硫酸磺化生成苯磺酸2；而在70-90oC磺化则生成间苯二磺酸，产率为90% 3；间苯二磺酸钠在汞盐的催化下，与15%的发烟硫酸于275oC反应，则以73%产率生成1，3，5-苯三磺酸 4。由于磺化反应是一可逆反应，磺酸基位置随反应温度不同而改变 5。例：甲苯的磺化与反应温度的关系6例：萘的磺化也有类似情况。低温，小于80oC磺化，主要生成-萘磺酸，这时由动力学控制，一旦达到160 oC 的反应温度，

9、主要产生-萘磺酸。这时由热力学控制7。例：磺化反应的可逆性的一个重要应用是将磺酸基先临时占据芳环某特定位置，然后再进行其他的反应，待反应完成后，再在稀硫酸中加热，以移去磺酸基。例如-溴代萘的合成8。芳香族化合物磺化时，芳环上存在的羟基，烷氧基，羧基，卤素等取代基均无影响。芳胺与硫酸反应，首先生成胺盐，继而受热重排成对胺基苯磺酸9。2. 2. 1. 2有机金属试剂与三氧化硫的加成三氧化硫对碳金属键的插入反应，提供了由芳卤或烯卤制备磺酸的又一条途径。有机锂是较为典型的试剂。由于三氧化硫在操作中较为不便，而使用三氧化硫吡啶或三氧化硫三甲胺复合试剂能使反应在更为温和，便利的条件下进行。以三氧化硫三甲胺

10、复合物为起始剂，在无水乙醚或四氢呋喃中与有机锂化合物反应，控制反应温度由78oC到室温，得到磺酸盐，酸化后即得磺酸10。2. 2. 1. 3芳香硫醇合成方法示例2To 4-bromotoluene (518 mg, 3.1 mmol) was added n-BuLi (2.3 M in hexane, 1.35 mL, 3 mmol) over 10 min with cooling (ice bath). After 6 hours, the supernatant solution used in the next stage. To a stirred suspension of cr

11、ystalline STTAC (sulfur trioxide-trimethylamine complex, commercially available) (431 mg, 3.1 mmol) in dry THF (15 mL) at 78 oC was added the preformed hexane solution of p-tolyllithium dropwise over 15 min. The reaction mixture was stirred for 2 hours at 78 oC and then allowed to warm to room tempe

12、rature over 18 hours. After removal of solvent, H2O (10 mL) and KOH (3M, 1 mL, 3 mmol) were added to the mixture, which was then extracted with Et2O to remove unreacted 4-bromotoluene. The aqueous solution was evaporated to a white solid. HCl(6 M, 4 mL, 24 mmol) was added. The mixture was extracted

13、with EtOAc (420 mL), and the combined organic extract was dried (MgSO4) and evaporated to give a moist solid. Et2O (15 mL) was added and some white solid precipitated. This was washed with further Et2O (210 mL). The combined Et2O extracts were concentrated to give white crystals (383 mg, 62%) of the

14、 monohydrate.2. 2. 1. 4 Sandermeyer反应合成芳香磺酸Sandermeyer反应的应用之一就是将芳香化重氮盐转化为芳香磺酸。这是一类很经典的反应。具体操作是将芳胺经重氮盐在二价金属离子催化下（一般是二价铜）用液态二氧化硫处理，就可以得到芳香磺酸。2. 2. 2 芳香磺酸或盐氯化制备芳香磺酰氯示例A mixture of sodium 4-cyanobiphenyl-4-sulfonate (251 g) and phosphorous oxychloride was refluxed for 16 h. The reaction mixture was pour

15、ed into a large quantity of ice/water and the resulting slurry was extracted with dichloromethane (1*1.8 L).The organic extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated to approximately 200 mL. Hexanes (200 mL) was added. The slurry was stirred for 30 min, filt

16、ered, washed with 1:1 dichloromethane/hexanes, and dried to give product (82.1 g).The mother liquor was concentrated and further purified by flash chromatography on silica gel (40-70percent dichloromethane/hexanes) to give an additional 16.2 g of white solid.2. 2. 3 芳香环磺化反应示例2-Nitro-phenylamine (13.

17、8 g) are dissolved in conc. H2SO4(75 mL), H3PO4 (100 mL) and water (50 mL). The solution of NaNO2 (8.3 g) in water (25 mL) was slowly added dropwise under ice-water cooling. The temperature was maintained at 1015 oC. NH3-SO3H was added in batches to remove the extra formed HNO2. The reaction was coo

18、led down to -10 oC, liquid SO2 (50 mL) was added dropwise. The reaction mixture was poured into another mixture of FeSO4.7H2O (55.7 g) and Cu (1 g). Half an hour later, the reaction was filtered, the residue cake was washed with mixture of ether (750 mL) and CH2Cl2 (750 mL). The combined filtrate an

19、d washings were washed with brine, dried and concentrated. The residue was precipitated in water (50 mL), then diluted ammonia was used to adjust pH equal 9 under stirring. Filtered, the filtrate was acidified with HCl (6 N), the precipitate was collected by filtration and dried to afford desired 2-

20、Nitro-benzenesulfonic acid, (9.4 g, 65% yield.) 2. 3芳香硫醇及相关衍生物氯代、氧化合成芳香磺酰氯芳香硫醇及相关衍生物，比如硫醚，二硫化物在氧化性氯化试剂存在下，均能够较容易的转变成磺酰氯。因此，芳香硫醇及其衍生物也是合成芳香磺酰氯的一类重要前体。 文献报道：对硝基硫酚在以下两种条件下都可以很容易的转变成对硝基苯磺酰氯11：Andrews, Stephen P. 报道：将如下底物悬浮于醋酸水中，导入氯气，就能以76的收率得到磺酰氯12。二硫化物也是一类可以通过氯气处理转化成磺酰氯的重要前体。如Berryman, K. A. 报道132. 3.

21、1硫酚变磺酰氯合成方法示例4-Nitro-3-trifluoromethyl-benzenethiol 47g was dissolved in AcOH (100 mL), chlorine gas was bubbled into the mixture at 010 oC, TLC indicate the reaction completed. The precipitate was collected by filtration, washed with water. Taken into CH2Cl2 (200 mL). Dried upon anhydrous MgSO4, fi

22、ltered, concentrated to afford the desired sulfonyl chloride (22.3 g) as an yellow oil, this sample could be used in next step without further purification. 2. 3. 2芳香硫醇相关衍生物氯代、氧化合成芳香磺酰氯举例Chlorine gas was bubbled through a suspension of methyl 4-benzylsulfanyl-3-nitrobenzoate (25.4 g, 83.7 mmol) in a

23、cetic acid/water (2:3, 500 mL) for 1.5 h. The mixture was stirred under the chlorine atmosphere for 19 h when the system was purged with nitrogen and the solvent was concentrated in vacuo. The resulting yellow precipitate was collected by filtration, washed with hexane (2 50 mL), and recrystallized

24、from chloroform/hexane to afford the sulfonyl chloride as a white crystal (17.8 g, 76%).2.3. 3应用硝酸钾-SO2Cl2的反应示例To above compound 1 (6.55 g, 14.4 mmol) and potassium nitrate (4.37 g, 43.0 mmol) in acetonitrile (45 mL) was added sulfuryl chloride (3.45 mL, 43.0 mmol) dropwise over 7 min and the reacti

25、on mixture was stirred at room temperature. After 5 h sodium bicarbonate (500 mL, aq satd) was added and the solution extracted with ethyl acetate (600 mL). The organic phase was washed with brine (400 mL), dried with magnesium sulfate, and evaporated in vacuo to give the title compound (6.6 g, 78%)

26、 as an oil. Used without further purification.2. 4. 芳香硫醇的制备有机镁与有机锂试剂与硫发生插入反应，生成物进一步水解，则生成硫醇或硫酚。由于硫醇可由多种其他方法制得。因此，本法合成硫酚更具有实用价值。例：苯基锂与硫发生放热反应，生成物进一步水解则生成苯硫酚14。二硫化物很容易被多种还原试剂还原成硫醇。二硫化物本身也能被氯化试剂作用直接得到磺酰氯。锌乙酸15，氢化铝锂16 等均为常用的还原试剂。若为硝基取代的二芳基二硫化物被锌乙酸还原时，硝基亦被还原成氨基。但用二硫化钠做还原剂时，硝基不受影响。铝二氯化镍，四叔丁基硼氢化物也能还原二硫醚成硫酚

27、。作为Sandermeyer直接芳磺化的一种替代方法，在某些二氧化硫不适宜的情况下，成为了一种变通的选择。邻氨基苯甲酸形成的重氮盐与二硫化钠反应，生成相应的二硫化物。它与锌乙酸共回流，则被还原生成邻巯基苯甲酸15。经过氯气处理，即可生成相应的磺酰氯。2. 4. 1. 1芳香硫醇合成方法示例2,4-Dibromo-6-methyl-benzothiazole（3.1 g） and NaHS (1.0 g) in methanol (30 mL) was heated to reflux for 1 hour. TLC indicated the reaction completed. The s

28、olvent was removed under reduced pressure. Water (30 mL) was added. The water layer was extracted with CH2Cl2 (100 mL) three times. Combined organic layer was washed with brine. Dried upon anhydrous Na2SO4, concentrated to afford desired product.2. 5 Sandermeyer 反应由芳胺合成芳香磺酰氯Sandermeyer反应的另一个应用是直接得到芳

29、香磺酰氯。这种反应对催化剂，反应条件的要求及控制都比成磺酸高。市场上有二氧化硫醋酸溶液出售。将芳胺做成重氮盐，以亚铜盐作为催化剂，醋酸做溶剂，再用二氧化硫处理就能够以较好的收率得到芳香磺酰氯。172. 5. 1 芳香环磺化反应示例 To a suspension of 4-amino-2-chloro-3-methyl-benzonitrile (500 mg, 3.00 mmol) in 1.8 mL of 6 N HCl at room temperature was added 2 mL of water followed by a solution of NaNO2 (220 mg,

30、3.13 mmol) in 1 mL of water dropwise and the suspension stirred at room temperature for 20 min. The suspension was added to a solution of SO2 in acetic acid (prepared by bubbling SO2 gas into acetic acid until saturation at room temperature) and copper(II) chloride dihydrate (60 mg, 3.52 mmol) in 0.

31、15 mL of water. The suspension was stirred at room temperature for 1.25 h and extracted with EtOAc. The organic layer was washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, CH2Cl2/Hexanes, 50:50,

32、 75:25 and 100:0) to afford the title compound (305 mg) as a white solid.3. 脂肪磺酰氯的制备脂肪磺酰氯大部分是由相应的硫醇及其衍生物用氯磺化试剂（比如氯气）作用得来。因此，硫醇及其衍生物的引入是合成脂肪族磺酰氯的重要手段。硫类得衍生物有多种，包括硫脲，异硫氰酸酯，硫代乙酸酯，磺原酸酯等等。3. 1 烷基硫醇的合成及通过烷基硫醇合成脂肪磺酰氯3. 1. 1 硫醇的合成硫醇可由硫氢化钠（钾）或硫化氢与烃化试剂进行亲核取代反应而制取。常用的烃化试剂有卤代烃，醇，硫酸酯等。将硫化氢通到乙醇钠的乙醇液中，首先得到的是硫氢化钠，继

33、而与1，7-二溴庚烷反应，以88%的产率生成1，7-庚二硫醇19。-氨基腈在室温下就可以同硫化氢反应，高产率的生成硫醇。-氨基腈易由相应的醛，酮制得。因此，本法是由醛酮合成硫醇的良好方法。例：3，4-二甲氧基苯甲醛与焦亚硫酸钠及叔丁胺在室温反应10分钟后加入氰化钠，就生成了氨基晴。它在三乙胺或吡啶的存在下，通入硫化氢，室温反应就能以92%的产率生成3，4-二甲氧基苯甲硫醇20。硫脲很容易烃化反应生成硫-烃基异硫脲盐，进一步用碱水解，就能以良好产率生成硫醇。例：1，2-二溴乙烷滴入到热的硫脲乙醇溶液中，马上形成硫-烃基异硫脲盐，再与氢氧化钾水溶液一同回流，就可以得到硫醇21。 羧酸硫醇酯在酸性或

34、碱性试剂催化下，均可水解成硫醇。例：对甲苯磺酸酯与硫代乙酸钾在乙醇或丙酮中共热，生成乙酸硫醇酯，再在5%氢氧化钾乙醇溶液中回流，就可以生成硫醇22。黄原酸乙酯单钾盐可由氢氧化钾与二硫化碳在乙醇中反应制得。它与卤代烃，磺酸酯等烃化试剂反应生成黄原酸酯，进一步氨解或水解，就能生成硫醇。本法适用于水溶性卤化物如氯乙酸合成相应的硫醇。例：黄原酸乙酯单钾盐在丙酮中与-苯基溴乙烷于室温下反应，即生成黄原酸酯。将黄原酸酯与氢化铝锂在乙醚中共热，即生成硫醇23。烯烃与硫化氢在压力下加热则生成硫醇，加成方向按马氏法则。例：在干冰冷却下将烯烃与硫化氢置于压力瓶中，然后于150oC加热，即生成硫醇24。3. 1.

35、2 通过硫醇合成芳香磺酰氯 目前有两种常用的方法将脂肪硫醇转变为脂肪磺酰氯，一是用NaClO4在酸性溶液中处理得来。另一种是在酸性介质中通入氯气制得。如：3. 2 通过烷基硫脲合成脂肪磺酰氯3. 2. 1烷基硫脲的合成硫脲极易发生烃化反应生成S烃基异硫脲盐，收率一般在（4090）。烷基硫脲是所有脂肪类硫醇衍生物中最重要的一类，它可以从前体卤代烷烃经硫脲处理得来。反应条件比较温和。如下例所示：本法的一种改良是在浓盐酸或浓氢溴酸存在下，醇与硫脲直接反应，即可生成S烃基异硫脲盐，不必由醇制备卤代烃再进行反应。3. 2. 2 通过烷基硫脲合成芳香磺酰氯 目前有两种常用的方法将脂肪硫脲转变为脂肪磺酰氯，

36、一是用NaClO4在酸性溶液中处理得来。另一种是在酸性介质中通入氯气制得。文献报道：183. 3 通过烷基异硫氰酸酯合成芳香磺酰氯3. 3. 1烷基异硫氰酸酯的合成烷基异硫氰酸酯是脂肪硫醇的另一类重要的衍生物。它也可以由烷基卤代烃作为前体与异硫氰酸钾反应生成。如：3. 3. 2 通过烷基异硫氰酸酯合成芳香磺酰氯异硫氰酸酯类化合物用氯气处理后也能得到磺酰氯：3. 4 通过羧酸硫醇酯合成芳香磺酰氯3. 4. 1 羧酸硫醇酯的合成 羧酸硫醇酯的制备一般都是通过卤代烷烃同乙酸硫醇钾反应生成。如：3. 4. 2 通过羧酸硫醇酯合成脂肪磺酰氯羧酸硫醇酯也是通过氯气的处理得到脂肪磺酰氯。如：3. 5 脂肪磺

37、酰氯合成反应示例3.5.1 脂肪族磺化反应示例1A solution of 4-(7-Bromo-2-ethoxymethyl-imidazo4,5-cquinolin-1-yl)-butane-1-thiol (1.73 g, 4.39 mmol) in concentrated hydrochloric acid (7.5 ML) and water (5 mL) was cooled to 0 oC. A solution of sodium chlorate (0.61 g, 5.7 mmol) in water (2. 5 mL) was added dropwise with vi

38、gourous stirring over a period of three minutes. The reaction was stirred at 0 oC for 90 minutes then diluted with dichloromethane (50 mL). Aqueous potassium carbonate (8 mL of 6M) was slowly added to adjust the mixture to pH equal 5. Dichloromethane (100 mL) and water (75 mL) were added, and the re

39、action was allowed to warm to ambient temperature with stirring. The aqueous layer was separated and extracted with dichloromethane (3 x 40 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 1.61 g of 4-(7-Bromo-2-ethox

40、ymethyl-imidazo4,5-cquinolin-1-yl)-butane-1-sulfonyl chloride as a tan solid.3.5.2脂肪族磺化反应示例2To a solution of methylthioglycolate (1.3kg, 12.25mol) in dichloromethane (9 litres) was added ice (4.5 litres). Chlorine gas was bubbled gently through the solution, maintaining the temperature below 5.deg.C

41、 until the solution maintained a slight green colouration. The solution was degassed with nitrogen to remove excess chlorine, the organic phase collected and the solvent removed under reduced pressure to give the subtitle compound (1.758 kg, 83 percent) which was used without further purification.3.

42、5.3 烷基硫醇衍生物合成反应示例3-4-(4-chlorophenoxy)phenyl-7-iodo-hept-2-enoate (59.8 g) and thiourea (9.39 g) in ethanol (123 ml) was refluxed for 24 hours. The resulting mixture was cooled and evaporated to give ethyl 7-amidinothio-3-4-(4-chlorophenoxy)phenylhept-2-enoate hydroiodide (70.2 g) (E:Z = 1:1 mixture

43、) as slightly yellow oil. This sample was then dissolved in AcOH (1000 mL), chlorine gas was bubbled into the mixture at 010 oC, TLC indicate the reaction completed. The precipitate was collected by filtration, washed with water. Re-dissolved in CH2Cl2 (1000 mL). Dried upon anhydrous MgSO4, filtered

44、, concentrated to afford the target sulfonyl chloride (52 g, 65 %).3.5.4 烷基硫醇衍生物合成脂肪磺酰氯反应示例A mixture of 1-iodo-3-methylbutane (12 g) and potassium thiocyanate (5.9 g) in acetone (110 ml) was refluxed for 4 hours. After precipitate was filtered off, the filtrate was evaporated in vacuo. Water was add

45、ed to the residue followed by extraction with chloroform. The extract was dried over magnesium sulfate and evaporated under reduced pressure to give the thiocyanate (8.3 g). A solution of above thiocyanate was bubbled with chlorine gas for 1 hour under ice-cooling (below 0.deg. C.) with stirring fol

46、lowed by extraction with diisopropyl ether. After extract was dried over sodium sulfate, the solvent was evaporated in vacuo to give sulfonyl chloride (9.0 g). To a 28percent ammonium hydroxide (50 ml) was added dropwise crude sulfonyl chloride in dichloromethane (15 ml) over 20 minutes at approxima

47、tely 0.deg. C. The reaction mixture was stirred vigorously overnight at ambient temperature. The phases were separated. The aqueous phase was extracted with chloroform/methanol (5/1). The combined organic extracts were washed with half-brine, dried over magnesium sulfate and evaporated under reduced

48、 pressure. The residue was purified by column (chloroform/methanol=95/5) to give 3-methyl-1-butanesulfonamide (4.3 g).参考文献：1. Nie, Zhe；et al; J. Med. Chem.; EN; 48; 5; 2005; 1596 - 1609.2. Tanasescu I, Bull. Soc. Chem. France 1938, 5; 11263. Fierz-David H. E., Helv. Chim. Acta 1942, 25, 36814. Suter C. M. Harringtong G. A. J. Am. Chem. Soc., 1937, 59, 25775. Gilbert E. E., Sulfonation and Related Reactions, New York, 19656. Vollbracht L. et al. Rec. Trav. Chim. 1961, 80,117. Euwes D. C. ibid. 1909, 28, 2988. Wolf W. C.