vitamin B12

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四吡咯及其衍生物
• 英文名称: vitamin B12
• 英文别名: cyanocobalamine；B12；cobalamin；CN-Cbl；α-(5,6-dimethyl-benzimidazolyl)cyanocobamide；hydrobexan；cyanoject；rubramin；cytamen；cyomin；cobalt(3+);[(2R,3S,4R,5S)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2R)-1-[3-[(1R,2R,3R,5Z,7S,10Z,12S,13S,17S,18S,19R)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2,7,12,17-tetrahydro-1H-corrin-24-id-3-yl]propanoylamino]propan-2-yl] phosphate;cyanide
• 化学式: C₆₃H₈₈CoN₁₄O₁₄P
• 分子量: 1355.44
• InChiKey: FDJOLVPMNUYSCM-WZHZPDAFSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  3.41
• 重原子数：
  93
• 可旋转键数：
  26
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  476
• 氢给体数：
  9
• 氢受体数：
  21

ADMET

代谢

维生素B12或氰钴胺从食物中获取时，最初会与_haptocorrin_结合，这是一种在唾液中发现的、对B12有高亲和力的蛋白质。这形成了_haptocorrin-B12_复合物。氰钴胺通过胃部，由于其与haptocorrin的结合，从而被保护免受酸性降解。在小肠的十二指肠，胰腺蛋白酶释放钴胺素从_haptocorrin-B12_复合物和其他含有与蛋白质结合的B12的蛋白质中。此后，钴胺素与第二种糖蛋白，即内因子结合，通过一个称为_cubilin_/AMN受体介导的内吞作用的过程，促进其被回肠末端粘膜细胞摄取。吸收进入肠细胞后，内因子在溶酶体中被分解，然后钴胺素被释放到血液中。位于肠道上皮细胞和其他细胞基底外侧膜上的转运蛋白ABCC1将结合了转钴胺素的钴胺素输出细胞。氰钴胺然后通过肝脏的门静脉，然后进入全身循环。氰钴胺的活性形式是甲基钴胺素和腺苷钴胺素。

Vitamin B12 or cyanocobalamin obtained from food is initially bound by _haptocorrin_, a protein found in the saliva with high affinity for B12. This forms a _haptocorrin-B12_ complex. Cyanocobalamin passes through the stomach and is protected from acid degradation due to its binding to haptocorrin. In the duodenum, pancreatic _proteases_ release cobalamin from the _haptocorrin-B12 complex_ and from other proteins containing protein-bound B12 that have been ingested. Following this, the binding of cobalamin to a second glycoprotein, _intrinsic factor_, promotes its uptake by terminal ileum mucosal cells by a process called _cubilin_/AMN receptor-mediated endocytosis. After absorption into enterocytes, intrinsic factor is broken down in the lysosome, and cobalamin is then released into the bloodstream. The transporter ABCC1, found in the basolateral membrane of intestinal epithelial and other cells, exports cobalamin bound to transcobalamin out of the cell. Cyanocobalamin then passes through the portal vein in the liver, and then reaches the systemic circulation. The active forms of cyanocobalamin are _methylcobalamin_ and _adenosylcobalamin_,.

来源:DrugBank

代谢

维生素B12被认为是转化成辅酶形式储存在肝脏中的，并且很可能会以这种形式储存在组织中。

Vitamin B12 is believed to be converted to coenzyme form in the liver and is probably stored in tissues in this form.

来源:Hazardous Substances Data Bank (HSDB)

代谢

细胞内维生素B12以两种活性辅酶形式存在，分别是甲钴胺和脱氧腺苷钴胺。

Intracellular vitamin B12 is maintained as two active coenzymes methylcobalamin and deoxyadenasylcobalamin.

来源:Hazardous Substances Data Bank (HSDB)

代谢

维生素B12被认为在肝脏转化为辅酶形式，并且可能以这种形式储存在组织中。

Vitamin B12 is believed to be converted to coenzyme form in the liver and is probably stored in tissues in this form.

来源:Hazardous Substances Data Bank (HSDB)

代谢

细胞内维生素B12以两种活性辅酶形式存在，分别是甲钴胺和脱氧腺苷钴胺。

Intracellular vitamin B12 is maintained as two active coenzymes methylcobalamin and deoxyadenasylcobalamin.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 药物性肝损伤

氰钴胺

Compound:cyanocobalamin

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

DILI 注解：无 DILI（药物性肝损伤）担忧

DILI Annotation:No-DILI-Concern

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

标签部分：没有匹配项

Label Section:No match

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 药物性肝损伤

参考文献：M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. 用于研究药物诱导肝损伤的FDA批准药物标签，药物发现今日，16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank：按在人类中发展药物诱导肝损伤风险排名的最大参考药物清单。药物发现今日2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

References:M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007 M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

来源:Drug Induced Liver Injury Rank (DILIrank) Dataset

毒理性

• 在妊娠和哺乳期间的影响

◉ 母乳喂养期间使用总结：维生素B12是人类母乳的正常组成部分。哺乳期妇女的推荐每日摄入量为2.8微克，对于6个月或以下的婴儿为0.4微克。一些权威机构建议在哺乳期间每日摄入量为5.5微克。为了达到这些推荐的每日摄入量或纠正已知的缺乏，可能需要补充。在B族复合维生素或孕期维生素中发现的低剂量（1到10微克）的维生素B12只能略微提高乳汁水平。在母亲缺乏的情况下，需要更高每日剂量的50到250微克。在这种情况下，母乳喂养的婴儿不会接触到过量的维生素B12，如果之前不足，他们的维生素B12状况应该会改善。 维生素B12缺乏的婴儿健康结果不良包括贫血、皮肤和头发发育异常、惊厥、肌张力弱、生长迟缓、智力发育迟缓，可能的异常运动。一个公认的处于风险中的群体是母亲由于极少量或没有摄入动物产品或由于母亲对维生素B12吸收不良导致的恶性贫血而维生素B12缺乏的，仅以母乳喂养的婴儿。通过在孕期和哺乳期补充维生素B12，可以改善婴儿的维生素B12状况。错过在孕期补充机会的缺乏母亲仍应鼓励在早期哺乳期进行补充，因为婴儿的维生素B12状况与母乳喂养婴儿在6个月大之前的乳汁维生素B12水平相关。尽管有报道称仅以母乳喂养的维生素B12缺乏婴儿通过充足的母体补充而有了生化和临床改善，但当有此类治疗时，建议直接补充婴儿。 母乳的闪蒸巴氏杀菌不会降低乳汁维生素B12的浓度。 ◉ 对母乳喂养婴儿的影响：12名仅以母乳喂养的婴儿，年龄在4到11个月之间，出现了与维生素B12缺乏一致的生化、血液和临床发现。他们的母亲接受了一次50微克肌内维生素B12的单剂量。在剂量后的5到8天内，婴儿的血红蛋白和网织红细胞计数显著增加，正常红细胞生成，精神状态改善，异常皮肤色素沉着消退，震颤减少。 在印度的366名孕妇从怀孕的第一季度开始每天接受一次50微克口服维生素B12或安慰剂胶囊，直到产后6周。在30个月大时接受神经发育测试的218名婴儿中，那些出生时母亲随机接受维生素B12的婴儿，在调整基线母亲维生素B12缺乏后，与安慰剂组相比，表现性语言评分更高。认知、接受性语言和运动评分在两组之间没有差异。在6岁时进行的神经生理学评估中，两组之间测量的脑活动没有差异。 ◉ 对哺乳和母乳的影响：截至修订日期，没有找到相关的已发布信息。

◉ Summary of Use during Lactation:Vitamin B12 is a normal component of human milk. The recommended daily intake in lactating women is 2.8 mcg and for infants aged 6 months or less is 0.4 mcg. Some authorities recommend 5.5 mcg per day during lactation. Supplementation may be necessary to achieve these recommended daily intakes or to correct a known deficiency. Low doses (1 to 10 mcg) of vitamin B12 found in B complex or prenatal vitamins increase milk levels only slightly. Higher daily doses of 50 to 250 mcg are needed in cases of maternal deficiency. The breastfed infant is not exposed to excessive vitamin B12 in such cases, and their vitamin B12 status should improve if it was previously inadequate. Poor health outcomes in infants with vitamin B12 deficiency include anemia, abnormal skin and hair development, convulsions, weak muscle tone, failure to thrive, mental developmental delay, and possibly abnormal movements. One well-recognized at risk group are exclusively breastfed infants of mothers with B12 deficiency due to minimal or no dietary intake of animal products or pernicious anemia caused by a maternal malabsorption of B12. Infant vitamin B12 status can be improved through maternal B12 supplementation during pregnancy and lactation. Deficient mothers who miss the opportunity to supplement during pregnancy should still be encouraged to supplement during early lactation since infant vitamin B12 status correlates with milk vitamin B12 levels in breastfed infants up to 6 months of age. Although there are cases reported of exclusively breastfed infants with vitamin B12 deficiency having biochemical and clinical improvement through adequate maternal supplementation alone, direct supplementation of the infant is recommended when such treatments are available. Flash heat pasteurization of breastmilk does not reduce milk vitamin B12 concentration. ◉ Effects in Breastfed Infants:Twelve exclusively breastfed infants between 4 and 11 months of age had biochemical, hematological and clinical findings consistent with vitamin B12 deficiency. Their mothers received a 50 mcg single dose of intramuscular vitamin B12. Within 5 to 8 days after the dose, the infants experienced significantly increased hemoglobin and reticulocyte counts, normoblastic erythropoiesis, improved mental status, regression of abnormal skin pigmentation, and reduction in tremors. Three hundred sixty-six pregnant women in India received 50 mcg of oral vitamin B12 or placebo capsules once daily beginning during their first trimester of pregnancy and continuing until 6 weeks postpartum. Among 218 infants that underwent neurodevelopment testing at 30 months of age, those born to mothers randomized to vitamin B12 had higher expressive language scores than the placebo group when adjusted for baseline maternal vitamin B12 deficiency. Cognitive, receptive language and motor scores were not different between the two groups. Neurophysiological assessments were then conducted at 6 years of age and there were no differences in the measured brain activity between the two groups. ◉ Effects on Lactation and Breastmilk:Relevant published information was not found as of the revision date.

来源:Drugs and Lactation Database (LactMed)

吸收、分配和排泄

• 吸收

维生素B12从肌肉注射（IM）和皮下注射（SC）部位迅速吸收；肌肉注射后约1小时达到血浆峰浓度。口服给药的维生素B12在通过胃部时与内因子（IF）结合。当存在钙时，维生素B12和IF在回肠末端分离，然后维生素B12被吸收进入胃肠粘膜细胞。之后，它通过转钴胺素结合蛋白进行运输。然而，被动扩散可以通过肠壁发生，但这种情况需要高剂量的维生素B12（即>1毫克）。在口服剂量小于3微克的情况下，由于维生素暂时滞留在回肠下壁，峰值血浆浓度需8到12小时才能达到。

Vitamin B12 is quickly absorbed from intramuscular (IM) and subcutaneous (SC) sites of injection; with peak plasma concentrations achieved about 1 hour after IM injection. Orally administered vitamin B12 binds to intrinsic factor (IF) during its transport through the stomach. The separation of Vitamin B12 and IF occurs in the terminal ileum when calcium is present, and vitamin B12 is then absorbed into the gastrointestinal mucosal cells. It is then transported by transcobalamin binding proteins. Passive diffusion through the intestinal wall can occur, however, high doses of vitamin B12 are required in this case (i.e. >1 mg). After the administration of oral doses less than 3 mcg, peak plasma concentrations are not reached for 8 to 12 hours, because the vitamin is temporarily retained in the wall of the lower ileum.

来源:DrugBank

吸收、分配和排泄

• 排除途径

这种药物部分通过尿液排出。根据一项临床研究，大约有3-8微克的维生素B12每天通过胆汁排入消化道。在内在因子水平充足的患者中，除了大约1微克之外，所有的维生素B12都会被重新吸收。当维生素B12以高剂量给药，饱和了血浆蛋白和肝脏的绑定能力时，未结合的维生素B12会迅速通过尿液排出。维生素B12在体内的储存量取决于剂量。

This drug is partially excreted in the urine. According to a clinical study, approximately 3-8 mcg of vitamin B12 is secreted into the gastrointestinal tract daily via the bile. In patients with adequate levels of intrinsic factor, all except approximately 1 mcg is reabsorbed. When vitamin B12 is administered in higher doses that saturate the binding capacity of plasma proteins and the liver, the unbound vitamin B12 is eliminated rapidly in the urine. The body storage of vitamin B12 is dose-dependent.

来源:DrugBank

吸收、分配和排泄

• 分布容积

维生素B12被分配到组织中，主要储存在肝脏和骨髓里。

Cobalamin is distributed to tissues and stored mainly in the liver and bone marrow.

来源:DrugBank

吸收、分配和排泄

• 清除

在维生素负荷期间，肾脏积累了大量未结合的维生素B12。这种药物部分通过肾脏清除，然而，多配体受体_megalin_促进了维生素B12被身体重新摄取和重吸收。

During vitamin loading, the kidney accumulates large amounts of unbound vitamin B12. This drug is cleared partially by the kidney, however, multiligand receptor _megalin_ promotes the reuptake and reabsorption of vitamin B12 into the body,.

来源:DrugBank

吸收、分配和排泄

在给小鼠静脉注射维生素B12的实验中，维生素B12迅速积累在胎盘并且缓慢转移到胎儿。胎儿中的维生素B12浓度在给药后24小时达到峰值，而且胎儿的积累量与剂量有关。

IN MICE INJECTED IV WITH VITAMIN B12, THE VITAMIN ACCUMULATED RAPIDLY IN THE PLACENTA & WAS TRANSFERRED SLOWLY TO THE FETUSES. PEAK CONCN IN THE FETUSES WAS REACHED 24 HR AFTER DOSING, & FETAL ACCUMULATION WAS DOSE-DEPENDENT.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  vitamin B12 在 sodium hydroxide 作用下， 以 盐酸 为溶剂， 生成 cyanoaquocobinamide
  参考文献：
  名称：

  1H NMR Studies of the isomers of dicyanocobalamin and dicyanocobinamide

  摘要：

  DOI：

  10.1016/s0277-5387(00)80812-8
• 作为产物：
  描述：

  methylcobalamine 、 2,3-二氯-5,6-二氰基-1,4-苯醌 以 乙醇 为溶剂， 以30%的产率得到vitamin B12
  参考文献：
  名称：

  Dolphin, D.; Johnson, A. W.; Rodrigo, R., Journal of the Chemical Society

  摘要：

  DOI：
• 作为试剂：
  描述：

  烯丙基丙二酸二乙酯 在 vitamin B12 、 水 、 氢溴酸 、 双氧水 、 potassium hydride 、 sodium hydride 作用下， 生成 triethyl 4-ethylsulfanylcarbonyl-1-methylhexane-1,1,5-tricarboxylate
  参考文献：
  名称：

  First hydrogen abstraction-rearrangement model for the coenzyme B12-dependent methylmalonyl-CoA to succinyl-CoA carbon skeleton rearrangement reaction

  摘要：

  DOI：

  10.1021/ja00046a073

文献信息

• CHEMICAL SYNTHESIS AND SOME BIOLOGICAL PROPERTIES OF THE COENZYME FORMS OF AN ALKANOLAMINE-TYPE B12-ANTIVITAMIN*†
  作者：W. Friedrich、H. C. Heinrich、E. Königk、P. Schulze

  DOI：10.1111/j.1749-6632.1964.tb45036.x

  日期：——

  socalled S 102 and biologically the most interesting alkanolamine type analogue of Vitamin Blz ) , prepared by partial chemical synthesis starting from factor Vla1v2 is at the present time the most active vitamin BIZantagonist in tests with Escherichia coli 113-3; Ochromonus malhumensis,4 chick^,^ and man.6 It was therefore of interest to investigate whether the biological properties of S 102 are changed

  C'3-2-甲基-2-氨基-丙醇(1)-维生素-B1z-类似物（所谓的S 102和生物学上最有趣的维生素Blz的链烷醇胺型类似物），从因子Vla1v2开始通过部分化学合成制备是目前在大肠杆菌 113-3 试验中活性最强的维生素 BIZantagonist；Ochromonus malhumensis，4 小鸡^，^ 和人。6 因此，研究S 102 的生物学特性是否通过将S 102 转化为光敏辅酶型衍生物而改变是很有意义的。
• Cell-Mediated Assembly of Phototherapeutics
  作者：Weston J. Smith、Nathan P. Oien、Robert M. Hughes、Christina M. Marvin、Zachary L. Rodgers、Junghyun Lee、David S. Lawrence

  DOI：10.1002/anie.201406216

  日期：2014.10.6

  light‐sensitive prodrugs are typically converted to their active forms using short‐wavelength irradiation, which displays poor tissue penetrance. We report herein erythrocyte‐mediated assembly of long‐wavelength‐sensitive phototherapeutics. The activating wavelength of the constructs is readily preassigned by using fluorophores with the desired excitation wavelength λex. Drug release from the erythrocyte carrier

  光激活药物有望以极好的时间和空间分辨率实现控释。然而，光敏前药通常使用短波长照射转化为其活性形式，这显示出较差的组织渗透性。我们在此报告了红细胞介导的长波长敏感光疗剂的组装。通过使用具有所需激发波长λ ex 的荧光团，可以很容易地预先指定构建体的激活波长. 通过标准分析工具和细胞培养中释放的药物的预期生物学后果证实了红细胞载体的药物释放：甲氨蝶呤，与细胞内二氢叶酸还原酶结合；秋水仙碱，抑制微管聚合；地塞米松诱导糖皮质激素受体的核迁移。
• Kinetic and thermodynamic studies on the cyanation reactions and base-on/base-off equilibria of alkyl-13-epicobalamins
  作者：Mohamed S. A. Hamza、Xiang Zou、Kenneth L. Brown、Rudi van Eldik

  DOI：10.1039/b304069k

  日期：——

  Ligand substitution equilibria of two different 13-epicobalamins (X-13-epiCbl, X = NCCH2 and CN−) with cyanide have been studied. It was found that CN− substitutes the 5,6-dimethylbenzimidazole (DMBz) moiety in the α-position to form X(CN)Cbl-13epi, which for X = NCCH2 in the presence of CN− subsequently gives (CN)2Cbl-13epi. The kinetics of the displacement of DMBz by CN− showed saturation behaviour at high cyanide concentration and the limiting rate constants are characterized by the activation parameters: X = NCCH2, ΔH≠ = 83 ± 1 kJ mol−1, ΔS≠ = +77 ± 4 J K−1 mol−1, ΔV≠ = +13.3 ± 1.0 cm3 mol−1; X = CN−, ΔH≠ = 106 ± 1 kJ mol−1, ΔS≠ = +82 ± 4 J K−1 mol−1 and ΔV≠ = +14.8 ± 0.5 cm3 mol−1. These parameters are interpreted in terms of a limiting D mechanism. The rate constants for the displacement of DMBz in the case of the 13-epicobalamins were found to be slower than those obtained in the case of the analogous alkylcobalamins, and consequently, the thermodynamic equilibrium constants for the 13-epicobalamins were found to be smaller than those obtained in the case of the alkylcobalmins. This clearly shows the effect of the epimerization of the e-side chain attached to the C-13 of the corrin ring on the rate and equilibrium constants for these ligand displacement reactions.

  研究了两种不同的 13-epicobalamins （X-13-epiCbl，X = NCCH2 和 CN-）与氰化物的配体取代平衡。研究发现，CN- 会取代 α 位的 5,6-二甲基苯并咪唑 (DMBz)，形成 X(CN)Cbl-13epi ；当 X = NCCH2 时，在 CN- 的存在下，会产生 (CN)2Cbl-13epi。在氰化物浓度较高时，DMBz 被 CN- 置换的动力学表现为饱和状态，极限速率常数由活化参数表征：X = NCCH2，ΔH≠ = 83 ± 1 kJ mol-1，ΔS≠ = +77 ± 4 J K-1 mol-1，ΔV≠ = +13.3 ± 1.0 cm3 mol-1；X = CN-，ΔH≠ = 106 ± 1 kJ mol-1，ΔS≠ = +82 ± 4 J K-1 mol-1，ΔV≠ = +14.8 ± 0.5 cm3 mol-1。这些参数是根据极限 D 机制解释的。研究发现，13-表二十八烷氨基中 DMBz 的位移速率常数比类似的烷基二十八烷氨基的速率常数慢，因此，13-表二十八烷氨基的热力学平衡常数比烷基二十八烷氨基的热力学平衡常数小。这清楚地表明了连接在茱萸环 C-13 上的 e 侧链的二聚化对这些配体置换反应的速率和平衡常数的影响。
• SOME REACTIONS OF THE VITAMIN B12 COENZYME AND ITS ALKYL ANALOGUES
  作者：D. Dolphin、A. W. Johnson、R. Rodrigo

  DOI：10.1111/j.1749-6632.1964.tb45035.x

  日期：——

  The important role of the vitamin BI2 coenzyme (FIGURE 1) in biochemistryl and the discovery of a relatively easy method of conversion of the cobalamins to the coenzymes as well as a wide variety of cobalt-alkyl and cobalt-acyl a n a l o g ~ e s ~ r ~ , ~ * ~ has stimulated a thorough examination of the structure, properties, and reactions of these unique compounds, which are the first examples of

  维生素 BI2 辅酶（图 1）在生物化学中的重要作用和发现一种相对容易的将钴胺素转化为辅酶的方法以及各种钴-烷基和钴-酰基类似物 ~ es ~ r ~ , ~ * ~ 激发了对这些独特化合物的结构、性质和反应的彻底检查，这些化合物是稳定的钴-烷基衍生物的第一个例子。 6
• Detailed kinetic and thermodynamic studies on the cyanation of alkylcobalamins. A generalized mechanistic description
  作者：Mohamed S. A. Hamza、Xiang Zou、Kenneth L. Brown、Rudi van Eldik

  DOI：10.1039/b206706d

  日期：——

  Ligand substitution equilibria of different cobalamins (XCbl, X = Ado, CF3CH2, n-Pr, NCCH2 and CN−) with cyanide have been studied. It was found that CN− substitutes the 5,6-dimethylbenzimidazole (DMBz) moiety in the α-position in all cases. A reinvestigation of the reactions of coenzyme B12 (X = Ado) and CF3CH2Cbl with CN− and an investigation of the same reaction for X = n-Pr, demonstrate that the unfavorable formation constants in these cases require very high cyanide concentrations to produce the 1 ∶ 1 complex, which causes the kinetics of the displacement of DMBz by cyanide to be too fast to follow. The kinetics of the displacement of DMBz by CN− could be followed for X = β-NCCH2 and CN− to form NCCH2(CN)Cbl and (CN)2Cbl, respectively. Both reactions show saturation kinetics at high cyanide concentration and the limiting rate constants are characterized by the activation parameters: X = NCCH2, ΔH≠ = 85 ± 2 kJ mol−1, ΔS≠ = +97 ± 6 J K−1 mol−1, ΔV≠ = +12.7 ± 0.5 cm3 mol−1; X = CN−, ΔH≠ = 105 ± 2 kJ mol−1, ΔS≠ = +81 ± 6 J K−1 mol−1 and ΔV≠ = +13.1 ± 0.3 cm3 mol−1. These parameters are interpreted in terms of a limiting D mechanism. A complete analysis of the trans effect order of the substituent X is presented. The results enable the formulation of a general mechanism that can account for the substitution behavior of all the investigated alkylcobalamins.

  研究了不同钴胺（XCbl，X = Ado、CF3CH2、n-Pr、NCCH2 和 CN-）与氰化物的配体取代平衡。研究发现，CN- 在所有情况下都取代了 α 位的 5,6-二甲基苯并咪唑（DMBz）分子。对辅酶 B12（X = 阿多）和 CF3CH2Cbl 与 CN- 反应的重新研究，以及对 X = n-Pr 相同反应的研究表明，在这些情况下，不利的形成常数需要非常高的氰化物浓度才能产生 1 ∶ 1 复合物，这导致氰化物置换 DMBz 的动力学速度过快，难以跟踪。在 X = β-NCCH2 和 CN- 的情况下，DMBz 被 CN- 置换的动力学可以被跟踪，分别生成 NCCH2(CN)Cbl 和 (CN)2Cbl。在氰化物浓度较高时，这两种反应都显示出饱和动力学，极限速率常数由活化参数表征：X = NCCH2，ΔH≠ = 85 ± 2 kJ mol-1，ΔS≠ = +97 ± 6 J K-1 mol-1，ΔV≠ = +12.7 ± 0.5 cm3 mol-1；X = CN-，ΔH≠ = 105 ± 2 kJ mol-1，ΔS≠ = +81 ± 6 J K-1 mol-1，ΔV≠ = +13.1 ± 0.3 cm3 mol-1。这些参数是根据极限 D 机制解释的。对取代基 X 的反式效应顺序进行了完整的分析。这些结果有助于制定一种通用机制，以解释所有研究过的烷基钴胺的取代行为。