河北医科大学药学院 1947 Nobel Prize in Chemistry 1947,1965 Nobel Prize in Chemistry 马线手的拉断就 Examples of Structure Elucidation 功好 9 奶 8 1962 Nobel Prize in Chemistry 1962年诺贝尔生理学或医学奖 Xry和丝物大分于 XV和D八A城流转热分新分手生物举的开裙 1964 Nobel Prize in Chemistry Xy和生物小分子结转分析 G CLE ed lodekin's I04th hirthday.May l 方OH A moldy ca 体王国之花 5a 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 1 90 Robert Robinson published 54 paper for structure elucidation And determined it in 1946 and got Nobel Prize in 1947. Robert B. Woodward Total Syn.in 1954 and 1947 Nobel Prize in Chemistry Robert Robinson N O H H H H O H N Strychnine 127 Years! Examples of Structure Elucidation 1947 Nobel Prize in Chemistry N N O OH Perkin.Jr. & Robinson 1910 N N O O Menon & Robinson 1931 N N O O Blount & Robinson 1932 N N O O Kotake & Mitsuwa 1932 N N O O Menon & Robinson 1932 Holmes & Robinson 1939 N N O O Prelog & Szpilfogel 1945 N N O O Robinson 1947 N O N O Chakravarti & Robinson 1947 Woodward,Brehm & Nelson 1947 马钱子碱的结构推断过程 1947 NP 1965 NP 1947, 1965 Nobel Prize in Chemistry Max F. Perutz 1914-2002 Hemoglobin 血红蛋白 Myoglobin 肌红蛋白 1962 Nobel Prize in Chemistry Sir John C. Kendrew 1917-1997 X-ray 和生物大分子结构分析 沃森James Watson和克里克Crick 1962年诺贝尔生理学或医学奖 X-ray 和DNA螺旋结构分析-分子生物学的开端 Rosalind Franklin 94 1964 Nobel Prize in Chemistry 晶体王国之花 Penicillin G Dorothy Crowfoot Hodgkin X-ray 和生物小分子结构分析 (1910-1994) 1964 NP A moldy cantaloupe 1945 Nobel Prize in Medicine Google commemorated Hodgkin's 104th birthday，May 12, 2014 Sir Robert Robinson did not like the b-lactam structure because this would be unstable, unlike penicillin. They were taken aback when a young woman... John W. Cornforth said “If penicillin turns out to have the b-lactam structure I shall give up chemistry and grow mushrooms.” He did not keep his threat but later received a Nobel prize for his enzyme work 30 years later
河北医科大学药学院 1969 Nobel Prize in Chemistry 1979年诺贝尔生理学或医学奖 X光行射构象分析诺贝尔奖 Computer Assisted Tomography (CT) 动材线属减仅开创了学诊断的断时代 1989年诺贝尔物理学奖 1991年诺贝尔化学奖 是，1 The Nobel Prize in Chemistry in 2002 2003年诺贝尔生理学或医学奖 “发明了对生物大分子进行确认和韩构分析的方法 MS、N1R开始应用到大分子结构分析 NR应用到临床减共标成像 ance Imaging《MR 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 2 Odd Hassel和Barton利用X-光衍射等方法发现了同一有机物有椅式 、船式等不同结构，提出了“构象分析”的原理和方法，获得1969年诺贝 尔奖。 Hassel是挪威第一个获诺贝尔奖的科学家。 X-光衍射-“构象分析”-诺贝尔奖 Odd Hassel (1897-1981) 1969 Nobel Prize in Chemistry Derek H. R.Barton 1918-1998 计算机辅助X-射线断层成像仪,开创了医学诊断的新时代 Allan M. Cormack 1924-1998 数学家 Godfrey N. Hounsfield 1919-2004 1979年诺贝尔生理学或医学奖 Computer Assisted Tomography (CT) 98 Norman Foster Ramsey Jr. N. F. Ramsey (1915–2011), Who introduced the concept of the chemicalshift and J coupling. 1989年诺贝尔物理学奖 Richard R Ernst 提出了利用核磁共振技术来测定物质结构的新方法， 将傅立叶变换方法真正引入到了核磁共振技术中，相对于化学界所使用 的传统光谱学方法，这一创新数十甚至数百倍的提高了物质结构测定的 敏感度（提高了两个数量级），并为二维和多维NMR技术，以及后来的 核磁共振成像铺平了道路。 R. R. Ernst (1933-) 1991年诺贝尔化学奖 The Nobel Prize in Chemistry in 2002 John B. Fenn （1917-2010）USA Koichi Tanaka 田中耕一 (1959-) Kurt Wüthrich (1938-) Swiss “发明了对生物大分子进行确认和结构分析的方法” MS、NMR开始应用到大分子结构分析 2003年诺贝尔生理学或医学奖 (Nuclear) Magnetic Resonance Imaging （MRI） Paul C. Lauterbur (1929-2007) USA Peter Mansfield (1933- ) Englisn NMR应用到临床-磁共振成像
河北医科大学药学院 2013年诺贝尔化学奖 ◆河北怎科大学研究生实验仪器平台课 Introduction of MS,NMR. X-Ray Crystallography 茜学晚405,86261270 htp:/202.206.48.213:8091/ 。 世纪神药一阿司匹林 Typical Mass Spectrum of Aspirin 在分子水平上长什么样？ Aspirin % Q 青霉素、青蒿素、胆固醇、吗啡、马钱子碱…？ 120m-0 n this is the ma H-NMR of Aspirin 3C-NMR of Cholesterol 天然药物化学教研室史清文教授 3
河北医科大学药学院 天然药物化学教研室 史清文教授 3 Karplus Equation: 确定了偶合常数和二面角之间的关系, 为确定分子结构找到了重要规律，也为后来蓬勃发展的结构生 物学奠定了基础。 Martin Karplus (1930-) J. Chem. Phys., 30, 11-15 (1959). 2013年诺贝尔化学奖 3J = J 0 cos2φ 0.28 (0o ≤φ≤90o) 3J = J 180 cos2φ 0.28 (90o ≤φ≤180o) 3J φ 103 药学院 405， 86261270 Introduction of MS, NMR, X-Ray Crystallography http://202.206.48.213:8091/ 研究生实验仪器平台课 世纪神药-阿司匹林 在分子水平上长什么样？ 青霉素、青蒿素、胆固醇、吗啡、马钱子碱…？ 105 Typical Mass Spectrum of Aspirin Aspirin 120 m/z-for singly charged ion this is the mass OH OAc O C9H8O4 Exact Mass: 180.04 1H-NMR of Aspirin 2019/10/31 Thursday 13C-NMR of Cholesterol
河北医科大学药学院 1H-NMR of Taxol®（紫杉醇 13 C NMR of Taxol@(紫杉醇@) 女 有多少C?郑装要型1 有多少日？那委表型？湘互之间的关系们 H-NMR 奎宁 0? 1 山 清清得测什么修名？位道？里分？为什么服分1额分高度？和什么相类？ Is this already known or not?? Lu 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 4 Taxol® (紫杉醇®) 1H-NMR of 有多少H？那些类型？相互之间的关系？ 13C NMR of 有多少C？那些类型？ 青蒿素13C-NMR 看看得到什么信息？位置？裂分？为什么裂分？积分高度？和什么相关？ 1H-NMR 奎宁 lsolated in 1820 Structure in 1907 Is this already known or not?? 3 2 4 1 O O CH3 13 12 11 5 9 10 6 7 8 H3C 15 O CH3 14 H H H H H
河北医科大学药学院 BIN-IMTM MS,NMR,X-Ray与结构鉴定 化合物的结构鉴定重要吗？ Whv? 有多少科学家因天然产物的结构研究获得诺贝尔奖； Before 1950s,structure studies were life-long NP winning activi 茶是品、上 天然产物化学结构研究与诺贝尔化学奖修雪 天然产物结构研究与诺贝尔奖 Forensic NMR Spectroscopy Just a beginning of a promising partnership 核磁共振波谱法 Nuclear Magnetic Resonance Spectroscopy ■■ The wwal flow of forensic analyses 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 5 1' 2' 3' 4' O CH3 9 10 8 5 7 6 2 3 O 1 4 OH O O G4 G5 O G1 G2 G3 HO HO HO G6 OH 化合物的结构鉴定重要吗？ Why？ 有多少科学家因天然产物的结构研究获得诺贝尔奖？ Robert Robinson 吗啡、马钱子碱 James Dewey Watson DNA Dorothy Hodgkin 青霉素、维生素B12 R. B. Woodward 河豚毒素、土霉素 Before 1950s, structure studies were life-long NP winning activities MS, NMR, X-Ray与结构鉴定 天然产物结构研究与诺贝尔奖 Emil Fischer (1852-1919) 1902NP Adof von Baeyer (1835-1917) 1905 NP R. M.Willstratter (1872-1942) 1915 NP H. Wieland (1877-1957)1927 NP A. R. Windaus (1876-1959)1928 NP Hans Fischer (1881-1945)1930NP W. N. Hawoth (1883-1950)1937 NP Paul Karrer (1889-1971)1937 Richard Kuhn (1900-1967)1938 Leopold Ruzica (1887-1976)1939 NP A. Butenandt (1903-1995)39 NP 因阐明糖和嘌呤(purine)的结构而获奖 因阐明靛蓝(indigo)的结构而获奖 因研究植物色素包括叶绿素(chlorophy)的结构而获奖 因阐明胆酸(bile acid)等甾体化合物的结构而获奖 因在甾体化合物结构鉴定及阐明甾体化合物和维生素D结构关系方面的工作而获奖 因在血红素和叶绿素结构研究方面的工作而获奖 因在维生素C结构阐明和糖的Haworth投影方面的工作而获奖 因在维生素A和B2结构研究方面的工作而获奖 因在类胡萝卜素和维生素方面的工作而获奖 因在胰岛素发现和结构鉴定方面的工作而获奖， 因在核酸结构测定方面的工作而二次获奖 因在维生素B12、青霉素和胰岛素结构鉴定方面的工作而获奖 因在众多化合物的结构鉴定和合成方面的工作而获奖 因在肌红蛋白(myoglobin)和血色素(haemoglobin)方面的工作而获奖 因在甾体激素、信息素和萜类化合物以及古老 的香水成分灵猫酮(civetone)的结构而获奖 因在马钱子碱、花青素和吗啡等生物碱的结构鉴定方面的工作而获奖 Emil Fischer (1852-1919) Adolf von Baeyer(1835-1917) Richard M. Willstätter(1872-1942) Heinrich Wieland (1877-1957) Adolf R. Windaus (1876-1959) Hans Fischer (1881-1945) Norman Haworth (1883-1950) Paul Karrer (1889-1971) Richard Kuhn (1900-1967) Adolf F. J. Butenandt (1903-1995) Leopold Ruzicka (1887-1976) Robert Robinson (1886-1975) Frederick Sanger (1918-2013) Max Perutz (1914-2002) John Kendrew (1917-1997) Dorothy Hodgkin (1910-1994) Robert B. Woodward (1917-1979) 1938 1902 1930 1939 1962 1927 1937 1928 1915 1905 天然产物化学结构研究与诺贝尔化学奖 1947 1958 1980 1964 1965 Forensic NMR Spectroscopy Just a beginning of a promising partnership NMR : highlighting the high reproducibility, the non-destructive and non-selective characteristics, and the ease of sample preparation. The usual flow of forensic analyses 核磁共振波谱法 Nuclear Magnetic Resonance Spectroscopy
河北医科大学药学院 核磁共振波谱法 Nuclear Magnetic Resonance 址遥婚展振NR)被暴为有数插的园故，它使 者机新的基和地扬入了一个金的。 核瑞共兼波谱(NMR spect 械雅故是原子枯自装产生的雅错 rum)主 是Nuclear Magnetic Resonance Speet NR)是：电（长约16一1 美星精结这造行的（满夏的）满之之 核磁共振波谱法 Nuclear Magnetic Resonance (Nuclear magnetic resonancel Nuclear Magnetic Resonance The problem the we want to solve by NMR 子长什么样？ What we“rea山y”se What we w速nto“se NMR 倒山 天然药物化学教研室史清文教授 6
河北医科大学药学院 天然药物化学教研室 史清文教授 6 120 核磁共振波谱法 核磁共振（Nuclear Magnetic Resonance，NMR）： 在外加磁场作用下，某些原子核能产生核自选能级分 裂，当用一定频率的射频照射分子时。可引起原子核自旋 能级的跃迁，吸收一定频率的射频，即产生核磁共振。 核磁共振波谱（NMR spectrum）： 以核磁共振信号强度对照射频率（或磁场强度）作图， 即为核磁共振波谱。 核磁共振波谱法（NMR spectroscopy）： 利用核磁共振波谱进行结构（构型和构象）测定、定 性及定量分析的方法。 核磁场共振(NMR)被誉为有机物的指纹，它使 有机物的鉴定和结构测定进入了一个全新的阶段。 核磁共振谱(Nuclear Magnetic Resonance Spectroscopy， NMR)是指：低能电磁波（波长约106—109μm)与暴露在磁 场中的磁性核相互作用，使其在外磁场中发生能级的共振跃 迁而产生吸收信号，称为核磁共振谱。 核自旋实际上已成为科学家探讨物质世界的“探针”。 Nuclear Magnetic Resonance 121 核磁就是原子核自旋产生的磁场 核磁共振波谱法 (Nuclear Magnetic Resonance) NMR是一种观察分子结构 中原子核动态的一种技术，借 由分析原子核自旋特性，进而 判断分子结构。 Nuclear Magnetic Resonance 桥与风发生共振而倒塌。NMR是核与磁发生共振—如同 拉小提琴时琴弓与琴弦的共振一样 Tacoma Narrows Bridge (1940) Nuclear Magnetic Resonance The free induction decay (FID) and Fourier transformation to generate MR images or MR spectra The problem the we want to solve by NMR What we “really” see What we want to “see” 分子长什么样？ NMR provides scientists with an elegant and precise way of determining chemical structure
河北医科大学药学院 核磁共振波谱 NMR Spectrum 乙摩CH,CH,OH 乙尊CH,CH,OH cH中三个1 个 NMR Spectrum Strategy of Structure Elucidation {品一 ID NMR D NMR X-Crystallograply:Cr Who Discovered NMR? "The man who invented the 20 Century How was NMR discovered? A Bit of History ■■ Nb1山(9广套天水，”意直之父”种断拉 ade the 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 7 核磁共振波谱 核磁共振谱- -是吸收率 (纵坐标)对 化学位移(横 坐标)的关系 曲线。 乙醇中三个核磁共振吸收谱 126 乙醇 CH3CH2OH 乙醇 CH3CH2OH NMR Spectrum Strategy of Structure Elucidation 1H-NMR 13C-NMR NOE DEPT 1H-1H COSY H-C-C-H, H-C-H HMQC H-C HMBC H-C-C, H-C-C-C, H-C-C=C-C NOESY (ROESY) H-H conformation INADEQUATE C-C 1D NMR 2D NMR UV IR HR-MS 共轭体系,顺反构型 官能团 C=O, C=C 分子式:双键,环数,杂原子 H的个数和相互关系 C的个数和SP, SP2, SP3 H的空间关系 C的种类C, CH, CH2, CH3 X-Crystallography: Crystalline sample 129 Who Discovered NMR? How was NMR discovered? A Bit of History "The man who invented the 20 Century" His discovery of the rotating magnetic field in 1882 made the operation of the alternating current (AC) motor possible, which is instrumental in NMR and MRI design. 磁感应强度的单位是特斯拉，简称特，符号是T Nikola Tesla (1856-1943)旷世天才,“電氣時代之父”特斯拉
河北医科大学药学院 Tesla was a Scientist,Edison was more of a Business Who Discovered NMR? Zeeman Spliting in 189 ,国中单一景钱格销先泽-下限支高T三含 Who Discovered NMR? Who Discovered NMR? Larmor Relationship in 1897 Thus NMR is. that the angular frequency of pree on of th 核磁共振研究始于Otto Ster 核磁共振研究始于Otto Stern 被想热额研克无联种悬（0)外会子来疾量开地岭 天然药物化学教研室史清文教授
河北医科大学药学院 天然药物化学教研室 史清文教授 8 "Tesla tried once and figured it out. Edison tried 1000 times and figured it out on the 1001st time." After promising $50,000 to Tesla if He would improve DC motors, Edison reneged on his word, dismissing the promise as "American humor." Tesla was a Scientist, Edison was more of a Businessman Who Discovered NMR? 自旋数不为零的原子核的能级在磁场中也会产生劈裂，这就是核 磁共振的物理基础。 在磁场中单一谱线的钠光谱一下裂变成了三条 Zeeman Splitting in 1896 Pieter Zeeman 1865-1943, 1902 NP Who Discovered NMR? Larmor Relationship in 1897 Sir Joseph Larmor 1857-1946 Sir Joseph Larmor developed the equation that the angular frequency of precession of the nuclear spins being proportional to the strength of the magnetic field-Larmor Relationship. Which explain the curious Zeeman Splitting. Who Discovered NMR? Otto Stern (1888-1969), 美国核物理学家 发现了质子磁矩 1922年, 1943年的诺贝尔物理学奖 苏黎世联邦理工学院和NMR颇有渊源-Bloch， Ernst，Wüthrich及制造商Bruker 核磁共振研究始于Otto Stern Otto Stern (1888-1969) was a German-American physicist and Nobel laureate in physics. He was the second most nominated person for a Nobel Prize with 82 nominations in the years 1925–1945 (most times nominated is Arnold Sommerfeld 索末菲with 84 nominations), ultimately winning in 1943. Otto Stern发现了质子磁矩，获得了1943年的诺贝尔物理学奖 核磁共振研究是从斯特恩（Otto Stern）的分子束实验开始的 核磁共振研究始于Otto Stern Otto Stern发展了核物理研究中的分子束方法并发现了质子磁矩，获得 了1943年的诺贝尔物理学奖 核磁共振研究是从斯特恩（Otto Stern）的分子束实验开始的 斯特恩－盖拉赫实验 Otto Stern 1888-1969 爱因斯坦的助手
河北医科大学药学院 Who Discovered NMR? Isidor Isaac Rabi,Man of the Century sidor Isa Rabi (1898. ho won the No in Physics in1944“f 193器牛发明了精清测定了一垂核限A性的才法 Isidor Isaac Rabi:walking the path of God Isidor Isaac Rabi- 从酰太黄成童中走端夏尔美的领奖合 A Pioneer In Atomic Physics 手伦比亚物系打成规一流的物理 RABI Related Nobel Prize Russell and Sigurd Varian and NMR d ies in 2010. 天然药物化学教研室史清文教授 9
河北医科大学药学院 天然药物化学教研室 史清文教授 9 Who Discovered NMR? 138 Isidor Isaac Rabi (1898-1988) was an American physicist who won the Nobel Prize in Physics in 1944 “For his resonance method for recording the magnetic properties of atomic nuclei” ， which is used in magnetic resonance imaging. 1938年发明了精确测定了一些核磁属性的方法 Harold C. Urey (1893-1981) 1934 Nobel Prize Rabi refined Stern technique to observe the effect from the nuclear magnetic moment in 1938， 1944 NP The 1927 Solvay Conference brought together the world's leading physicists, including Niels Bohr, Albert Einstein, and Max Planck et al 17 NP laureates. The Presidential Science Advisory Committee meets with U.S. President Eisenhower in the mid-50 Isidor Isaac Rabi，Man of the Century Bill Moyers presents a profile and interview of I.I. Rabi, winner of the 1944 Nobel Prize in physics and an early developer of radar for use in World War II. Rabi also participated in the Manhattan Project and was present at the detonation of the first atomic bomb — an event which transformed him into an advocate for restraint in the use of nuclear power. Rabi (1944 NP) with fellow Nobel Prize laureates (standing left to right) Val Fitch (1980), James Cronin(1980 NP), Samuel Chao Chung Ting (1976 NP) and Chen-Ning Yang (1957 NP seated, left) Isidor Isaac Rabi: walking the path of God Niels Bohr (1922) with James Franck(1925), Albert Einstein,(1921) and Isidor Isaac Rabi (1944) 从犹太贫民窟中走诺贝尔奖的领奖台 Isidor Isaac Rabi—— A Pioneer In Atomic Physics Rabi was one of the founders of the Brookhaven National Laboratory also built up the world's finest physics departments at Columbia University Brookhaven National Laboratory Columbia University 把哥伦比亚物理系打造成超一流的物理王国 1952年诺贝尔物理学奖：布洛赫(Felix Bloch ) & 珀赛尔 (Edward Purcell)因发展了核磁精密测量的新方法及由此所作的发现——核磁共振。 Felix Bloch ETH Zürich Stanford University 海森堡、Rabi的学生 Edward Purcell Harvard University Related Nobel Prize " Developmented of new ways and methods for nuclear magnetic precision measurements“ 精确测定物质的核磁 属性,核磁共振开始真 正进入实用技术领域 The A-60 was the workhorse NMR instrument for decades as it allowed chemists to determine molecular structures easily and quickly and to follow the progress of chemical reactions. Russell Varian 1898–1959 Sigurd Varian (1901–1961) Russell and Sigurd Varian and NMR In 1948 two brothers, Russell and Sigurd Varian, armed with $22,000, founded Varian Associates to manufacture scientific instruments. Varian used its Stanford connection to develop NMR instruments. In 1953 Varian HR-30， 1960 A-60. Varian, Inc., was acquired by Agilent Technologies in 2010
河北医科大学药学院 Varian Co.was established twelye vears sartier on April 20.1948 Bruker Co.founded in 1960 in Karlsruh Why the Name Bruker The Founding of Bruker-Physik AG rooorteg BR心民R Zurich's Contributions to Bruker Why Do We Need NMR? materials,and is widely used in physics and chemistry. NMR 20th century. 天然药物化学教研室史清文教授 10
河北医科大学药学院 天然药物化学教研室 史清文教授 10 Varian A-60 spectrometer(1961) The first 40 MHz NMR spectrometer (Varian, 1953) The first 90 MHz FTNMR spectrometer (Bruker, 1967) Varian Co. was established twelve years earlier on April 20, 1948 Prof. Günther Laukien (1923-1997) and his first pulse NMR spectrometer Bruker Co. founded in 1960 in Karlsruh Why the Name Bruker ? Bruker Physik AG’s first operational facility in Hardtstraße, Karlsruhe, Germany in September 7th, 1960. The Founding of Bruker-Physik AG Frank H. Laukien (born 1959/1960) chairman and CEO of Bruker since 1991. Hans Primas (1928-2014) Zurich's Contributions to Bruker Vladimir Prelog (1906-1998， 1975 NP) Why Do We Need NMR? NMR provides scientists with an elegant and precise way of determining chemical structure and properties of materials, and is widely used in physics and chemistry. NMR also is the basis of magnetic resonance imaging (MRI), one of the most important medical advances of the 20th century