Using 2D NMR Strategy Organic Structure Analysis, Crews, Rodriguez and Jaspars

THE PROCESS OF STRUCTURE ELUCIDATION Organic Structure Analysis, Crews, Rodriguez and Jaspars

Organic Structure Analysis, Crews, Rodriguez and Jaspars

DEREPLICATION: The process of rapidly discovering whether a compound has previously been reported. Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-C CONNECTIVITY Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-C CONNECTIVITY PROBLEMS Based on 13C-13C correlations – 1/10 000 chance Need large amounts of sample Sample must have high solubility Need long acquisition times (>24 h) Correlations across heteroatoms not possible – these must be determined using HMBC data Gives no information about C-H correlations – need to get HSQC data to assign protons BUT: If possible to use INADEQUATE, connectivity information is unambiguous (unlike HMBC) Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-C CONNECTIVITY EXAMPLE F-B C-E A-D D-C A-B Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-C CONNECTIVITY EXAMPLE F B A D C E Gives topology of molecule Chemical shift information gives: Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-C CONNECTIVITY REAL EXAMPLE G-O H-N I-J E-M E-L G-H C-N D-J D-G F-D A-K B-F E-C B-E D-C A-I A-B Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-C CONNECTIVITY REAL EXAMPLE Data: A-B, A-I, A-K, B-E, B-F, E-C, E-L, E-M, C-D, C-N, N-H, H-G, G-D, G-O, D-F, D-J, J-I O J I K A G D F B H C E N L M Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY & & HMBC data is ambiguous (2 or 3 bond correlations – impossible to tell which) Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – DEPT DATA Label from left to right in capitals A B C D E F Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HSQC DATA A B C D E F dC f e d’ diastereotopic protons d c b a label protons in lower case letters Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HSQC DATA ATOM dC (ppm) DEPT dH (ppm) A 131 CH 5.5 B 124 5.2 C 68 4.0 D 42 CH2 3.0 2.5 E 23 CH3 1.5 F 17 1.2 Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HSQC DATA Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HSQC DATA Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HSQC DATA Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HSQC DATA diastereotopic protons Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – COSY DATA b-f c-e a-d/d’ a-b And many more… Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – COSY DATA ATOM dC (ppm) DEPT dH (ppm) COSY (HH) A 131 CH 5.5 b, c, d/d’, f B 124 5.2 a, d/d’, f C 68 4.0 a, d/d’, e D 42 CH2 3.0 2.5 a, b, c, d, e E 23 CH3 1.5 c, d/d’ F 17 1.2 a, b Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – COSY DATA diagonal Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – COSY DATA Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – COSY DATA HSQC suggests diastereotopic protons: 3.08/2.44 ppm 1.86/2.07 ppm ? OK Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HMBC DATA D-c A-b B-a C-a And many more… Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HMBC DATA ATOM dC (ppm) DEPT dH (ppm) COSY (HH) HMBC (CH) A 131 CH 5.5 b, c, d/d’, f b, c, d, f B 124 5.2 a, d/d’, f a, d, f C 68 4.0 a, d/d’, e a, d, e D 42 CH2 3.0 2.5 a, b, c, d, e a, b, c, e E 23 CH3 1.5 c, d/d’ c, d F 17 1.2 a, b Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HMBC DATA Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HMBC DATA Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY – HMBC DATA Organic Structure Analysis, Crews, Rodriguez and Jaspars

Combinatorial explosion STRATEGY BASED ON C-H CONNECTIVITY RETROSPECTIVE CHECKING Combinatorial explosion Pieces: Possibilities: Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY RETROSPECTIVE CHECKING HMBC data (C-C-H & C-C-C-H) from C  H And similarly for COSY data Organic Structure Analysis, Crews, Rodriguez and Jaspars

PROSPECTIVE CHECKING Pieces: Organic Structure Analysis, Crews, Rodriguez and Jaspars

COMPARISON OF C-H AND C-C STRATEGIES C-C Strategy C-H Strategy Experiment Time 1H NMR < 1 min 1 min 13C NMR 1 – 4 h DEPT 135 HSQC nt=1, ni=256 15 min HSQC nt=4, ni=256 1 h HMBC nt=1, ni=512 HMBC nt=4, ni=512 NOESY nt=4, ni=256 INADEQUATE 24 h COSY nt=1, ni=256 Total time ~26 h 6 – 12 h Sample conc 6 M 10 – 100 mM Organic Structure Analysis, Crews, Rodriguez and Jaspars

EXERCISE 1. For a simple organic compound the mass spectrum shows a molecular ion at m/z 98. The following data has been obtained from various 1D and 2D NMR experiments. Using this information determine the structure of the molecule in question and rationalise the 2D NMR data given. Atom dC (ppm) dH (ppm) 1H - 1H COSY (3 bond only) 1H  13C Long range (2 - 3 bonds) A 218 s - A-b, A-c, A-d, A-e B 47 t 1.8 dd b-d B-c, B-d, B-e, B-f C 38 t 2.3 m c-e C-b, C-d, C-e D 32 d 1.5 m d-b, d-e, d-f D-b, D-c, D-e, D-f E 31 t 2.2 m e-c, e-d E-b, E-c, E-d, E-f F 20 q 1.1 d f-d F-b, F-d, F-e Organic Structure Analysis, Crews, Rodriguez and Jaspars

An additional peak is present in the 1H NMR at 11.6 ppm (bs). Atom EXERCISE 2. For a simple organic compound the mass spectrum shows a molecular ion at m/z 114. The following data has been obtained from various 1D and 2D NMR experiments. Using this information determine the structure of the molecule in question and rationalise the 2D NMR data given. An additional peak is present in the 1H NMR at 11.6 ppm (bs). Atom dC (ppm) dH (ppm) 1H - 1H COSY (3 bond only) 1H  13C Long range (2 - 3 bonds) A 178 s - A-d, A-b B 136 d 5.7 m b-c, b-d B-d, B-c, B-e C 118 d 5.5 m c-b, c-e C-b, C-d, C-e, C-f D 38 t 3.0 d d-b D-b, D-c E 25 t 2.1 m e-c, e-f E-b, E-c, E-f F 13 q 1.0 t f-e F-c, F-e Organic Structure Analysis, Crews, Rodriguez and Jaspars

SELECTIVE 1D - TOCSY 90o (selective) Spin-lock Preparation Mixing Detection J. Mag. Res. 1989, 85, 1-14. J. Mag. Res. 1989, 81, 186-190 Organic Structure Analysis, Crews, Rodriguez and Jaspars

SELECTIVE 1D – TOCSY SUBSPECTRA Organic Structure Analysis, Crews, Rodriguez and Jaspars

Mystery Compound: Eunicellin Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-C CONNECTIVITY REAL EXAMPLE Data: A-B, A-I, A-K, B-E, B-F, E-C, E-L, E-M, C-D, C-N, N-H, H-G, G-D, G-O, D-F, D-J, J-I Organic Structure Analysis, Crews, Rodriguez and Jaspars

STRATEGY BASED ON C-H CONNECTIVITY RETROSPECTIVE CHECKING Pieces: Possibilities: Organic Structure Analysis, Crews, Rodriguez and Jaspars