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

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Presentation on theme: "Using 2D NMR Strategy Organic Structure Analysis, Crews, Rodriguez and Jaspars."— Presentation transcript:

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

2 THE PROCESS OF STRUCTURE ELUCIDATION

3 Organic Structure Analysis, Crews, Rodriguez and Jaspars

4 DEREPLICATION: The process of rapidly discovering whether a compound has previously been reported.

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

6 Based on 13 C- 13 C 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) STRATEGY BASED ON C-C CONNECTIVITY PROBLEMS Organic Structure Analysis, Crews, Rodriguez and Jaspars

7 STRATEGY BASED ON C-C CONNECTIVITY EXAMPLE A-B A-D D-C C-E F-B

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

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

10 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 A K B I F E ML C D N H G OJ

11 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)

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

13 Organic Structure Analysis, Crews, Rodriguez and Jaspars STRATEGY BASED ON C-H CONNECTIVITY – DEPT DATA CH CH 2 CH 3 Label from left to right in capitals ABCDEF

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

15 Organic Structure Analysis, Crews, Rodriguez and Jaspars STRATEGY BASED ON C-H CONNECTIVITY – HSQC DATA ATOM C (ppm) DEPT H (ppm) A131CH5.5 B124CH5.2 C68CH4.0 D42CH 2 3.0 2.5 E23CH 3 1.5 F17CH 3 1.2

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

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

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

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

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

21 Organic Structure Analysis, Crews, Rodriguez and Jaspars STRATEGY BASED ON C-H CONNECTIVITY – COSY DATA ATOM C (ppm) DEPT H (ppm)COSY (H H) A131CH5.5b, c, d/d, f B124CH5.2a, d/d, f C68CH4.0a, d/d, e D42CH 2 3.0 2.5 a, b, c, d, e E23CH 3 1.5c, d/d F17CH 3 1.2a, b

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

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

24 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 ?

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

26 Organic Structure Analysis, Crews, Rodriguez and Jaspars STRATEGY BASED ON C-H CONNECTIVITY – HMBC DATA ATOM C (ppm) DEPT H (ppm)COSY (H H)HMBC (C H) A131CH5.5b, c, d/d, fb, c, d, f B124CH5.2a, d/d, fa, d, f C68CH4.0a, d/d, ea, d, e D42CH 2 3.0 2.5 a, b, c, d, ea, b, c, e E23CH 3 1.5c, d/dc, d F17CH 3 1.2a, b

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

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

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

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

31 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

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

33 Organic Structure Analysis, Crews, Rodriguez and Jaspars COMPARISON OF C-H AND C-C STRATEGIES C-C StrategyC-H Strategy ExperimentTimeExperimentTime 1 H NMR< 1 min 1 H NMR1 min 13 C NMR< 1 min 13 C NMR1 – 4 h DEPT 135< 1 minDEPT 1351 – 4 h HSQC nt=1, ni=25615 minHSQC nt=4, ni=2561 h HMBC nt=1, ni=51215 minHMBC nt=4, ni=5121 h NOESY nt=4, ni=2561 hNOESY nt=4, ni=2561 h INADEQUATE24 hCOSY nt=1, ni=25615 min Total time~26 h6 – 12 h Sample conc6 M10 – 100 mM

34 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. Atomd C (ppm)d H (ppm) 1 H - 1 H COSY (3 bond only) 1 H 13 C Long range (2 - 3 bonds) A218 s--A-b, A-c, A-d, A-e B47 t1.8 ddb-dB-c, B-d, B-e, B-f C38 t2.3 mc-eC-b, C-d, C-e D32 d1.5 md-b, d-e, d-fD-b, D-c, D-e, D-f E31 t2.2 me-c, e-dE-b, E-c, E-d, E-f F20 q1.1 df-dF-b, F-d, F-e

35 Organic Structure Analysis, Crews, Rodriguez and Jaspars 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 1 H NMR at 11.6 ppm (bs). Atomd C (ppm)d H (ppm) 1 H - 1 H COSY (3 bond only) 1 H 13 C Long range (2 - 3 bonds) A178 s--A-d, A-b B136 d5.7 mb-c, b-dB-d, B-c, B-e C118 d5.5 mc-b, c-eC-b, C-d, C-e, C-f D38 t3.0 dd-bD-b, D-c E25 t2.1 me-c, e-fE-b, E-c, E-f F13 q1.0 tf-eF-c, F-e

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

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

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

39 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

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


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