ENDO EXO STORY.......cis-norborene-5,6-endo-dicarboxylic anhydride

You will react cyclopentadiene with maleic anhydride to form the Diels-Alder product below. This Diels-Alder reaction produces almost solely the endo isomer upon reaction at ambient temperature.




The preference for endo–stereochemistry is “observed” in most Diels-Alder reactions. The fact that the more hindered endo product is formed puzzled scientists until Woodward, Hoffmann, and Fukui used molecular orbital theory to explain that overlap of the p orbitals on the substituents on the dienophile with p orbitals on the diene is favorable, helping to bring the two molecules together.

Hoffmann and Fukui shared the 1981 Nobel Prize in chemistry for their molecular orbital explanation of this and other organic reactions. In the illustration below, notice the favorable overlap (matching light or dark lobes) of the diene and the substituent on the dienophile in the formation of the endo product:






Oftentimes, even though the endo product is formed initially, an exo isomer will be isolated from a Diels-Alder reaction. This occurs because the exo isomer, having less steric strain than the Endo , is more stable, and because the Diels-Alder reaction is often reversible under the reaction conditions. In a reversible reaction, the product is formed, reverts to starting material, and forms again many times before being isolated.

The more stable the product, the less likely it will be to revert to the starting material. The isolation of an exo product from a Diels-Alder reaction is an example of an important concept: thermodynamic vs kinetic control of product composition. The first formed product in a reaction is called the kinetic product. If the reaction is not reversible under the conditions used, the kinetic product will be isolated. However, if the first formed product is not the most stable product and the reaction is reversible under the conditions used, then the most stable product, called the thermodynamic product, will often be isolated.



The NMR spectrum of cis-5-norbornene-2,3-endo-dicarboxylic anhydride is given below:





Cis-Norbornene-5,6-endo-dicarboxylic anhydride 
Cyclopentadiene was previously prepared through the cracking of dicyclopentadiene and kept under cold conditions.  In a 25 mL Erlenmeyer flask, maleic anhydride (1.02 g, 10.4 mmol) and ethyl acetate (4.0 mL) were combined, swirled, and slightly heated until completely dissolved.  To the mixture, ligroin (4 mL) was added and mixed thoroughly until dissolved.  Finally, cyclopentadiene (1 mL, 11.9 mmol) was added to the mixture and mixed extensively.  The reaction was cooled to room temperature and placed into an ice bath until crystallized.  The crystals were isolated through filtration in a Hirsch funnel.  The product had the following properties: 0.47 g (27.6% yield) mp: 163-164 °C (lit: 164 °C).  ¹H NMR (CDCl₃, 300 MHz) δ: 6.30 (dd, J=1.8 Hz, 2H), 3.57 (dd, J=7.0 Hz, 2H), 3.45 (m, 2H), 1.78 (dt, J=9.0,1.8 Hz, 1H), 1.59 (m, 1H) ppm.  ¹³C NMR (CDCl₃, 75Hz) δ: 171.3, 135.5, 52.7, 47.1, 46.1 ppm.  IR 2982 (m), 1840 (s), 1767 (s), 1089 (m) cm^-1.

Reaction Mechanism The scheme below depicts the concerted mechanism of the Diels-Alder reaction of cyclopentadiene and maleic anhydride to formcis-Norbornene-5,6-endo-dicarboxylic anhydride.

Results and Discussion 
When combining the reagents, a cloudy mixture was produced and problems arose in the attempt to completely dissolve the mixture.  After heating for about 10 minutes and magnetically stirring, tiny solids still remained. The undissolved solids were removed form the hot solution by filtration and once they cooled, white crystals began to form. Regarding the specific reaction between cyclopentadiene and maleic anhydride, the endo isomer, the kinetic product, was formed because the experiment was directed under mild conditions.   The exo isomer is the thermodynamic product because it is more stable.3

A total of 0.47 g of the product was collected; a yield of 27.6%. The melting point was in the range of 163-164 °C which indicates the absence of impurities because the known melting point of the product is 164 °C.

The ¹H NMR spectrum of the product revealed a peak in the alkene range at 6.30 ppm, H-2 and H-3 (Figure 1).  In addition, it exhibited two peaks at 3.57 and 3.45 ppm because of the proximity of H-1, H-4, H-5, and H-6 to an electronegative atom, oxygen.  Finally, two peaks at 1.78 and 1.59 ppm corresponded to the sp³ hydrogens, Hb and Ha, respectively.  Impurities that appeared included ethyl acetate at 4.03, 2.03, and 1.31 ppm as well as acetone at 2.16 ppm.

Regarding the ¹³C NMR, a peak appeared at 171.3 ppm, accounting for the presence of two carbonyl functional groups, represented by C-7 and C-8 in Figure 1.  The alkene carbons, C-2 and C-3, exhibited a peak at 135.5 ppm, while the sp³ carbons close to oxygen, C-5 and C-6, displayed a peak at 52.7 ppm.  Finally, peaks at 46.1 and 47.1 ppm accounted for the sp³ carbons, C-1 and C-4, and C-9.  Impurities of ethyl acetate appeared at 46.6, 25.8, and 21.0 ppm accompanied with acetone at 30.9 ppm.

The IR spectrum revealed a peak at 2982 cm^-1 representing the C-H stretches.  A peak at 1840 cm^-1 accounted for the carbonyl functional group, while a peak at 1767 cm^-1 accounted for the alkene bond.  A peak at 1089 cm^-1 represented the carbon-oxygen functional group.

In order to distinguish between the two possible isomers, properties such as melting point and spectroscopy data were analyzed.  The exo product possessed a melting point in the range of 140-145 °C which is significantly lower than the endo product.  The observed melting point in this experiment supported the production of the endo isomer. 
The ¹H NMR spectum exhibited a doublet of doublets at 3.57 ppm for the endo isomer.  The exo isomer would possess a triplet around 3.50 ppm due to the difference in dihedral angle between the hydrogen molecules of H-1 and H-4, and H-5 and H-6 (Figure 1).  A peak at 3.00 ppm would appear in the exo isomer spectra as opposed to a peak at 3.60 ppm as shown in the observed endo product.³ This is because of the interaction and coupling with the H-5 and H-6, as displayed in Figure 1.

Conclusion 
Through the Diels-Alder reaction, 27.6% yield of cis-Norbornene-5,6-endo-dicarboxylic anhydride was produced. The distinction of the presence of the endo isomer was proven by analyzing physical properties of both possible isomers.

Martin, J.; Hill, R.; Chem Rev, 1961, 61, 537-562.

2 Pavia, L; Lampman, G; Kriz, G; Engel, R. A Small Scale Approach to Organic Laboratory   Techniques, 2011, 400-409.

3 Myers, K.; Rosark, J. Diels-Alder Synthesis, 2004, 259-265.
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The oxidation of the alcohols mixture with sodium hypochlorite in pure ethanoic acid produces only 3-a-chloro-3-exo-decanoyl-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-one.

3-chloro-3-decanoyl-1,7,7 trimethylbicyclo[2.2.1]heptan-2-one.



The oxidation of the alcohols mixture with sodium hypochlorite in pure ethanoic acid produces only 3-a-chloro-3-exo-decanoyl-1,7,7-trimethyl bicyclo[2.2.1]heptan-2-one.

Oxidation with NaClO/ CH₃CO₂H

0.16 g (0.52 mmol) of the alcohols mixture was stirred for 12 h at 50° C with 1M (2.5 mL) aqueous solution of sodium hypochlorite and pure ethanoic acid (4mL). The products were extracted with ethyl ether (3 x 40 mL) and the organic phase was washed with distilled water and dried with anhydrous sodium sulfate. The organic fractions obtained were concentrated and the products were purified in a liquid column chromatography.

Under the reaction conditions studied the oxidation of the alcohols mixture with hypochlorite in pure ethanoic acid gives only product (8).

Compound (8) is a colorless liquid and the IR spectrum shows two bands at n 1754,9 cm^-1 and n 1722,7 cm^-1 for the carbonyl groups stretching of this compound. 

The ¹H-NMR spectrum (Figure 6) and the ¹H-¹H-COSY shows two groups of signals for the H5 methylenes; at d 3.15 (1H, ddd, J= 7.8, 7.6, 3.9 Hz) for H₅-endo and the signal for H₅-exo at d 2.51 (1Hb, ddd, J= 7.8, 7.6, 6.5 Hz). 

The signals d 198.8 and d 212.0 in the ¹³C-NMR spectrum assigned to the two carbonyls support structure (8). Moreover the DEPT (135) experiment shows a new chemical shift at d 72.2, while the signal at d 75.77 for the methine (C3) disappears. 

 ¹³C-NMR experiments help to the signals assignment for all of the carbons of the bicyclic ring and a part of the lateral aliphatic chain. Thus C2 at d 36.9 show coupling with the two signals for the diasterotopic hydrogens which signals appear at d 3.15 and 2.51. 

Besides the protons of the syn methyl group at C9 are shielded (d 0.62), because of the proximity to exo carbonylic group at C1'. The signals for the protons at C5 and C6 are very close, H5a and H6a are at d 2.03 and H5b and H6b at d 1.73. 

The incorporation of a chlorine atom on the alpha face was postulated due to both the shield induced on protons of one methyl at C7 and the chemical shift of H5a and H6ato lower field due to the fact that they are on the same face with respect to the chlorine.

Figure 6. 1H-NMR of 3-chloro-3-decanoyl-1,7,7 trimethylbicyclo[2.2.1]heptan-2-one.

A probable explanation for the formation of compound (8) lies on the fact that an acidic solution of sodium hypochlorite has a certain concentration of Cl₂ at the thermodynamic equilibrium (figure 8). Chlorine can add to the double bond of the enol structure of the oxidation products. 

It is expected that the attack by the chlorine is on the most exposed alpha face of the enol structure, producing the intermediate showed in Figure 8. This intermediate can quickly rearrange to the more stable compound (8).

4H⁺(ac) + 2 Cl ^- + 2 ClO ^-(ac) = 2 Cl₂(g) + 2 H₂O (l)

Figure 8

3-chloro-3-decanoyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (8)

¹H-NMR : 6.36 (1H, dd, J= 7.76, 7.67 Hz), 2.16-2.08 (2H, m, 1.73-1.60 (2H, m), 1.37 (2H, m, 1.26 (8CH2, s), 0.96 (6H,s), 0.90 (t, J= 8 Hz), 0.78 (s, 3H). 

¹³C-NMR: 207.1, 142.7, 130.5, 57.7, 47.5, 45.9, 31.8, 30.3, 29.3, 28.7, 28.6(2CH2), 26.4, 22.5, 20.4, 18.2, 14.0, 9.1. 

MS: 186 (base peak), 312, 297,155, 83, 55. 

Anal. Calcd. for C₂₀H₃₃ClO₂; C, 70.46; H, 9.76. found. C 70.42; H, 9.77.

Aldolization procedure

Lithium diisopropylamide (LDA) was prepared from diisopropylamine (12.4 mL, 92.1 mmol) with n-butyllithium (51.4 mL of a 1.6 M solution in hexane, 82.24 mmol) in 30.0 mL of dry THF at -78°C. The solution was stirred for 30 min. and then a solution of camphor (12.0 g, 78.9 mmol) in dry THF (52.0 mL) was added dropwise. After the addition, the solution was stirred for 2.5 h, treated with freshly distilled aldehyde (79.0 mmol) and stirred for an additional 20 min. the reaction was quenched at -78°C with a saturated aqueous solution of NH₄Cl (200 mL). The cold bath was then removed and the mixture extracted with ethyl ether (3 x 100 mL). The combined organic layers were washed with an aqueous NaCl solution, dried over Na₂SO₄, and concentrated in vacuum to afford the adduct mixture. The products were purified by liquid column chromatography and the adducts ratio obtained was quantified by ¹H-NMR.

3-exo-1-hydroxydecyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (4)

¹H-NMR: 4.15(1H, s), 3.90(1H, m), 2.04(1H, m), 1.97-1.91 (2H, m), 1.76-1.26 (26H, s), 0.94 (3H, s), 0.91 (3H, s), 0.88(3H, s), 0.85 (3H, s). 

¹³C-NMR: 223.6, 73.30, 59.56, 57.84, 46.01, 36.17, 31.90, 29.61-29.31 (7CH₂), 24.76, 22.67, 21.67, 20.44, 14.05, 9.04. 

Anal. Calcd. for C₂₀H₃₆O₂ ; C, 77.87; H, 11.76. found. C, 77.90; H, 11, 79.

3-endo-1-hydroxydecyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-one. (5)

¹H-NMR: 3.92(1H, s), 3.74(1H, m), 2.34 (1H, m), 2.10 (1H, s), 1.77-1.69 (2H, m), 1.47-1.39 (4H, m), 1.27(8CH2, s), 0.98(3H, s), 0.92(3H, s), 0.88(3H,s), 0.85(3H, s). 

¹³C-NMR: 223.90, 73.23, 70.89, 65.77, 59.38, 57.76, 54.88, 46.84, 45.86, 36.05, 34.82, 31.52, 29.56, 29.24, 24.67, 20.81, 19.54, 18.53, 15.20, 9.24

INTERPRETATIONS WILL BE UPDATED...............

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EXO ENDO ,,,UNDERSTAND STEREOCHEMICAL CONSIDERATIONS USING NMR

Endo-exo isomerism is a special type of isomerism found in organic compounds with a substituent on a bridged ring system. The prefix endo is reserved for the isomer with the substituent located closest, or "syn," to the longest bridge. The prefix exo is reserved for the isomer with the substituent located farthest, or "anti", to the longest bridge. Here "longest" and "shortest" refer to the number of atoms that comprise the bridge. This type of molecular geometry is found in norbornane systems such as dicyclopentadiene.

The terms endo and exo are used in a similar sense in discussions of the stereoselectivity in Diels–Alder reactions.

Descriptors of the relative orientation of groups attached to non-bridgehead atoms in a bicyclo[x.y.z]alkane (x ≥ y > z > 0).

If the group is orientated towards the highest numbered bridge (z bridge, e.g. C-7 in example below) it is given the description exo; if it is orientated away from the highest numbered bridge it is given the description endo. If the group is attached to the highest numbered bridge and is orientated towards the lowest numbered bridge (x bridge, e.g. C-2 in example below) it is given the description syn; if the group is orientated away from the lowest numbered bridge it is given the description anti.

• 
  

Cyclopentanes. 

The conformational analysis of substituted cyclopentanes is much more complicated than that of cyclohexanes. 

The energy differences between various envelope and twist conformations in five-membered rings are generally small, and there are as many as ten different envelope and ten different twist conformations, and each conformation has multiple dihedral angle relationships. 

Several of the 20 possible conformations may be populated in an individual structure. Thus the vicinal couplings in 5-membered rings are highly variable. 

For cyclopentanes in envelope conformations J_cis > J_trans in the flat part part of the envelope, whereas in twist conformations the tendency is for J_trans > J_cis. 

In general, no firm assignments of stereochemistry can be made using the size of couplings alone unless a specific substitution pattern or heterocyclic system has been carefully investigated, or if substitution patterns allow prediction of the conformation.

  

  

Inspection of the double Karplus curves indicates a significant difference between the typical behavior of adjacent CH₂ groups in cyclohexanes and cyclopentanes. 

In a chair cyclohexane only one of the four vicinal couplings can be large (> 7 Hz), whereas in a cyclopentane it is common for 2 or even 3 of the ³J couplings to be large.

  

In most cyclopentanes, the C-C-C-C dihedral angles are significantly smaller than the 60° found in cyclohexanes. Cis protons will tend to have H-C-C-H dihedral angles close to 0°, andtrans near 120°. 

The cis couplings (8-10 Hz) are usually larger than trans (2-9 Hz). 

However the Karplus curves for cyclopentane have a region where the cis and trans lines cross (Figure above, at ca 20° dihedral angle), so there are cases where cis and trans couplings are identical (see below, where the allylic proton is a quartet of doublets, arising from accidental equivalence of three vicinal couplings), as well as a smaller region where J_trans > J_cis .

  

  

If the ring puckering is strong enough, then J_trans > J_cis. In bicyclo[2.2.1]heptanes the endo-endo and exo-exo ³J are always greater than endo-exo couplings. 

Thus stereochemical relations among vicinal protons in 5-membered rings cannot be reliably determined by simply measuring coupling constants, except in cases where the substitution pattern of the specific ring system has been carefully investigated. 

For example, in the benzodihydrofurans below, changing the size of the substituent R causes a reversal in the size of J_cis and J_trans.

  



READ'
http://www.unk.edu/uploadedFiles/academics/gradstudies/ssrp/Myers.pdf

AND
http://pubs.acs.org/doi/abs/10.1021/ed068p426?journalCode=jceda8

The ENDO product is the one where the "outside" groups on the diene are on the SAME side of the 6-membered ring as the electron withdrawing group (EWG). The EXO product is the one where the "outside" groups are on the OPPOSITE side of the ring as the 6-membered ring.
Note how the Endo and Exo products are related - they're diastereomers
Here's some examples.








OVERLAPS