Chem 206D. A. Evans Useful LIterature Reviews a73 Problems of the Day Matthew D. Shair Wednesday, September 25, 2002 http://www.courses.fas.harvard.edu/~chem206/ Bucourt, R. (1973). “The Torsion Angle Concept in Conformational Analysis.” Top. Stereochem. 8: 159. Chemistry 206 Advanced Organic Chemistry Lecture Number 4 Acyclic Conformational Analysis-1 a73 Ethane, Propane, Butane & Pentane Conformations a73 Introduction to Allylic Strain a73 Reading Assignment for week A. Carey & Sundberg: Part A; Chapters 2 & 3 Glass, R. R., Ed. (1988). Conformational Analysis of Medium-Sized Ring Heterocycles. Weinheim, VCH. Juaristi, E. (1991). Introduction to Stereochemistry and Conformational Analysis. New York, Wiley. Juaristi, E., Ed. (1995). Conformational Behavior of Six-Membered Rings: Analysis,Dynamics and Stereochemical Effects. (Series: Methods in Stereochemical Analysis). Weinheim, Germany, VCH. Kleinpeter, E. (1997). “Conformational Analysis of Saturated Six-Membered Oxygen-Containing Heterocyclic Rings.” Adv. Heterocycl. Chem. 69: 217-69. Schweizer, W. B. (1994). Conformational Analysis. Structure Correlation, Vol 1 and 2. H. B. Burgi and J. D. Dunitz. Weinheim, Germany, V C H Verlagsgesellschaft: 369-404. Eliel, E. L., S. H. Wilen, et al. (1994). Stereochemistry of Organic Compounds. New York, Wiley. O OPredict the most stable conformation of the indicated dioxospiran? R. W. Hoffmann, Chem. Rev. 1989, 89, 1841-1860Allylic 1-3-Strain as a Controlling Element in Stereoselective Transformations diastereoselection 98:2 EtO Me O n-C4H9 OTs H Hn-C4H9 O Me EtO Can you predict the stereochemical outcome of this reaction? Acyclic Conformational Analysis-1 R. W. Hoffmann, Angew. Chem. Int. Ed. Engl. 2000, 39, 2054-2070Conformation Design of Open-Chain Compounds F. Weinhold, Angew. Science 2001, 411, 539-541"A New Twist on Molecular Shape" LiNR2 Chem 206D. A. Evans Acyclic Conformational Analysis-1 The following discussion is intended to provide a general overview of acyclic conformational analysis Ethane & Propane The conformational isomerism in these 2 structures reveals a gratifying level of internal consistency. ? E = +3.4 kcal mol-1 (R = Me) staggered conformation ? E = +3.0 kcal mol-1 (R = H) +1.4 kcal mol -1+1.0 kcal mol -1 Incremental Contributions to the Barrier. +1.0 kcal mol -1 1 (H?Me)2 (H?H) 3 (H?H) propane ethane δ E (kcal mol -1)Eclipsed atomsStructure For purposes of analysis, each eclipsed conformer may be broken up into its component destabilizing interactions. Van derWaals radii of vicinal hydrogens do not overlap in ethane In propane there is a discernable interaction Ethane Rotational Barrier: The FMO View One can see from the space-filling models that the Van der Waals radii of the hydrogens do not overlap in the eclipsed ethane conformation. This makes the steric argument for the barrier untenable. One explanation for the rotational barrier in ethane is that better overlap is possible in the staggered conformation than in the eclipsed conformation as shown below. σ* C–HLUMO σ C–HHOMO In the staggered conformation there are 3 anti-periplanar C–H Bonds σ C–HHOMO σ* C–HLUMO σ C–H σ? C–H In the eclipsed conformation there are 3 syn-periplanar C–H Bonds σ? C–H σ C–H Following this argument one might conclude that: R C HH C H H HH RH H H H C C C CC H C H C C HH MeMeMe Calculate the the rotational barrier about the C1-C2 bond in isobutane H H eclipsed conformation a73 The staggered conformer has a better orbital match between bonding and antibonding states. a73 The staggered conformer can form more delocalized molecular orbitals. J. P. Lowe was the first to propose this explanation "A Simple Molecuar Orbital Explanation for the Barrier to Internal Rotation in Ethane and Other Molecules" J. P. Lowe, JACS 1970, 92, 3799 F. Weinhold, Angew. Science 2001, 411, 539-541"A New Twist on Molecular Shape" H H Chem 206D. A. Evans Acyclic Conformational Analysis: Butane The 1,2-Dihaloethanes X = Cl; ?H° = + 0.9–1.3 kcal/molX = Br; ?H° = + 1.4–1.8 kcal/mol X = F; ?H° = – 0.6-0.9 kcal/mol Observation: While the anti conformers are favored for X = Cl, Br, the gaucheconformation is prefered for 1,2-difluroethane. Explain. X C XH HH H H C XH HH X Discuss with class the origin of the gauche stabiliation of the difluoro anaolg. pKeq0 -1 -2 0 –1.4 1.0 10 100 ?G?Keq ? G?298 = 1.4 pKeq pKeq = – Log10Keq ? G?298 = –1.4 Log10Keq ? G? = –2.3RT Log10K At 298 K: 2.3RT = 1.4 (?G in kcal Mol–1 ) ? G° = –RT Ln KRelationship between ?G and Keq and pKa –2.8 kcal /mol Recall that: or Since Hence, pK is proportional to the free energy change +3.6 +5.1 +0.88Ref = 0 G E1 E2 n-Butane Torsional Energy Profile ? E = ? Eclipsed atoms δ E (kcal mol -1) +1.0 kcal mol -11 (H?H) +2.8 kcal mol -12 (H?Me) ? E est = 3.8 kcal mol -1 The estimated value of +3.8 agrees quite well with the value of +3.6 reported by Allinger (J. Comp. Chem. 1980, 1, 181-184) eclipsed conformationstaggered conformation Using the eclipsing interactions extracted from propane & ethane we should be able to estimate all but one of the eclipsed butane conformationsButane HC Me H HH Me C MeH HH Me H MeC Me C H H HH H H HH Me Me Me C MeH C H H HH HH H Me Me ener gy A From the energy profiles of ethane, propane, and n-butane, one may extractthe useful eclipsing interactions summarized below: Hierarchy of Eclipsing Interactions δ E kcal mol -1+1.0 +1.4+3.1 eclipsed conformationstaggered conformation +2.2 Incremental Contributions to the Barrier. +2.01 (Me?Me)2 (H?H) δ E (kcal mol -1)Eclipsed atoms ? E = +5.1 kcal mol-1 From the torsional energy profile established by Allinger, we should be able toextract the contribution of the Me?Me eclipsing interaction to the barrier:Butane continued Acyclic Conformational Analysis: ButaneD. A. Evans Chem 206 MeC H C H H MeH Me H HMe H H C CX Y HH H H X YH H H MeMe Me Eclipsed Butaneconformation General nomenclature for diastereomers resulting from rotation about a single bond R C R R C R R CR sp sc (Klyne, Prelog, Experientia 1960, 16, 521.) sc acac ap C R R CR R C R R 0° +60° +120° 180° -60° -120° Torsion angle Designation Symbol0 ± 30° +60 ± 30°+120 ± 30° 180 ± 30°-120 ± 30° -60 ± 30° ± syn periplanar+ syn-clinal + anti-clinalantiperiplanar - anti-clinal- syn-clinal ± sp+ sc (g+) + acap (anti or t) - ac- sc (g-) Energy MaximaEnergy Minima E2G E1A E1G n-ButaneConformer Nomenclature for staggered conformers: C HH HH Me Me C HH MeH H Me C HMe HH H Me trans or tor (anti) gauche(+)or g+ gauche(-)or g- Conformer population at 298 K: 70% 15% 15% Let's extract out the magnitide of the Me–Me interaction 2 (H?H) + 1 (Me?Me) = +5.11 (Me?Me) = +5.1 – 2 (H?H) 1 (Me Me) = +3.1 ~ 2.2 It may be concluded that in-plane 1,3(Me?Me) interactions are Ca +4 kcal/mol while 1,2(Me?Me) interactions are destabliizing by Ca 2.2 kcal/mol. ~ 3.7 ~3.9 ~ 7.6 Estimates of In-Plane 1,2 &1,3-Dimethyl Eclipsing Interactions 1,3(Me?Me) = + 3.7 kcal mol -1 ? G° = +5.5 kcal mol -1? G° = X + 2Y where: X = 1,3(Me?Me) & Y = 1,3(Me?H) Estimate of 1,3-Dimethyl Eclipsing Interaction 1,3(Me?Me) = ? G° – 2Y = 5.5 –1.76 = + 3.7 kcal mol -11,3(Me?H) = Skew-butane = 0.88 kcal mol -1 The double-gauche pentane conformationn-Pentane Acyclic Conformational Analysis: PentaneD. A. Evans Chem 206 Me Me MeMe Me MeMeMe Me Me H H H H Me H H H H Me Me H H Me H H Me Me Me Me Me MeMe Me Me Me Me Me Rotation about both the C2-C3 and C3-C4 bonds in either direction (+ or -): tg+ g-g+ g-t g-g- tg- g+g- g+t g+g+ t,t From prior discussion, you should be able to estimate energies of 2 & 3 (relative to 1).On the other hand, the least stable conformer 4 requires additional data before is relative energy can be evaluated. Anti(2,3)-Anti(3,4) 1 1 1 1 3 3 3 3 5 5 5 5 Gauche(2,3)-Anti(3,4) Gauche(2,3)-Gauche(3,4)Gauche(2,3)-Gauche'(3,4)double gauche pentane 1 (t,t) 4 (g+g–) 3 (g+g+) 2 (g+t) The new high-energy conformation: (g+g–) X Y Acyclic Conformational Analysis: Natural ProductsD. A. Evans Chem 206 The syn-Pentane Interaction - Consequences (R. W. Hoffmann, ACIE 1992, 31, 1124-1134.) R R' Me Me R R' Me Me R R' H MeMe H Me Me R' HH R R Me H R'Me H Me R' R HH H ≡ ≡ tt g-g- tg gt or or Consequences for the preferred conformation of polyketide natural products Analyze the conformation found in the crystal state of a bourgeanic acid derivative! Me Me Me OH Me O OR Bourgeanic acid Ferensimycin B, R = MeLysocellin, R = H Lactol & Ketol Polyether Antibioitics RHO O O O Me Me OH O Et Me HOH O Me Me Me OH Et EtOHH Me The conformation of these structures are strongly influenced by the acyclic stereocenters Alborixin R = Me; X-206 R = H O O O O OHMe Me Me OH Me Me O C Me OH OHOH O O Et OHMe H MeOH Me MeH R Internal H-Bonding The conformation of these structures are strongly influenced by the acyclic stereocenters and internal H-bonding O O O O OHMe Me Me OH Me Me O C Me O OHOH O O Et OHMe H MeOH Me MeH R Metal ion ligation sites (M = Ag, K) M Synthesis: Evans, Bender, Morris, JACS 1988, 110, 2506 D. A. Evans Chem 206 O O O O OHMe Me Me OH Me Me O C Me OH OHOH O O Et OHMe H MeOH Me MeH Internal H-Bonding O O O O OHMe Me Me OH Me Me O C Me O OHOH O O Et OHMe H MeOH Me MeH R Metal ion ligation sites (M = Ag, K) M Conformational Analysis: Ionophore X-206/X-rays X-ray of Ionophore X-206 ? H2O X-ray of Ionophore X-206 - Ag+ - Complex D. A. Evans Chem 206Conformational Analysis: Ionophore X-206/X-ray overlay