Chem. 27 Section 1 – Conformational Analysis W. E. Kowtoniuk

Week of Feb. 6, 2006

1

TF:

Walter E. Kowtoniuk

wekowton@fas.harvard.edu

Mallinckrodt 303 Liu Laboratory

Office hours are:

Monday and Wednesday

3:00-4:00pm in Mallinckrodt 303

Course Notes:

1.) Problem sets must be placed in your TF's

mailbox (2nd floor Sci Center) BEFORE

11:00AM on the assigned date (usually Fridays) to receive credit. If this is a problem for

any student he/she must contact me PRIOR to 11:00AM on the due date.

2.) Section attendance is mandatory. If there is ever a problem with making to a section

please email me in advance. I teach two sections we can easily work out any problems if

plans are made in advance.

3.) Please bring your blue book to section. We will commonly work through a number of the

problems in the blue book during section.

Section 1 – Conformational Analysis W. E. Kowtoniuk

Week of Feb. 6, 2006

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Ethane (anti, gauche, eclipsed):

H

H HH

HH

H

H H

H

H HH

H H

H

HH

Staggeredconformation

Eclipsedconformation

+3.0 kcal/mol

H

H

H

H

HH

Saw horse

Newman Projection

eclipsing interaction

eclipsing interactionanti configuration

anti configuration

gauche interaction

gauche interaction

Anti configuration is preferred both due to sterics and electronics. Stericly placing the groups as

far away as possible is preferred (minimize eclipsing interactions). Electronically there is a

stabilizing hyperconjugation between anti substituents.

C-H --> * C-H

Anti configuration maximizes hyperconjugation

60o 120o

poor orbital overlap symmetry disallowed

Butane

HHH

H

H

H

H

HHHH

H

H

HH

HHH

+0.9 kcal/mol

C-C bonds anti C-C bonds gauche

H

H CH3

H

HH3CH

H CH3

CH3

HH

120o

HH

Anti and gauche interactions of the methyl group dominate the confirmation of butane. Notice

that the methyl-methyl eclipsed interaction is too high energy to even be considered.

Section 1 – Conformational Analysis W. E. Kowtoniuk

Week of Feb. 6, 2006

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Penatane – Syn-pentane

HH

HH

H

H

H

H

HHH

HH

anti-anti

HH

H

H

H

H

HHH

HH

anti-gauche

+0.9 kcal/mol

H

HH

H

H

H

H

HH

gauche-gauche

HHH

+0.9 kcal/molHH

H

H

H

H

HHHHHH

+4-5 kcal/mol

syn-pentane The key high energy interaction in the syn-pentane configuration to avoid is the 1,5 methyl-

methyl interaction. Notice how the hydrogens on these methyls are brought into very close

proximity. These disfavoring interactions only increase, as the substituents get larger.

Cycohexane

HH

H

H

HHHH

HH

H

H

H

H

H

H

HH

HH

1,3-diequitorialanti-anti

1,3-diaxialsyn-pentane

ring flip

Along the lines of syn-pentane interaction is it easy to see that the diaxial chair enforces a syn-

pentane interaction thus making it the high energy conformer.

H3C

H

equitorial methyl2-anti interactions

H

CH3

+1.8 kcal/mol

axial methyl2-gauche interactions

Even without a methyl-methyl syn-pentane the axial conformer is disfavored. The axial

substituent has two gauche interactions with the ring thus for methyl an A value of 1.8kcal//mol

(0.9 kcal/mol x 2).

HH

H

H

HH

H

H

HHHHHH

vs.

Section 1 – Conformational Analysis W. E. Kowtoniuk

Week of Feb. 6, 2006

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The apparent syn-pentane interaction that is found in every cyclohexane is not actually a

destabilizing interaction. The C-H electrons that were previously repelling are bound to a

bridging methylene. This eliminates the disfavoring interactions while also placing the other

hydrogens in non-interacting positions.

Propene – A1,3 strain

H

H

HH

H

H +2.0 kcal/mol

H

H

H

H

H

H

HH

HH

HH H

HStaggered

conformationEclipsed

conformation

H

HH H

H

H

13 13

Staggered conformation is disfavored due to electron repulsion between the system and the two

C-H bonds. In the eclipsed conformation the single hydrogen facing the system is

interacting with the nodal plane. This conformational preference is a result of A1,3 strain (or

allylic strain).

H3C

H

H3CH

CH3

CH3 +3.5 kcal/mol H

CH3

H3CH

CH3

CH3

The effect of A1,3 strain is only amplified as the propene becomes substituted. Notice the

similarity between A1,3 and syn-pentane interactions. Note that the double methyl staggering

would be even higher energy than the single methyl staggered.

Amino Acid Conformation

Valine

NH

O

H

CH3

H

H3CNH

O

H

CH3

H

H3C

NH

O

H

CH3

H

H3CNH

O

H

CH3

H

H3C

NH

O

H

H

CH3

H3C

NH

O

H

H

CH3

H3C

NH

O

H

H

CH3

H3C

NH

O

H

H

CH3

H3C

low energy conformation +0.9 kcal/mole (additional gauche)

Section 1 – Conformational Analysis W. E. Kowtoniuk

Week of Feb. 6, 2006

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The low energy conformation of valine contains two gauche and two anti interactions. The

higher energy conformations of valine contain three gauche and one anti interaction. Thus the

energy difference between conformers is estimated at +0.9kcal/mol (>82% of the population).

Leucine

NH

O

H

H

H

CH3

H

H3C

low energy conformationsNH

O

H

H

H

CH3

CH3

H

NH

O

H

H

H

CH3

CH3H

rotate 2

highly disfavoredsyn-pentane interactions

rotate 2

NH

O

H

H

H3C

CH3

H

H

rotate

1 and 2

The low energy conformation of leucine avoids syn-pentane interactions. Rotations of 1 and 2

lead to the creation of syn-pentane interactions. Two of these rotations are shown, although there

are more. The two low energy conformers are equal in energy and thus equally populated.

Isoleucine

NH

O

H

H

H

H

CH3

CH3

low energy conformation

NH

O

H

H3C H

NH

O

H

H

H3C

H

H

CH3

rotate 1

H3CH

H

rotate 2

Isoleucine is considered a rigid amino acid despite having seemingly free to rotate bonds.

Rotation of 1 generates two gauche interactions while rotation of 2 generates a syn-pentane

interaction. Therefore, isoleucine is 95% populated by this low energy conformer.

Methionine

NH

O

H

H

H

H

S

H

H3C

NH

O

H

H

H

H

S

HCH3

rotate 3NH

O

H

H

H

rotate 1

SH

H

H3C Methionine is a floppy amino acid. The key to this added flexibility is the increased length of the

C-S bond relative to the C-C bond. There will be less efficient orbital overlap between C-S

relative to C-C, thus the bond length will increase. This greater length greatly diminishes the

conformational effects that lead to one conformer being favored over another. The

conformational analysis shows that there will be large distribution of conformers as there are few

distinct destabilizing interactions. The increased C-S length permits the syn-pentane and gauche

conformer to contribute to the total methionine population. Thus, it is not surprising to find that

many general enzymes – enzymes accepting multiple substrates – incorporate this flexible, yes

hydrophobic, amino acid into the active site of the enzyme.

Section 1 – Conformational Analysis W. E. Kowtoniuk

Week of Feb. 6, 2006

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Peptide backbone

NH

OHR

O

NH

OH

R

Ovs.

NH

O

H

R

O

A1,3 minimized

The key to conformation of the polypeptide chain is minimization of A 1,3 strain. The amide

nitrogen can delocalize into the carbonyl forming the resonance structures shown above. The key

to the polypeptide chain is noting that these resonance structures are representative off the amide

conformation and thus the conformation will be the one that minimized A 1,3. Notice that the

staggered conformation is not even considered; rather the primary factor is placing the small

hydrogen in plane with the system. Furthermore, due to the bulk of the amid side chains the

finding the cis configuration about the N-C double bond is rare. It can occur with proline and

glycine residues due to the smaller size (gly) and imposed rigidity (pro) of these amino acids.

Protein Folding

-helix

In all of the amide moieties of a peptide chain there is a hydrogen

bonded to the nitrogen (with the exception of proline). Additionally, on

each carbonyl oxygen there is a lone pair of electrons. The hydrogen

bound to the nitrogen represents a hydrogen bond donor while the

oxygen lone pair represents a hydrogen bond

acceptor. Proteins will fold in such a

way to maximize hydrogen bonding.

-Helices are common motifs for

accomplishing this, notice in the

figure the -helix places the N-H and

C=O moieties on the inside of the

helix forming hydrogen bonds while

also placing the side chains on the

exterior. The other figure shows the ribbon

structure representation of the -helix.

-sheet

Another motif for maximizing hydrogen

bonding between the peptide chain of amino

acid chains is the -sheet motif. In this case

the peptide chain of one amino acid chain

hydrogen bonds with the peptide chain of an

adjacent chain. However, like -helices the

key interaction is the N-H hydrogen bond

Parallel

Section 1 – Conformational Analysis W. E. Kowtoniuk

Week of Feb. 6, 2006

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donor and the C=O hydrogen bond acceptor of the peptide

chain. Interestingly the adjacent peptide chains that come

together to form the -sheet can be aligned parallel (N C

directionality

the same) or

antiparallel

(N C

directionality

opposite). The

ribbon structures

highlight the -

-Turn

-turns are most significant because

they lead to a change in chain directionality.

The carbonyl oxygen hydrogen bond acceptor

and nitrogen hydrogen bond donor are separated by

10 atoms, as shown in the figure to the right.

Additionally, the figure points out the turns are

commonly generally containing a proline and glycine

residue. The proline provides the necessary structural

rigidity to force a turn

while the glycine is a

small and flexible

amino acid capable of

rotating to form the

necessary hydrogen

bond.

Salt Bridge

Salt bridges are electrostatic interactions between oppositely charged amino acid

residues. Often times these interactions involve positively charged arginine side chains and

negatively charged glutamate side chains. These interactions are most

important on the interior of proteins where there is a low dielectric

constant in the nonpolar core. However, salt bridges are found on the

surface of proteins with less overall energetic consequence due to the

higher dielectic constant of the surrounding environment

Disulfide Bonds

Disulfide bonds are formed when two thiols are oxidized to

release two electrons and two protons. These bonds are commonly

found between to cysteine side chains and are much stronger than

hydrogen bonds. However, since the inside of a cell is a reducing

environment disulfide bonds are generally not found on the inside of

a cell. They are frequently found in secreted proteins, such as

hormones like insulin. The dihedral angle of disulfide bonds are 90°

Anti-parallel

Section 1 – Conformational Analysis W. E. Kowtoniuk

Week of Feb. 6, 2006

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due to the hyperconjugation of the lone pair

on the S donating into theadjacent S-C

antibonding orbital. By placing the sulfur

lone pair antiperiplanar to the C-C bond the

orbital overlap is maximized thus providing a

strong conformational preference for 90° dihedral angles.

Hydrophobic

Hydrophobic amino acid side chains pack closely together when in aqueous media in

order to minimize their interaction with water. For

example phenylalanine, valine, and leucine pack into the

core of a protein, as shown, in order to minimize their

contact with the polar environment. By interacting with

each other the hydrophobic sidechains are effectively

solvating each other rather than being solvated by water.

Furthermore, when a hydrophobic structure is forced to

interact with water the water forms a highly organized

lattice called clathrate water. An example of these

clathrate structures is

shown below. Thus,

by folding hydrophobic side chains to the interior of the

protein this highly organized form of water is not present and

thus the folding of hydrophobic sidechains into the interior is

favored due to the greater entropy of not forming the clathrate

water.

Problems:

B06, B08, B11, C01, C04, C06, C09, C11, C12