Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 1

Cyclohexanes

Cyclohexane rings (six atom rings in general) are the most well studied of all ring systems. They have a limited number of, almost strain free, conformations. Because of their well defined conformational shapes, they are frequently used to study effects of orientation or steric effects when studying chemical reactions. Additionally, six atom rings are the most commonly encountered rings in nature. Cyclohexane structures do not choose to be flat. Slight twists at each carbon atom allow cyclohexane rings to assume much more comfortable conformations, which we call chair conformations. (Chairs even sound comfortable.) The chair has an up and down shape all around the ring, sort of like the zig-zag shape seen in straight chains (...time for models!).

C C C C C C

lounge chair - used to kick back and relax while you study your organic chemistry chair conformation

Cyclohexane rings are flexible and easily allow partial rotations (twists) about the C-C single bonds. There is minimal angle strain since each carbon can approximately accommodate the 109o of the tetrahedral shape. Torsional strain energy is minimized in chair conformations since all groups are staggered relative to one another. This is easily seen in a Newman projection perspective. An added new twist to our Newman projections is a side-by-side view of parallel single bonds. If you look carefully at the structure above or use your model, you should be able to see that a parallel relationship exists for all C-C bonds across the ring from one another.

There are three sets of parallel C-C bonds in cyclohexane rings. Any 'set' could be used to draw two parallel Newman projections.

Two simultaneous Newman projection views are now possible as shown below. Remember, that any two bonds on opposite sides of the ring can be used and they can viewed from front or rear directions.

Once the first bond is drawn in a Newman projection of a chair conformation of cyclohexane ring, all of the other bonds (axial and equatorial) are fixed by the staggered arrangements and the cyclic connections to one another. Once you have drawn all of the bonds in a Newman projection, you merely fill in the blanks at the end of each line, based on the substituents that are present (determined from the name or a 2D drawing).

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 2

How to draw a Newman projection of a cyclohexane ring.

H

Stagger back Divide front groups view into thirds. relative to front groups. This single bond fixes all of the other bonds in the Newman projection. Draw connections over to parallel Newman projection. Make sure front connects to front and back parallel views of Newman projections connects to back.

Add the other two front groups, dividing the front view into thirds and stagger the back groups.

Ideal dihedral angles of cyclohexane (the real ones are slightly different)

H H

H H

H H

H H

o dihedral angles 60 Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 3

Problem 1 - How many possible Newman perspectives of chairs are possible on the numbered cyclohexane below? Consider all numbers and front/back views. Write them as, C1C2, C5C4, etc.)

23 1 4 6 5

A Newman projection of a chair conformation of cyclohexane clearly shows that torsional strain is minimized, since all groups are staggered. Additionally, either bond-line or Newman formulas reveal that the two hydrogen atoms at each CH2 are not the same. Three hydrogen atoms point straight up and three H's point straight down (at alternate positions) relative to the approximate plane of the carbon atoms. Those six parallel C-H bonds are also parallel to the highest axis of symmetry, (which we are ignoring in this book). Because these six C-H bonds are parallel to an axis of symmetry, they are called the axial positions (axial = along an axis). There is one axial position at every carbon atom in the ring and, again if you look carefully, you will see that axial positions alternate pointing up and then pointing down. You should also observe that when they point up they are on the top face of the ring, and when they point down they are on the bottom face of the ring.

cis Three axial groups are on the top Axial positions in cyclohexane rings 3 face. The other two are cis to the C H H reference reference hydrogen atom in this example.

A C3 axis of symmetry means if you H rotate the molecule about that axis by trans o 120 the new structure will be Three axial groups are on the indistinguishable from the original bottom face. They are trans to structure. H the reference hydrogen atom in this example. H H

There are six other hydrogen atoms present, one at each of the carbon atoms in the ring. However, these hydrogen atoms are approximately in the plane of the ring of carbon atoms. These hydrogen atoms all point out, around the perimeter of the ring (…or around the “equator”). These positions are called equatorial positions (equator  equatorial). The equatorial positions also alternate around the ring, being on top when axial points down and being on the bottom when axial points up. These terms (axial and equatorial) create a common point of confusion for students. When students hear that two groups are axial, they often assume they must be the same in all respects, i.e. on the same side (cis). This is true at alternate positions about the ring, but it is not true at adjacent positions or directly across the ring, where they are trans.

Equatorial positions H * C C H C * = top side, trans to reference hydrogen atom Hreference H C H = bottom side, cis to reference hydrogen atom C C *

H * Drawing a Cyclohexane

You will need to learn how to draw a cyclohexane ring, with all of its axial and equatorial positions, if you are to ever understand cyclohexane and related ring structures. Once you can draw cyclohexane rings, it is simply fill in the blank to add the substituent atoms (using a name as your guide). You can generate an endless number of substituted possibilities. If you switch out a carbon atom for an oxygen atom and you are set to study the pyranoses of biochemistry (e.g. cyclic glucose). As you work through this section, keep your models by your side. First you have to generate the outline of the ring. (You should actually practice these steps several times.) This can be done by drawing two parallel lines, slightly off center, tracing slightly up or slightly down. Next a V shape is Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 4 added on both sides so that it points in an opposite sense to the direction of the parallel lines. These two chair conformations are the most common shapes of cyclohexane rings, and interconvert with one another (thousands of times per second).

add tilted, upside down "V" on one add tilted, right side side up "V" on the other side

Two parallel lines, slanting down and slanting up. These two chair conformations will interconvert very rapidly.

add tilted, right add tilted, upside side up "V" on down "V" on the one side other side

An alternate strategy is to draw a slanted V shape first, then add the parallel lines in an opposite direction. Then the other V shape is added in the opposite direction to the parallel lines. Use whatever works best for you. Make sure you practice until you can do this with ease.

add parallel lines add tilted, upside down "V" on the other side

Alternatively you can draw the slanting "V" shapes first. These two chair conformations will interconvert very rapidly. add tilted, right add parallel lines side up "V" on the other side

Our next task is to draw in the axial and equatorial positions. The ring is very helpful to us in this regard. The ring always points to the axial positions. If a ring carbon atom is in an up position, the axial position is pointing straight up (on the top of the ring). If a ring carbon atom is in a down position, the axial position is pointing straight down (on the bottom of the ring). The axial positions can now be added to our chair below.

add axial groups at the up positions add axial groups (top face), where at the down positions the ring points up (bottom face), where the ring points down

These two chair conformations will interconvert very rapidly. add axial groups at the up positions add axial groups (top face) at the down positions (bottom face)

The equatorial positions are added last, about the perimeter (or equator) of the ring. The two opposite positions, in the plane of the paper are the easiest to add since our perspective is a side-on view and they follow the zig-zag shape we expect in straight chains. Notice that one of these equatorial positions is on the top of the ring and one of Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 5 them is on the bottom. They should both be drawn parallel to the ring bonds that are parallel to the plane of the paper.

Add equatorial equatorial bond on the top equatorial bond positions in the on the bottom plane of the page.

= equatorial position = axial position Axial and equatorial positions switch places in the two conformations.

Add equatorial equatorial bond positions in the on the bottom plane of the page. equatorial bond on the top = axial position = equatorial position

The other equatorial positions require slightly better artistic skills. To represent the equatorial positions coming out of the plane of the page, toward the viewer, wedges are drawn; if projecting behind the page, away from the viewer, dashed lines are drawn. These bonds will be parallel to bonds in the ring already drawn and in fact they have an anti relationship with those parallel bonds (use models). Use the ring bonds to guide you in drawing the equatorial bonds in the ring.

bold lines bold lines C C indicate C C C C C C indicate C C parallel bonds C parallel bonds C C C C C C C

Heavy lines indicate parallel equatorial and ring bonds (above). Use the ring bonds to help you draw the equatorial bonds and then add the proper 3D perspective as simple lines, wedged lines or dashed lines (below).

C C Equatorial positions in the two chair C C C C C conformations of a cyclohexane ring. C C C C C

conformations C C rapidly This is what you need C C C to be able to draw to interconvert C C C analyze six atom rings. C C C C

Equatorial and axial positions in the two chair conformations of a cyclohexane ring.

If you practice this several times, you should be able to generate a chair cyclohexane structure in seconds. Substituents can be added as indicated from a chemical name. These two chair conformations are the most common and comfortable of all the conformational possibilities available to a cyclohexane ring. Almost all of your work with cyclohexanes will involve chair conformations. Boat and Twist Boat Conformations

There are additional conformations of cyclohexane rings: boat, twist boat and half-chair conformations. These are high potential energy conformations that are encountered when one chair rotates to the other chair conformation. Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 6

Torsional strain and van der Waals strain cause an increase in the potential energy of these conformations. We will take a limited look at the boat conformation (but not the twist boat or half-chair). Occasionally these conformations are found in rigid, fixed structures having cyclohexane subunits, either by design or in nature.

Boat Conformation

Bolded bonds of the boat conformation are parallel and can be used to draw parallel Newman projections. Boat conformation of cyclohexane A boat.

A Newman projection viewing down the two parallel bonds of the boat conformation clearly shows the increased torsional strain from eclipsing interactions. H2 C H2 C H H H H Newman projection

H H Boat conformation H H of cyclohexane Several groups are eclipsed in a boat conformation of cyclohexane rings,increased torisional strain.

An additional destabilizing feature present in the boat is van der Waals strain between the two hydrogen atoms pointing inward, towards each. These interfering groups are called "flagpole" interactions, and also contribute to the overall ring strain of the boat conformation. The van der Waals radius for a hydrogen atom is 1.2 A and represents the radius of a sphere of space occupied by the electron cloud of a hydrogen atom. The nuclei of two hydrogen atoms would be expected to approach no closer than 2.4 A ( = 2 x 1.2 A) without considerable repulsion. The flagpole hydrogen atoms are 1.8 A apart in the boat conformation. We classify this as a steric effect.

1.8 A 2.4 A destabilizing no van der Waals strain if flagpole at least 2.4 angstroms between interactions hydrogen atoms H H H H

A chair does not immediately become a boat, and then the other chair. There is an even higher transitory conformation, which is called a half chair. Due to the torsional strain and bond angle strain this conformation is even higher in potential energy than the boat. We can consider the half chair as a transition state that exists only on the way to a chair or boat conformation. The potential energy of the half chair is estimated to be about 11 kcal/mole. A potential energy diagram for interconverting the two possible chair conformations would look something like the following. Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 7

chair 1 half chair 1 twist boat 1 boattwist boat 2 half chair 2 chair 2 12

10 Background thermal energy is about 20 kcal/mole, more than enough to make all of 8 these conformations accesible.

PE 6  11  11

4  5.0  6.4  5.0 2

0 Energy changes of cyclohexane conformations.

However, we will view the interconversion of the two cyclohexane conformations, simplistically, as chair 1 in equilibrium with chair 2 via the boat conformation.

van der Waals strain, (flag pole interactions)

Boat Chair 2 Chair 1 Groups along parallel bonds in the ring are eclipsed, which increases torsional strain. Groups pointing into the center All groups are staggered, which of the ring on the carbon atoms pointing up crowd one All groups are staggered, which minimizes torsional strain energy. allows maximum stabilization. another, which increases van der Waals strain.

Equilibration, back and forth, between the two chair conformations is rapid at room temperature and occurs on the order of 80,000 times per second. At lower temperatures interconversion is much slower (there is less thermal background energy). At -40oC the interconversion occurs about 40 times per second, at -120oC interconversion occurs about once every 23 minutes and at -160oC it is estimated to occur once every 23 years. The equilibration can occur in either of two directions as shown below.

a b b a boat 1 b

chair 1 a chair 2 b a boat 2

Notice that all axial positions (top and bottom) become equatorial positions with the flip-flop of two chairs. Of course, all equatorial positions become axial positions at the same time.

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 8

= axial = equatorial = equatorial axial on top becomes equatorial on top = axial

transition via "boat"

equatorial on top becomes axial on top

chair 1 axial on bottom becomes chair 2 equatorial on bottom

Since the two chair conformations are so much more stable than the boat or half chair over 99.99% of the molecules are in one of the two chair conformations. If all of the ring substituents are hydrogen atoms, there should nearly be a 50/50 mixture of two indistinguishable chair structures.

G - (6400 cal/mole) boat 2.3RT K = = 10 = 10 (2.3)(2 cal/mol-K)(298 K) = 10-4.60 = 2.1x10-5 = 0.002% chair 99.998%

G - (0 cal/mole) chair 1 2.3RT (2.3)(2 cal/mol-K)(298 K) 0 1 50% K = chair 2 = 10 = 10 = 10 = = 1 50%

Real molecules actually exist that illustrate most of the cyclohexane conformations mentioned, above, as substructures (chair, boat and twist boat). Adamantane has four chair cyclohexane rings in its complicated tricyclic arrangement. Twistane has a good example of a twist boat conformation and is isomeric with adamantane. Norbornane has a boat conformation locked into its rigid bicyclic framework with a bridging CH2 holding the boat shape in place. Each of these is highlighted below. Your models can help you see this a lot more clearly than these pictures.

chair (from back) boat twist boat chair chair

chair side view front view Adamantane Twistane - has a twist boat conformation Every face is a Norbornane - has a chair conformation. boat conformation

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 9

Mono Substituted Cyclohexanes

A single substitution of a hydrogen atom with another group complicates the analysis of cyclohexane conformations. There are still two rapidly equalibrating chair conformations, but they are no longer equal in potential energy. H

H R

R "R" is on the bottom in both conformations. Of course, if you turn the ring over, then "R" is on the top in both conformations. R is equatorial in the left conformation and axial in the right conformation.

A Newman perspective using the C1C2 and C5C4 bonds can help to evaluate which of these two conformations is more stable. Both chair conformations have an all staggered orientation about the ring, but chair 2 has gauche interactions of the substituent and the ring, which are not present in chair 1. H H H H "R" is on the bottom in both H conformations. Of course, if 3 2 2 H 4 3 6 H 5 1 you turn the ring over, then 5 1 R H H H 4 "R" is on the top in both conformations. R is equatorial H 6 H H R in the left conformation and H axial in the right conformation.

Newman projections: chair 1 chair 2 C5 C4 and C1 C2

H H H H H H H H

H H H R H H H R

Equatorial "R" is anti to the ring on two sides. Axial "R" is gauche to the ring on two sides. Only one shows in this Newman projection. Only one shows in this Newman projection.

If we view down the C1C6 bond and the C1C2 bond, it is clear that an axial R substituent is gauche with both sides of the ring. Any axial substituent in a cyclohexane ring really has two gauche interactions. H H

2 chair 2 4 3 6 chair 2 2 4 3 6 H 5 1 H 5 1 H H R R viewed from C C6 the rear 1 C1 C2 viewed from Newman projection: Newman projection: the front H H

H ring C2 ring C6 H

H ring C5 ring C3 H R R is also gauche on the R is also gauche on the other side of the ring R other side of the ring Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 10

We have previously seen that a CH3/CH3 gauche interaction raises the potential energy about 0.8 kcal/mole. CH3 CH 3 gauche CH3

CH3 gauche CH /CH = 0.8 kcal/mole anti CH3/CH3 = 0 kcal/mole 3 3

Two such relationships should raise the energy by approximately (2)x(0.8 kcal/mole) = 1.6 kcal/mole. The actual value observed for an axial CH3 in cyclohexane relative to equatorial is 1.7 kcal/mole, very close to what we expect.

G - (1700 cal/mole) chair 2 2.3RT 1 = 10 = 10 (2.3)(2 cal/mol-K)(298 K) -1.2 6% axial CH3 K = chair 1 = 10 = 0.058 = 17 = = 94% equatorial CH3 12 half chair 1 half chair 2

10

8 boat 6% PE 6 11 11 94%   4  6.4 chair 2 2 chair 1 kcal G = 1.7 mole 0 Energy changes of methylcyclohexane conformations.

The two gauche interactions of axial R substituents and the ring carbon atoms in cyclohexane structures, are called 1,3-diaxial interactions. In the axial position, the substituent R, is forced close to the other two axial groups on the same side of the ring. Since these are both three atoms away from the ring carbon atom with the R substituent, the 1,3-diaxial descriptor is appropriate.

R H H 1,3-diaxial interaction 1 3' ( two gauche interactions) 2' 3 2 Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 11

Problem 2 - Which boat conformation would be a more likely transition state in interconverting the two chair conformations of methylcyclohexane...or are they equivalent? Explain your answer.

flip "R" side down first R boat 1

first flip non-"R" R boat 2 R side up

A wide range of substituents has been studied and almost all show a preference for the equatorial position. Several examples are listed in the table below. The actual energy difference between equatorial substituents and axial substituents is often called the A value (axial strain). Larger A values indicate a greater equatorial preference for the substituent due to larger destabilizing 1,3-diaxial interactions (or double gauche interactions). axial

equatorial S

S axial PE Go = equatorial S = substituent group (table of energy values below)

Substituent Go (A value) Substituent Go (A value) -H 0.0 -CH2OH 1.8 -CH3 1.7 -CH2Br 1.8 -CH2CH3 1.8 -CF3 2.4 -CH(CH3)2 2.1 -O2CCH2CH3 1.1 -C(CH3)3 > 5.0 -OH 0.9 -F 0.3 -OCH3 0.6 -Cl 0.5 -SH 1.2 -Br 0.5 -SCH3 1.0 -I 0.5 -SC5H6 1.1 -CH=CH2 1.7 -SOCH3 1.2 -CH=C=CH2 1.5 -SO2CH3 2.5 -CCH 0.5 -SeC6H5 1.0 -CN 0.2 -TeC6H5 0.9 -C6H5 (phenyl) 2.9 -NH2 1.2(C6H5CH3), 1.7(H2O) -CH2C6H5 (benzyl) 1.7 -N(CH3)2 1.5 (C6H5CH3), 2.1(H2O) -CO2H 0.6 -NO2 1.1 -CO2 2.0 -HgBr 0.0 -CHO 0.7 -HgCl -0.2 -MgBr 0.8

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 12

The energy differences in the table between equatorial and axial positions for substituent groups from methyl through ethyl, isopropyl and t-butyl appear puzzling. Ethyl definitely is larger than methyl and isopropyl is larger than either of those two, but they all have similar A values. The A value for the t-butyl group, on the other hand, suddenly jumps to a much higher energy. Examination of the three dimensional axial conformation provides insight into this observation. R axial R axial PE equatorial Go = equatorial R = methyl, ethyl, isopropyl or t-butyl

5 PE 4 equatorial axial difference in G kcal 3 mole Go > 5.0 kcal/mole 2 1 o Go = 2.1 kcal/mole G = 1.7 kcal/mole Go = 1.8 kcal/mole

isopropyl methyl ethyl t-butyl

Compare axial interactions on the top face of the two conformations. Rotation is possible around R this bond, which allows H H R R different "R" groups to face H R H C in towards the center of the ring. H C Severe crowding C R H when a nonhydrogen R atoms faces into the chair 1H chair 2 middle of the ring. H H R R R R substituent G Keq axial C PE R H C H H H methyl +1.7 5% / 95% H G = equatorial H H CH3 ethyl +1.8 5% / 95% H H CH3 CH3 isopropyl +2.1 3% / 97% H CH3 CH3 CH3 t-butyl >5.0 0.02% / 99.98%

Top view Newman projection.

R R R can be a hydrogen atom pointing into the R H C center of the ring, when the axial substituent ring R is methyl, ethyl and isopropyl. It is not possible H when the ring substituent is t-butyl. If the t-butyl H substituent is axial, a methyl has to point into the R H center of the ring. This is very destabilizing and for the most part, t-butyl substituents are in the ring equatorial position. chair 2 R

In the case of methyl, ethyl or isopropyl there is always a hydrogen atom that can (and most often will) point inward toward the center of the ring. Free rotation is possible about the R3C-C(ring) bond. Since van der Waals strain is lower for a hydrogen atom pointing toward the middle of the ring than methyl, any substituent from methyl (R = H, R = H, R = H) to ethyl (R = H, R = H, R = CH3) to isopropyl (R = H, R = CH3, R = CH3) will choose an Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 13 inward pointing hydrogen as its preferred conformation. When the substituent is t-butyl (R = CH3, R = CH3, R = CH3), there is no such option. All possible orientations of an axial t-butyl point a CH3 toward the center of the ring, which is extremely destabilizing (easy to see with a model) and chair 1 is overwhelmingly preferred. Even though an equatorial substituent is preferred for all of the examples above, both chair conformations are present in rapid equilibrium. What varies is the percent of each chair conformation that is present. Even with t-butyl as the substituent, a tiny fraction of cyclohexane rings will have a transient, axial t-butyl (see the table above).

Problem 3 – a. Propose an explanation for why ethenyl (-CH=CH2) has a larger preference for the equatorial position than ethynyl (-CCH). H substituent = C C H C = attachment to the ring

ethynyl ethenyl C H

H b. Propose an explanation for why ethenyl (-CH=CH2) has a smaller preference for the equatorial position than phenyl (-C6H5). H H

H C C

C C H = attachment to the ring substituent = C

C H CC ethenyl phenyl H H H c. Benzyl would seem to be a larger group than phenyl, but has a smaller A value. Propose a possible explanation. H H H H

C C C C

H2 substituent = C C C H C C H = attachment to the ring

CC CC benzyl phenyl H H H H Disubstituted Cyclohexanes Here is an excellent example of why memorization does not work in organic chemistry. Not only is it easier to learn a limited number of basic principles and logically use them in newly encountered situations, it is down right impossible to memorize every possible situation you might encounter. When we add a second substituent to monosubstituted cyclohexane rings, the possibilities increase tremendously. Seven flat ring structures are drawn below, which just emphasize the top and bottom positions on the ring. Flat structures can be drawn as time average approximations between two interconverting chairs, although in actuality none of the structures are flat. These structures are only used as a short hand to show that substituents are on the same side or are on opposite sides. In biochemistry they are sometimes called Haworth projections and commonly used with cyclic sugar molecules.

R1 = R2 R1  R2 gauche interactions are possible when substituents are 1,2-substituted

R1 R1 R1 R1 R1 R1 R2 R1

R2 R2

R2 R2

R2 R2 1,1-di "R" cis-1,2-di "R" trans-1,2-di "R" cis-1,3-di "R" trans-1,3-di "R" cis-1,4-di "R" trans-1,4-di "R"

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 14

Even though we have gone from a single monosubstituted cyclohexane to seven disubstituted cyclohexane rings, the situation is even more complicated yet! Just as our monosubstituted cyclohexane had two chair conformations, there are two possible chair conformations for each of the flat structures shown above. In some cases the two conformations are equivalent in energy, but in other cases one conformation is preferred. We need a systematic method of analysis or we will quickly become hopelessly lost in the wilderness of flip- flopping cyclohexane rings. I recommend the following strategy for every cyclohexane analysis.

Possible systematic approach to Analyze Cyclohexane Conformations 1. Draw the cyclohexane ring framework as a bond-line formula (chair). 2. Add both axial and equatorial positions. Axials point straight up or down in alternating fashion (the ring points to the axial positions). Equatorials are off to the side (use the axial positions to guide you as to top and bottom positions). Both alternate on top or bottom of the face of the ring as you move around the ring. Use parallel bonds in the ring to guide you where to draw the equatorial bonds. 3. Add in the necessary substituents according to the name of the structure (fill in the blank). It is generally easier to visualize substituents drawn on the extreme left or extreme right carbon atoms of the ring because those bonds will be in the plane of the paper, so these are good places to draw your first substituent. 4. Draw the other conformation by flipping one side up and flip the other side down. All of the axial and equatorial positions will interchange, but the top will still be the top and the bottom will still be the bottom. 5. In addition to 1,3-diaxial interactions look for an extra gauche interactions when substituents are substituted 1,2 (vicinal substitution). We will use gauche values from the table in Topic 5 (page 13) or 0.8 if not available. 6. Evaluate which is the preferred conformation using the available energy values. Use H to calculate a ratio. -G -H K = 10 2.3RT  10 2.3RT

Example 1 cis 1,4-dimethylcyclohexane

1.Draw the bond line formula of a chair.

2. Add axial and equatorial positions (ring points axial).

3. Add the indicated substituents. Generally the easiest positions to fill are the positions on the far left and far right carbon atoms (1 and 4, just above), since their representation is drawn in the plane of the page. At least the first substituent should be drawn at one of these positions and then fill in any other substituent(s) as required.

CH3 cis = same side, so both CH3 groups should be on the same side (top side H H3C 4 as written in this example). If you H3C 4 1 2 3 turned the structure over, the two 1 2 3 methyl groups would still be on the same H side, but that side would be the bottom. H 1,4 substitution tells One CH3 is axial and one us that the second CH is equatorial, but both substituent goes here. 3 are on the same side.

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 15

4. Draw the other conformation (flip up, flip down). Axial/equatorial interchange occurs but the structure is still cis.

CH3 flip down CH3 flip H up H3C 4 2 H 1 1 3 CH3 3 2 4 H H

5. There is one axial CH3 (+1.7 kcal/mole) and one equatorial CH3 in each conformation.

6. 1,2-gauche interactions are not applicable in this example, since there are no vicinal substituents.

7. Since the two conformations are equivalent in energy we would expect a 50/50 mixture.

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 16

Newman Projections CH3 H CH3 H 5 H 6 6 5 H 1 H 4 H H 2 4 CH 1 2 3 3 H3C H 3 H H H H Newman projections:

C C and C C chair 1 4 5 2 1 chair 2

CH H H CH3 3 anti gauche gauche anti H CH H3C H 3

H H HH H H H H H One axial methyl and one equatorial methyl One axial methyl and one equatorial methyl

Example 2 trans-1,2-dimethylcyclohexane

1. See above.

2. Add axial and equatorial positions wherever substituents are present (the ring points to axial).

3. Add the indicated substituents.

trans = opposite side, so the second CH3 should be on the bottom side H H3C since we drew the first CH3 on the 1 2 top side. H3C 1 2 H CH 1,2 substitution tells 3 H us that the second Both CH3 groups are substituent goes here. equatorial, but are on the opposite sides.

4 & 5. Draw the other conformation and estimate the energy expense of each conformation.

flip H flip CH3 up down H3C H 1 2 H CH3 H CH3 0 axial substituents kcal kcal 2 axial substituents (opposite sides) = 2(1.7) = 3.4 1 gauche interaction = 0.8 mole mole 0 gauche interaction

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 17

6. Chair 1 has a gauche relationship between the two CH3 substituents, which increases energy of that conformation by +0.8 kcal/mole.

H3C

One gauche CH3 interaction.

7. The potential energy difference between the two conformations is (3.4 – 0.8) = 2.6 kcal/mole. Use this value to calculate Kequilibrium.

CH3 H H H 5 H 6 6 5 H 1 H 4 H H 2 4 H 1 2 3 H3C H 3 H3C CH3 H H Newman projections:

C C and C C chair 1 4 5 2 1 chair 2

CH H H 3 H H H H3C H

H H H3C H

H H CH3 H both methyls equatorial with gauch interaction both methyls axial, anti Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 18

Example 3 trans- 1-t-butyl-3-methylcyclohexane 1. See above. 2. Add axial and equatorial positions wherever substituents are present (the ring points to axial).

3. Add the indicated substituents. CH3 CH trans = opposite side, so the CH3 3 C H3C should be on the bottom side since 1 we drew the t-butyl on the top side. C H3C 3 H3C H 1 H H3C 3

H CH3 1,3 substitution tells us that the second The t-butyl group is equatorial substituent goes here. and the CH3 group is axial, and they are on opposite sides.

4 & 5. Draw the other conformation and estimate the energy expense of each conformation.

CH3 H3C CH3 flip 5 H3C 4 C up C 6 flip H C H 3 2 down H H C 1 3 6 5 3 H 1 H CH3 4 2 3 CH3

kcal kcal 1 axial CH3 substituent = 1.7 1 axial t-butyl substituent > 5.0 mole mole 0 gauche interaction = 0 0 gauche interaction = 0.0

C C and C 1 6 C3 4 C1 C6 and C3 C4

Newman projections: chair 1 chair 2 CH3 CH3 H H3C H C H CH 3 C 3 H C H H H H3C H H H CH3 H CH3 H H Axial "t-butyl group" Equatorial "CH " is anti t-butyl group Axial "CH3" is gauche to 3 is gauche to the ring to the ring on two sides. is anti to the the ring on two sides. on two sides. Only one ring. Only one shows in this shows in this Newman Only one shows in this projection. Newman projection. Newman projection.

6. Gauche relationships are not applicable because substituents are not 1,2 (vicinal).

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 19

7. The potential energy difference between the two conformations is (5.0 – 1.7) = 3.3 kcal/mole. Use this value to calculate Kequilibrium. G - (3,300cal/mole) chair 2 -0.004 1 0.3% K= =102.3RT (2.3)(2 cal/mol-K)(298 K) =10 = = chair 1 =10 255 99.7% 12 half chair 1 half chair 2 10

8 0.3% 99.7% boat chair 2 PE 6 6 5 4 6 5 1 1 2 3 2 3 4 kcal 4 chair 1 G = (5.0 - 1.7) = 3.3 change mole kcal G > 5.0 2 mole kcal G=1.7 mole 0 Energy changes of trans-1-t-butyl-3-methylcyclohexane conformations.

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 20

Problem 4 – Draw all isomers of dimethylcyclohexane and evaluate their relative energies and estimate an equilibrium distribution for the two chair conformations. Use the given energy values for substituted cyclohexane rings. If the two substituents on the ring were different, all 14 conformations below would have different energies!

Potential Energy One axial methyl group increases the potential energy by 1.7 kcal/mole, Two axial methyl groups, on the same side (cis), increase the potential energy by 5.5 kcal/mole, kcal 1,2 gauche methyl groups increase the potential energy by 0.8 kcal/mole. mole 6.0

5.0

4.0

3.0

2.0 G = 2x(1.7) = 3.4

1.0

0.0

AB CD EF GH IJ KL MN

cis-1,3 trans-1,4 cis-1,4 trans-1,3 trans-1,2 cis-1,2 1,1

Problem 5 - Both cis and trans 1-bromo-3-methylcyclohexane can exist in two chair conformations. Evaluate the relative energies of the two conformations in each isomer (use the energy values from the table presented earlier). Estimate the relative percents of each conformation at equilibrium using the difference in energy of the two conformations from you calculations. Draw each chair conformation in 3D bond line notation and as a Newman projection using the C1C6 and C3C4 bonds to sight down.

2 Br CH3 1 3 1-bromo-3-methylcyclohexane 6 4 5 Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 21

Topic 7 Possible answers to problems

Problem 1 (p 3) - How many possible Newman perspectives of chairs are possible on the numbered cyclohexane below? Consider all numbers and front/back views. Write them as, C1C2, C5C4, etc.)

C C 6 6 4 4 5 5 4 5 C2 C1 C 6 5 C4 2 5 4 C C C C 3 2 6 1 4 3 C1 C2 1 1 3 1 2 3 6 5 4

C6 C5 C C C1 C6 3 4 2 6 6 1 3 C2 C3 5 4 5 4

1 2 2 C 3 1 3 C5 6 C3 C2

Problem 2 (p 11) - Which boat conformation would be a more likely transition state in interconverting the two chair conformations of methylcyclohexane...or are they equivalent? Explain your answer.

H H boat 1

H H R a b b a R b H a chair 1 a chair 2 (more stable) b R H H (less stable) boat 2 H R Boat 2 raises the potential energy more than boat 1 because the larger 'R' group is pointing into the middle of the ring causing greater electron-electron repulsion from the crowded positions. Boat 1 keeps the larger 'R' group pointing out away from the rest of the ring until the final flip puts it in the less stable axial position.

Problem 3 (p 13) – a. Propose an explanation for why ethenyl (-CH=CH2) has a larger preference for the equatorial position than ethynyl (-CCH).

Ethynyl is a sterically H Ethenyl is a sterically smaller group in the larger group in the H axial position because of axial position, causing its linear shape. It is C more severe 1,3 diaxial C parallel to the other 1,3 crowding. H H diaxial positions causing H C H C very little crowding. H H H H

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 22 b. Propose an explanation for why ethenyl (-CH=CH2) has a smaller preference for the equatorial position than phenyl (-C6H5). less strained with hydrogen pointing to H middle of ring H rotate C rotate H axial H C Ha H H axial group b H C group H C H H H H H H H b H Ha H H H H

Even when ethenyl is axial it has the option of turning a hydrogen Nothing changes when the phenyl substituent rotates 180o. It is sterically in towards the middle of the ring, greatly reducing the axial crowding. crowded in both positions, so will have larger axial strain (energy). c. Benzyl would seem to be a larger group than phenyl, but has a smaller A value. Propose a possible explanation.

less strained with hydrogen pointing to H middle of ring H H C Ha H H H H H b H Because the attached carbon is sp3 hybridized, benzyl has an option of turning a hydrogen As seen above, phenyl does not in towards the middle of the ring, have any options for the relief of greatly reducing the axial crowding. A strain (1,3 diaxial interactions).

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 23

Problem 4 (p 20) – Draw all isomers of dimethylcyclohexane and evaluate their relative energies and estimate an equilibrium distribution for the two chair conformations. Use the given energy values for substituted cyclohexane rings.

Potential Energy One axial methyl group increases the potential energy by 1.7 kcal/mole, Two axial methyl groups, on the same side (cis), increase the potential energy by 5.5 kcal/mole, kcal 1,2 gauche methyl groups increase the potential energy by 0.8 kcal/mole. mole 6.0

eis 1,3 diaxial methyls are very 5.0 crowded, raises energy by 5.5

4.0

trans 1,2 has 3.0 two axial methyl groups = 2x(1.7)=3.4

2.0 G = 2x(1.7) = 3.4 cis 1,2 has a gauche and an axial methyl = 0.8+1.7=2.5 1.0 both isomers have a single both isomers axial methyl have a single trans 1,2 has 1,1 has an axial a gauche = 1.7 axial methyl methyl = 1.7 interaction = 0.8 = 1.7 0.0

AB CD EF GH IJ KL MN

trans-1,4 cis-1,4 trans-1,3 cis-1,3 trans-1,2 cis-1,2 1,1

Chem 201/Beauchamp Topic 6, Conformations (cyclohexanes) 24

Problem 5 (p 20) - Both cis and trans 1-bromo-3-methylcyclohexane can exist in two chair conformations. Evaluate the relative energies of the two conformations in each isomer (use the energy values from the table presented earlier). Estimate the relative percents of each conformation at equilibrium using the difference in energy of the two conformations from you calculations. Draw each chair conformation in 3D bond line notation and as a Newman projection using the C1C6 and C3C4 bonds to sight down.

1-bromo-3-methylcyclohexane 2 Br CH3 1 3

6 4 5

H = -1.2 kcal/mole H = 2.2 kcal/mole

axial Me = 1.7 axial Br = 0.5 zero axial strain axial Me + Br = 1.7 + 0.5 = 2.2

CH3 5 4 5 6 CH3 4 4 5 6 Br 3 4 5 H3C H C 3 1 2 1 3 Br 2 6 3 3 2 Br Br 1 2 1 6

trans-1-bromo-3-methylcyclohexane cis-1-bromo-3-methylcyclohexane

G chair 2 G K = = 10 2.3RT chair 1 chair 2 = 10 2.3RT K = chair 1 - (- 1,200 cal/mole) - ( 2,200 cal/mole) = 10 (2.3)(2 cal/mol-K)(298 K) = 10 (2.3)(2 cal/mol-K)(298 K) 7.4 88% = 10+0.9 = = 1 2% 1.0 12% = 10-1.6 = = 39 98%

Probably a little higher because the CH3 and Br are both axial on the same side. 1.7 (Shows gauche on one side, but there is a second gauche on the other side.) 1.7 0.5

H H CH3 H H H CH3 Br H H H3C H H C 3 Br H H

H Br H H H H H BrH H H H Br H HH H H

0.5 (Shows gauche on one side, but there is a second gauche on the other side.)