Stereochemistry

Question 1

Reaction of an aldehyde and a cyanide…

How many three dimensional products can be created? Why?

Answer 1

Two: CN- (nucleophile) can attack (electrophilic - electrons pulled by O of carbonyl) carbon from above or below the plane of the carboynyl group. This will change the orientation of bonds relative to each other as seen in the image.

Question 2

What is the definition of an enantiomer?

Answer 2

Stereoisomers that are not identical but are mirror images of each other, and which are chiral (their mirror images cannot be superimposed on each other - like left and right hands palm-down!)

Question 3

Achiral reactants that create chiral products form these enantiomers as a _______ mixture. What does this mean?

Answer 3

Racemic

50/50 of each enantiomer

Question 4

How can you tell a chiral from an achiral structure?

Answer 4

Look for planes (NOT LINES) of symmetry - any structure with such a plane can’t exist as two enantiomers, and is achiral.

Question 5

Most biological receptors are chiral or achiral? Why?

Answer 5

Chiral - because they are made up from chiral building blocks such as amino acids.

Question 6

Define: constitutional isomers and stereoisomers

Answer 6

C: the way atoms are connected up differs

S: the atoms have the same connectivity, but are arranged differently (eg: enantiomers or E/Z [double bond] isomers)

Question 7

What is the difference between configuration and conformation?

Are enantiomers a different configuration or a different conformation?

Answer 7

Changing the configuration of a molecule always means that bonds are broken (different config = different molecule).

Changing the conformation of a molecule means rotating about bonds (different conforms = interconvertible = same molecule)

Enantiomers = different configurations (as you have to break bonds to turn one enantiomer into the other)

Question 8

What is a stereogenic/chiral centre? Will it have any planes of symmetry?

Answer 8

A carbon (usually) atom carrying four different groups

No (that’s why it can be called a chiral centre)

Question 9

What do wiggly bonds indicate?

Answer 9

That is referring to both stereoisomers (a racemic mixture of enantiomers), or unknown stereochemistry

Question 10

What is Strecker synthesis?

How does this differ to natural synthesis of its products?

Answer 10

Process in lab to create an amino acid (it will be a racemic mixture)

In nature, amino acids are usually just one of the enantiomers (L-amino acids … or mostly S, except for cysteine)

Question 11

What are the Cahn-Ingold-Prelog rules used for?

How do they work?

Answer 11

Figuring out whether we are looking at an R or S enantiomer

1) Number substituents of sterogenic centre according to priority (higher atomic numbers = rank 1)
2) Rotate so that lowest priority points away from you
3) Draw a circle from priority 1 to priority 2 to priority 3. If the circle is moving rightwards/clockwise, it is R. If it is leftwards/anti-clockwise, it is S.

Question 12

Cahn-Ingold-Prelog rules for R and S enantiomers: what is the fast way of doing it (once you have calculated priorities)?

Answer 12

Switch the lowest priority substituent with whichever substituent is facing away from you (dashed line), draw the little circle thing, and just take the OPPOSITE result (so, if it looks like R, the answer is S, and vice versa)

[NB: may not work, so just try and rotate]

Question 13

Cahn-Ingold-Prelog rules for R and S enantiomers: what two ways are there of handling double/triple bonds that are attached to the substituent atoms (when calculating priority)?

Answer 13

Simple: just counts as another version of a single bond (so [C]=C and C-[C]-C would both be CCH)

Complex: involves ‘ghost’ atoms (A=B is considered to be singly bound to B and and a copy of B [the ghost] that isn’t bound to anything else), but it won’t be needed for this course… plus, you don’t wholly get it anyway.

Question 14

Enantiomers have identical properties in regards to what? What important difference is there?

Answer 14

Identical: physical properties (eg: melting points) and spectroscopical properties (UV, IR, NMR, MS)

Different: they rotate plane-polarized light in opposite directions

Question 15

Can enantiomers be separated by traditional chromatographic techniques (TLC, GC, HPLC)?

Answer 15

No.

Question 16

Normal light has electric and magnetic field components in ___ planes. How do you get plane-polarized light? What do you use to measure it? What is the name for this number (that is specific to each compound)? What does the sign (+/-) indicate?

Answer 16

All

By putting it through a specific filter. You measure the specific rotation by using a polarimeter (+ = right, - = left)

Question 17

How do you calculate specific rotation?

Answer 17

[Alpha] = rotation / concentration (g cm^-3)*path length (dm)

1 dm = 10 cm

Question 18

28mg dissolved in 1mL of ethanol and transferred into a 10cm long polarimeter cell. Observed rotation is -4.35 degrees. What is the specific rotation?

Answer 18

[alpha] = alpha/concentration*path length

1mL = 1 cm^-3 ——> 28mg/cm^-3 -> 0.028g/cm^-3

10cm = 1 dm

-4.35/1*0.028 = -155.4

Question 19

(S)-(+)-alanine

Is there any correlation between +/- and R/S? Explain.

Answer 19

No. +/- is an inherent physical property of each optically active compound, whereas R/S is based on an artificial nomenclature system (that refers to its absolute configuration)

Question 20

What is the difference between absolute and relative configuration?

Answer 20

Absolute configuration represents the precise arrangement of substituents at a stereogenic center (as calculated via R/S, or using techniques such as x-ray crystal structure, spectroscopy, etc.

Relative configuration represents the arrangement of something relative to something else (eg: cis/trans definition is talking about the position of two groups/atoms relative to eachother, or the old way they used to calculate D and L)

Question 21

(S)-(+)-alanine

What would its enantiomer be?

Answer 21

(R)-(-)-alanine

There may be no correlation between R/S and +/-, but the enantiomers of a given compound will always be opposite…

Question 22

Is it possible to assign absolute stereochemistry from +/- or D/L?

Is it possible to assign +/- or D/L from a structure?

Are D/L and +/- connected?

Answer 22

No and no and no. D/L is only always the same as +/- for glycerinaldehyde (which used to be used–via relative stereochemistry–to assign it to other compounds… it was not always effective, which is why D/L aren’t used anymore…)

Question 23

What are diastereoisomers?

How are they different to enantiomers?

Answer 23

Stereoisomers that are not enantiomers (they are neither mirror images nor super-imposable)

They have different physical and spectroscopic properties (unlike enantiomers, which only differ in how they twist plane-polarized light)

Question 24

What does it mean for a molecule to be cis/trans?

How does the E/Z system differ?

Answer 24

In nomenclature, “cis” is used to distinguish the isomer where two identical groups (e.g. the two chlorines in 1,2-dichlorocyclopentane) are pointing in the same direction from the plane of the ring/double bond, and trans to distinguish the isomer where they point in opposite directions.

E/Z system assigns priorties (using Cahn-Ingold-Prelog) to the substituents of the atoms connected on either side of the double bond. ‘E’ (= Enemies) refers to the higher priority groups being on opposite sides of the double bond, and ‘Z’ refers to them being on the same side.

Question 25

Are diastereoisomers chiral or achiral?

Answer 25

They can be either - it still depends on whether or not they have a plane of symmetry. If they do, then they are achiral.

Question 26

What is the general rule for calculating the number of possible stereoisomers from stereogenic centres?

Answer 26

2ⁿ (where n = number of centres) (NB: this is the maximum - there aren't always this many)

Question 27

Thinking of a molecule with 2 stereogenic centres, how many stereoisomers could there be? How many enantiomers would it have? How many diastereoisomers? How would you convert from one enantiomer to the other? And from one diastereoisomer to the other?

Answer 27

2ⁿ = 4 stereoisomers (1 enantiomer, and both enantiomers would have 2 diastereoisomers) Enantiomer -\> enantiomer requires switching all stereogenic centres (RS \<-\> SR, RR \<-\> SS), whereas in diasteroisomers less than all stereogenic centres are switched (eg: SS \<-\> RS)

Question 28

Can you tell anything about the specific rotation of one diastereoisomer from the sign (+/-) of another?

Answer 28

No. Only enantiomers have opposite rotations - diastereoisomers need to be calculated experimentally.

Question 29

Diastereoisomers are _______ compounds with ______ names and ________ properties. How do enantiomers differ?

Answer 29

Different, different, different Enantiomers are the same compound and differ only in regards to plane polarized light NB: example from lecture - ephedrine (1R,2S - vs 1S, 2R +)(mp: 40, [alpha] -/+6.3) and its diastereoisomer pseudoephedrine (1S, 2S + vs 1R,2R -)(mp 117, [alpha] +/-52)

Question 30

How many stereoisomers might there be of this compound? Each stereoisomer has how many enantiomers/diastereoisomers? What direction would the OH groups be facing in the SSS form? In the SRS form?

Answer 30

8 1 enantiomer and 6 diastereoisomers SSS = reversed from picture, SRS = up, up, up (NB: up/down groups on the switching letter reverses)

Question 31

How many possible stereoisomers of this compound (two stereogenic centres) are there? How many pairs of enantiomers are there? Why? So how many stereoisomers are there actually?

Answer 31

4 Just one pair. When OH groups are both pointing the same way, it forms a non-superimposable mirror image (= one set of enantiomers). When they are pointing different ways, you can rotate around the C-C bond, and the molecule has a plane of symmetry, and so it is achiral (and optically inactive, and doesn't have create a second pair of enantiomers). A pair of enantiomers and an achiral meso compound

Question 32

How do you define a meso compound?

Answer 32

Compounds that contain stereogenic centres but are themselves achiral (and thus do not have an enantiomer and display no optical rotation - also lowers the number of actual stereoisomers from 2ⁿ)

Question 33

What does syn and anti refer to?

Answer 33

Just where groups are (usually around double bonds) - syn means on the same side/orientation (eg: both pointing up), and anti on the other side (up/down)

Question 34

How would you go about figuring out how many stereoisomers there are?

Answer 34

4 stereoisomers in total (one pair of enantiomers and two meso compounds)

Question 35

Can you have chiral compounds with no stereogenic centres?

Answer 35

Yes. Look for mirror images that can't be superimposed (as normal) [not for exams]

Question 36

What types of symmetry are chiral? What types are achiral?

Answer 36

Chiral: axis Achiral: plane and centre (dot in middle - if, in both directions all the way around, there are the same atoms, then it is achiral)

Question 37

What is the process of separating enantiomers called? How does it work?

Answer 37

Resolution: react racemic mixture with chiral auxilary (must be present in only one enantiomer). Then generate product (covalent product or salt). While one component (eg: alcohohol) is racemic, the reagant (eg: acid) is only present as one enantiomer - overall, when combined, they are diastereoisomers of each other (can then be separated by chromotography as they will have different physical properties, and then the acid can be recovered)

Question 38

With regular chromotography, racemic mixtures elute together. Describe how chromotography on a racemic mixture would be made to work.

Answer 38

You use a chiral phase (a modified silica gel, which on its own would be achiral) that has a greater affinity for one of the enantiomers. You load the racemic mixture in at the top of the column, and the high-affinity enantiomer will move through more slowly - you can then collect the enantiomers separately.

Question 39

Why is it important to be able to separate enantiomers from each other, and test them separately?

Answer 39

They can have drastically different effecs (eg: thalidomide - R was great vs morning sickness, S was teratogenic and made malformed babies)

Question 40

What is barrier to rotation?

Answer 40

The amount of energy needed to make a bond rotate

Question 41

A rotational barrier of what energy allows one rotation per second? How much energy at 25 degrees centigrade changes this rate by 10x?

Answer 41

73kJ/mol (6kJ/mol)

Question 42

What is the difference between staggered and eclipsed conformations (of ethane: Me-Me)? What is the name of the drawing that shows the conformation?

Answer 42

Eclipsed: hydrogens in line (when face on to molecule), staggered: same gap inbetween every hydrogen (when face on) Newman projections

Question 43

Rotational energy profile for ethane (CH3-CH3): what is the difference between each eclipsed and staggered conformation? Which is lower? What is the dihedral angle (theta)?

Answer 43

12kJ/mol (so it spins happily around at room temperature) - staggered is lower Theta: angle between two hydrogens separated by the carbon-carbon bond.

Question 44

Why is the staggered conformation lower in energy than the eclipsed conformation?

Answer 44

Eclipsed: filled orbitals repeal each other Staggered: stabilizing interaction between filled C-H sigma bond, and empty C-H sigma anti-bonding orbital

Question 45

What do the staggered and eclipsed conformations of propane look like? [Newman projection]

Answer 45

Question 46

Butane (CH3-CH2-CH2-CH3): what do the staggered and eclipsed newman projections look like? What are the angles, the conformations at each of those angles, and the name of each one of those positions? [6 positions]

Answer 46

Question 47

Butane (CH3-CH2-CH2-CH3): which conformation has the lowest energy? Which has the highest? Energy difference?

Answer 47

Low: anti-periplanar, high: syn-periplanar [NB: anti = methyl groups opposite, syn = same side] 20 \<-\> 5 (15kJ difference)

Question 48

What is ring strain? What is torsional strain? What does this lead to in terms of the shape of the ring structures?

Answer 48

Ring strain: SP3 carbons in cyclic molecules that are forced to deviate from ideal angle (109.5). Tortional strain: strain caused by eclipsing interactions with neighbouring atoms (hydrogens and carbon wanting to get away from each other) -\> means most cyclic hydrocarbons aren't planar.

Question 49

Cyclic hydrocarbons: geometrically, which rings should be the most stable? Why? Which ring is actually the most stable?

Answer 49

Five carbon rings = lowest ring/angle strain (six carbon rings are actually most stable)

Question 50

Cyclic ring size: what is considered small, normal, medium, and large by chemists?

Answer 50

3-4 small, 5-7 normal, 8-14 medium, 14+ large

Question 51

Is cyclopropane reactive? Why?

Answer 51

Yes. Very. All C-H bonds are eclipsed, and it desperately just wants to open up its bonds and add more substituents to reduce the enormous ring and torsional strain.

Question 52

What conformation does cyclobutane (4C) take? Why?

Answer 52

The puckered wing conformation (means C-H bonds are no longer fully eclipsed)

Question 53

Planar ring structure of cyclopentane (5C) has almost no ring strain, so what makes it go to a different conformation? What shape does it take on?

Answer 53

Torsional strain (eclipsing interaction between neighbouring hydrogens). Most stable conformation is the 'open envelope'.

Question 54

Cyclohexane (6C): what conformation does it take when it is most stable?

Answer 54

The 'chair' conformation (all C-H bonds are staggered - why it is the most stable cyclic molecule) - four carbons on a plane, then one above and one below.

Question 55

What is the cyclohexane (6C) conformation when all C-H bonds are eclipsed? [NB: energetically not favourable - why is it important to know about?

Answer 55

Boat conformation [Because it needs to pass through this conformation to reach the other 'chair' conformation]

Question 56

What is the twist-boat conformation of cyclohexane (6C)?

Answer 56

A boat conformation in which some of the eclipsing interactions have been reduced (more favourable)

Question 57

Draw cyclohexane (accurately!) [NB: the ₁C⁴ conformer]

Answer 57

[NB: remember to look at the other conformer, and how it's done]

Question 58

At room temperatures, cyclohexane rings can easily flip. After ring inversion, what happens to the bonds?

Answer 58

All bonds that were axial become equatorial and vice versa

Question 59

What do these drawings represent?

Answer 59

The same cyclohexane conformer just viewed from different vantage points (can add a substituent group to any carbon?)

Question 60

How do the different conformations of cyclohexane (chair, half-chair, twist-boat, true boat) compare in terms of energy?

Answer 60

Question 61

Cyclohexane chair conformations (only ones we really need to worry about in terms of additional substituents): for any substituent that isn't hydrogen, would axial or equatorial be lower in energy? Why?

Answer 61

Equatorial (if it axial, there is 1,3 diaxial interaction - hydrogens are too close, which makes it more likely to just rotate into the lower energy conformer)

Question 62

Monosubstituted cyclohexane (C6 w/1 hydrogen replaced with X): how do you calculate the equilibrium between the two conformers (axial and equatorial)?

Answer 62

K = [equatorial conformer]/[axial conformer] Larger value of K = equilibrium far more towards equatorial (should never be negative) [NB: X = OCH₃ = very low K coz the hydrogens are out of the way]

Question 63

How do you handle disubstituted cyclohexanes (w/2 hydrogens replaced by something else) in terms of deciding if there is a preferred conformer?

Answer 63

General approach: draw out structure, draw both conformers, and then decide if there is a preferred one (by inverting the ring, and seeing if the relevant groups are both in the equatorial position).

Question 64

Disubstituted cyclohexanes: if when comparing conformers, they are equal in terms of axial:equatorial, how can you decide which is favoured?

Answer 64

The size of the substituents (bulkier components should be equatorial in the more stable conformation)

Question 65

What is a locking group (t-butyl)? What happens if you attach two such groups at positions that would force one of them into an axial position?

Answer 65

Demonstrates severe 1:3 diaxial interactions - can never be axial, and so can be used as a 'locking group' from going through ring inversion (it will always be axial, so other groups have to assume the axial positions) It will assume a twist-boat conformer (with both groups in pseudo-equatorial positions) as this is lower energy than the chair conformer.

Question 66

How do fused ring structures (eg: a pentane attached to a hexane at the 1 and 4 carbons) look? Think of trans molecule (1H up, 4H down), and a cis molecule (1H up, 4H up).

Answer 66

They just follow the normal rules (so if the 1H is up = axial, then the bond to the carbon of the pentane will be down = equatorial). Follow same rules for the cis molecule.

Question 67

Decalines (two fused cyclohexanes at 1 and 2C, cis [both H up] and trans [1 up, 2 down]): what does the conformation of the molecule look like?

Answer 67

Question 68

Why is understanding the way in which fused rings form (in terms of conformation) important to organic/biological chemistry?

Answer 68

Because it underlies things like the structure of steroid based chemicals/hormones

Question 69

What is the difference in conformation between cyclohexane and cyclohexane oxide?

Answer 69

Half chair conformation in cyclohexane oxide (orange = pseudoaxial, green = pseudoequatorial)

Question 70

What conformation does cyclohexene (6C, w/1 double bond) take?

Answer 70

Half chair with 4 of the carbons in the same plane (NB: numbering is off on picture

Question 71

What is the conformation of cyclohexanone (6C, with carbonyl at position 1)?

Answer 71

NB: green bits of molecule are planar on picture (but this doesn't change very much) - carbonyl sticks out between axial/equatorial, and can be inverted

Question 72

NB: Card dealing with larger cycloalkanes

Answer 72

Ø double bonds are normally cis up to cycloheptene Ø it is possible to get cis and trans isomers of cyclooctene and cyclononene Ø cycloalkenes in general are reasonably stable in 8-membered and larger rings Ø 8 to 10-membered rings: trans double bond introduces greater strain Ø 11 to 12-membered rings: cis and trans isomers are of similar energy Ø greater than 12-membered rings: trans isomers become more stable than cis isomers