1
Isomers
Isomers: different compounds with the same molecular formulaConstitutional isomers: isomers with a different connectivityStereoisomers: isomers with the same molecular formula, the same connectivity but a different orientation of their atoms in space that cannot be interconverted by rotation about a single bond
2
Isomerism Constitutional Isomers and Stereoisomers
Stereoisomers are isomers with the same molecular formula and same connectivity of atoms but different arrangement of atoms in space
3
Stereochemistryis the chemistry of molecules in three
dimension
4
HandednessStereochemistry of organic molecules can be understood, if we understand the meaning of handednessthe fundamental reason for this is that our hands are not identical, rather they are mirror images
5
The mirror imageof a chiral object isdifferent and will notsuperimpose on the original object.
Objects which are chiral have a sense of “handedness” and exist in two forms.
Chirality
6
• Although everything has a mirror image, mirror images may or may not be superimposable.
• Some molecules are like hands. Left and right hands are mirror images, but they are not identical, or superimposable chiral (property of handedness)
The reason for Handedness chirality
7
Mirror Image
8
Chirality and Nonchirality
Mirror image: the reflection of an object in a mirrorObjects that are not superposable on their mirror images are said to be chiral, that is, they show handednessObjects that are superposable on their mirror images are said to be achiral, that is, they do not show handedness. An achiral object has at least one element of symmetry
9
• Do these molecules contain a Plane of Symmetry (Mirror Plane)?
Achiral Molecules
10
• The molecule labeled A and its mirror image labeled B are not superimposable. No matter how you rotate A and B, all the atoms never align. Thus, CHBrClF is a chiral molecule, and A and B are different compounds.
• A and B are stereoisomers—specifically, they are enantiomers.
• A carbon atom with four different groups is a tetrahedral stereogenic center.
Chiral Molecules
11
• With one stereogenic center, a molecule will always be chiral.
• With two or more stereogenic centers, a molecule may or may not be chiral, e.g. Meso compound (contains a plane of symmetry or a mirror plane)
Chiral vs. Achiral
12
Chiral vs. AchiralChiral:Chiral: from the Greek, cheir, hand
an object that is not superposable on its mirror image
Achiral:Achiral: an object that lacks chirality; one that lacks handedness
an achiral object has at least one element of symmetryplane of symmetryplane of symmetry:: an imaginary plane passing through an object dividing it so that one half is the mirror image of the other halfcenter of symmetrycenter of symmetry:: a point so situated that identical components are located on opposite sides and equidistant from that point along the axis passing through it
13
Elements of SymmetrySymmetry in objectsSymmetry in objects
14
Plane of Symmetry or Mirror plane
Cl
ClBr
F F
Br
Cl Cl
plane ofsymmetry
TWO VIEWS OF THE PLANE OF SYMMETRY
side view
edgeview
FClBr
16
Plane of Symmetry
C
COOHHH
COOH
C
CH3
H
COOH
OH
Symmetry plane No symmetry plane
achiral chiral
17
ClCl
Br
H
H
Br
center of symmetry
Elements of Symmetry
Center of symmetry: a point so situated that identical components of the object are located equidistant on opposite sides and equidistant from the point along any axis passing through the point
18
Chiral Center
The most common (but not the only) cause of chirality in organic molecules is a tetrahedral atom, most commonly carbon, bonded to four different groups
A carbon with four different groups bonded to it is called a chiral centerchiral center
all chiral centers are stereocenters, but not all stereocenters are chiral centers.
STEREOGENIC CARBON ATOMSSTEREOGENIC CARBON ATOMS
20
BrFH
Cl stereocenterThis is one type of ….
…. others are possible
A stereogenic carbon is tetrahedral and has four different groups attached.
Stereogenic Carbon Atoms
21
• To locate a stereogenic center, examine the four groups—not the four atoms—bonded to each tetrahedral carbon atom in a molecule.
• Omit from consideration all C atoms that cannot be tetrahedral stereogenic centers. These include
• Methylene and methyl units, i. e. CH2 and CH3 groups respectively.
• Any sp or sp2 hybridized Carbons, e.g. triple bonds, and double bonds in alkenes (C=C) and carbonyls (C=O).
Stereogenic Centers
22
Enantiomers
23
One of a pair of molecular species that are mirror images of each other and not superposable.
They are mirror-image stereoisomers.
Enantiomers
24
• To draw both enantiomers of a chiral compound such as 2-butanol, use the typical convention for depicting a tetrahedron: place two bonds in the plane, one in front of the plane on a wedge, and one behind the plane on a dash. Then, to form the first enantiomer, arbitrarily place the four groups—H, OH, CH3 and CH2CH3—on any bond to the stereogenic center. Then draw the mirror image.
Drawing Enantiomers
25
Pairs of Enantiomers
26
BrFH
Cl Cl
HBrF
HFBr
Cl
rotate
this moleculeis chiral note that the fluorine
and bromine have beeninterchanged in theenantiomer
Enantiomers
27
Enantiomers
Lactic acidC
C
HOCH3
H
OHO
C
C
OHH3CH
O OH
28
Enantiomers3-Chlorocyclohexene
Cl Cl
29
Enantiomers
1,2-propanediolCH3CHCH2OH
OH
C
OH
H
CH2OHH3C C
OH
H
HOH2C CH3
30
EnantiomersA nitrogen chiral center
N
CH2CH3H3C
N
CH3CH3CH2
A pair of enantiomers
++
31
Enantiomers &
Diastereomers
32
Enantiomers & Diastereoisomer
Enantiomers: opposite configurations at all stereogenic centers.Diastereomers: Stereoisomers that are not mirror images of each other. Different configuration at some locations.
33
Two Stereocenters
diasteromers
entaiomers
entaiomers
Br Cl
H3CH
HCH3
Cl Br
HH3C
CH3
H
Cl Br
HH3C
HCH3
Br Cl
HH3C
HCH3
34
Enantiomers & Diastereomers
For a molecule with 1 stereocenter, 2 stereoisomers are possibleFor a molecule with 2 stereocenters, a maximum of 4 stereoisomers are possibleFor a molecule with n stereocenters, a maximum of 2n stereoisomers are possible 2n-1 pairs of enantiomers
35
Enantiomers & Diastereomers
2,3,4-Trihydroxybutanaltwo chiral centers 22 = 4 stereoisomers exist; two pairs of enantiomers
Diastereomers:Diastereomers:stereoisomers that are not mirror imagesrefers to the relationship among two or more objects
C
C
H OH
CHO
OH
CH2OH
H
C
C
HHO
CHO
HO
CH2OH
H
C
C
H OH
CHO
H
CH2OH
HO
C
C
HHO
CHO
H
CH2OH
OH
A pair of enantiomers(Erythreose)
A pair of enantiomers(Threose)
36
Enantiomers & Diastereomers
2,3-Dihydroxybutanedioic acid (tartaric acid)
two chiral centers; 2n = 4, but only three stereoisomers exist
Meso compound:Meso compound: an achiral compound possessing two or more chiral centers that also has chiral isomers
C
C
H OH
COOH
OH
COOH
H
C
C
HHO
COOH
HO
COOH
H
C
C
H OH
COOH
H
COOH
HO
C
C
HHO
COOH
H
COOH
OH
A pair of enantiomersA meso compound(plane of symmetry)
37
Enantiomers & Diastereomers
2-Methylcyclopentanol
H H
CH3 OH
H H
HO H3C
H OH
CH3 H
HO H
H H3C
cis-2-Methylcyclopentanol (a pair of enantiomers)
trans-2-Methylcyclopentanol (a pair of enantiomers)
diastereomers
38
Enantiomers & Diastereomers
1,2-Cyclopentanediol
H H
OH HO
H H
OH HO
H HO
OH H
OH H
H HO
cis-1,2-Cyclopentanediol (a meso compound)
trans-1,2-Cyclopentanediol (a pair of enantiomers)
diastereomers
39
Enantiomers & Diastereomers
cis-3-Methylcyclohexanol
OHH3C HO CH3
40
Enantiomers & Diastereomers
trans-3-Methylcyclohexanol
OH
H3C
HO
CH3
41
Meso compounds
Meso compounds are achiral by virtue of a symmetry plane, but contain a stereogenic center.
Cl Cl
HH3C
HCH3
Cl Cl
HH3C
HCH3
plane of symmmetry mirror
42
Meso compound: achiral despite the presence of stereogenic centers
Not optically activeSuperposable on its mirror imageHas a plane of symmetry
Meso compounds
43
The Three Stereoisomers of 2,3-dibromobutane
• Because one stereoisomer of 2,3-dibromobutane is superimposable on its mirror image, there are only three stereoisomers, not four.
NUMBER OF NUMBER OF STEREOISOMERS POSSIBLESTEREOISOMERS POSSIBLE
How Many Stereoisomers How Many Stereoisomers Are Possible?Are Possible?
maximum number of stereoisomers = 2n,
where n = number of stereocenters(sterogenic carbons)
sometimes fewerthan this numberwill exist
CH3 C
CH2OH
CH3
CH2 CH CH
CH3
CH3
OH*
*
22 = 4 stereoisomers
R RR SS RS S
CH3
OH
CHCH3 CH3
***
23 = 8 stereoisomers
R R RR R SR S RS R R
R S SS R SS S RS S S
CONFIGURATIONCONFIGURATION
ABSOLUTE CONFIGURATION ( R / S )
CONFIGURATIONCONFIGURATION
The three dimensional arrangement of the groups attached to an atom
Stereoisomers differ in the configuration at one ormore of their atoms.
2
CONFIGURATION CONFIGURATION R,S conventionR,S convention
clockwise counterclockwise
(rectus) (sinister)
view with substituentof lowestpriority inback
1 2
4
3
C C
1
4
3
R S
50
• Since enantiomers are two different compounds, they need to be distinguished by name. This is done by adding the prefix R or S to the IUPAC name of the enantiomer.
• Naming enantiomers with the prefixes R or S is called the Cahn-Ingold-Prelog system.
• To designate enantiomers as R or S, priorities must be assigned to each group bonded to the stereogenic center, in order of decreasing atomic number. The atom of highest atomic number gets the highest priority (1).
Rules for Labeling Stereogenic Centers with R or S
51
• If two atoms on a stereogenic center are the same, assign priority based on the atomic number of the atoms bonded to these atoms. One atom of higher priority determines the higher priority.
Priority Rules for Naming Enantiomers (R or S)
52
• If two isotopes are bonded to the stereogenic center, assign priorities in order of decreasing mass number. Thus, in comparing the three isotopes of hydrogen, the order of priorities is:
Priority of Isotopes on a Stereogenic Center
53
• To assign a priority to an atom that is part of a multiple bond, treat a multiply bonded atom as an equivalent number of singly bonded atoms. For example, the C of a C=O is considered to be bonded to two O atoms.
Priority Rules for Multiple Bonds in (R or S) Labeling
• Other common multiple bonds are drawn below:
54
Examples Assigning Priorities
55
Cahn-Ingold-Prelog System for Naming Enantiomers R
or S
56
R or S Enantiomers
57
Positioning the Molecule for R/S Assignment
58
R-enantiomer (Clockwise Rotation)
S-enantiomer (Counterclockwise Rotation)
59
Manipulation of Chiral Molecules
60
The molecule is rotated to put the lowest priority group back
If the groups descend in priority (a,b then c) in clockwise direction the enantiomer is RIf the groups descend in priority in counterclockwise direction the enantiomer is S
61
R,S Convention
Priority rules (Cahn, Ingold, Prelog)Each atom bonded to the stereocenter is assigned a priority, based on atomic number. The higher the atomic number, the higher the priority
Increasing Priority
H CH3 NH2 OH SH Cl Br I
1 6 7 8 16 17 35 53
62
R,S Convention
If priority cannot be assigned on the basis of the atoms bonded to the stereocenter, look to the next set of atoms. Priority is assigned at the first point of difference.
CH2 H CH2 CH3 CH2 NH2 CH2 OH1 6 7 8
Increasing Priority
63
R,S Convention Atoms participating in a double or triple bond are considered to be bonded to an equivalent number of similar atoms by single bonds
-CH=CH2
O
-CH
C CH
O
H
C
C
O
C
-CH-CH2
C
C C HC
C
C
C
is treated as
is treated as
is treated as
64
Priorities
1. -OH2. -COOH3. -CH3
4. -H (R)-(-)-lactic acid
C
HHO COOH
CH3
C
H
CH3
HOOC OH
(S)-(+)-lactic acid
65
I
C
BrCl
F
I
C
ClBrF
1
2
3
4
RR SS
1
32
4
Enantiomers
Bromochlorofluoroiodomethane
66
• When a compound has more than one stereogenic center, the R and S configuration must be assigned to each of them.
R and S Assignments in Compounds with Two or More Stereogenic Centers.
One stereoisomer of 2,3-dibromopentaneThe complete name is (2S,3R)-2,3-dibromopentane
67
Stereoisomerism of Cyclic Compounds
1,4-dimethylcyclohexaneNeither the cis not trans isomers is optically activeEach has a plane of symmetry
68
1,3-dimethylcyclohexaneThe trans and cis compounds each have two stereogenic centersThe cis compound has a plane of symmetry and is mesoThe trans compound exists as a pair of enantiomers
69
Properties of Stereoisomers
70
Properties of Stereoisomers
Enantiomers have identical physical and chemical properties in achiral environmentsDiastereomers are different compounds and have different physical and chemical properties
meso tartaric acid, for example, has different physical and chemical properties from its enantiomers (see Table 3.1)
71
Plane-Polarized Light
Ordinary light:Ordinary light: light vibrating in all planes perpendicular to its direction of propagationPlane-polarized light:Plane-polarized light: light vibrating only in parallel planesOptically active:Optically active: refers to a compound that rotates the plane of plane-polarized light
72
Plane-Polarized Lightplane-polarized light is the vector sum of left and right circularly polarized lightcircularly polarized light reacts one way with an R chiral center, and the opposite way with its enantiomerthe result of interaction of plane-polarized light with a chiral compound is rotation of the plane of polarization
73
Plane-Polarized Light
Polarimeter:Polarimeter: a device for measuring the extent of rotation of plane-polarized light
74
Optical Activityobserved rotation:observed rotation: the number of degrees, , through which a compound rotates the plane of polarized light
dextrorotatory (+):dextrorotatory (+): refers to a compound that rotates the plane of polarized light to the right
levorotatory (-):levorotatory (-): refers to a compound that rotates of the plane of polarized light to the left
specific rotation:specific rotation: observed rotation when a pure sample is placed in a tube 1.0 dm in length and concentration in g/mL (density); for a solution, concentration is expressed in g/ 100 mL
DD
H3CC
OHH
COOH
CH3
C
HOH
COOH
[]21 = -2.6°= +2.6°21
[]
(R)-(-)-Lactatic acid(S)-(+)-Lactic acid
75
Optical PurityOptical purity:Optical purity: a way of describing the composition of a mixture of enantiomers
Enantiomeric excess:Enantiomeric excess: the difference between the percentage of two enantiomers in a mixture
optical purity is numerically equal to enantiomeric excess, but is experimentally determined
x 100[]samplePercent optical purity =
[]pure enantiomer
x 100[R] + [S][R] - [S]
Enantiomeric excess (ee) = = %R - %S
76
Resolution
Racemic mixture:Racemic mixture: an equimolar mixture of two enantiomers
because a racemic mixture contains equal numbers of dextrorotatory and levorotatory molecules, its specific rotation is zero
Resolution:Resolution: the separation of a racemic mixture into its enantiomers
77
• An equal amount of two enantiomers is called a racemate or a racemic mixture. A racemic mixture is optically inactive. Because two enantiomers rotate plane-polarized light to an equal extent but in opposite directions, the rotations cancel, and no rotation is observed.
Racemates
78
• Specific rotation is a standardized physical constant for the amount that a chiral compound rotates plane-polarized light. Specific rotation is denoted by the symbol [] and defined using a specific sample tube length (l, in dm), concentration (c in g/mL), temperature (25 0C) and wavelength (589 nm).
Specific Rotation
79
Discovery of Enantiomers
“There is no doubt that in dextro tartaric acid there exists an assymetric arrangement having a nonsuperimposible image.”
C
C
COO-Na+
COO-Na+
H
HO H
OH
80
H COOHH
OHOH
HOOCHOOC HH COOH
OHOH
H HCOOH
OHOH
HOOC
meso
enantiomers
(as a minor component)ALSO FOUND
more about thiscompound later
H COOHH
OHOH
HOOCHOOC HH COOH
OHOH
H HCOOH
OHOH
HOOC
meso
enantiomers(+)-tartaric acid (-)-tartaric acid
[]D = 0
meso -tartaric acid
Tartaric Acid
81
DiastereoisomerStereoisomers that are not mirror images of each other. Different configuration at some locations.
COOH
C
C
H
HCH3
NH2
OH
COOH
C
C
H
H OHCH3
H2N
82
DiastereomersThreonine: 2 pairs of enantiomers
COOH
C
C
H
H OHCH3
H2N
COOH
C
C
H
HCH3
NH2
OH
2R, 3S 2S, 3R
2R, 3R 2S, 3S
COOH
C
C
H
HHOH3C
NH2
COOH
C
C
H
HH3C
H2N
HO
2R,3R 2S,3S 2R,3S & 2S,3R2S,3S 2R,3R 2R,3S & 2S,3R2R,3S 2S,3R 2R,3R & 2S,3S2S,3R 2R,3S 2R,3R & 2S,3S
83
Enantiomers & Diastereomers
For tartaric acid, the three possible stereoisomers are one meso compound and a pair of enantiomers.
Meso compound: an achiral compound possessing two or more stereocenters.
84
Symmetry Plane2R, 3S and 2S, 3R are identicalMolecule has a plane of symmetry perpendicular to C-C and is therefore achira
COOH
C
C
H
HO HCOOH
OH
2R, 3S 2S, 3R
2R, 3R 2S, 3S
COOH
C
C
H
OHHCOOH
OHCOOH
C
C
H
HO HCOOH
HO
COOH
C
C
H
OHCOOH
HO
H
85
Symmetry Plane2R, 3S and 2S, 3R are identicalMolecule has a plane of symmetry perpendicular to C-C and is therefore achiraOne meso compound and a pair of enantiomers
COOH
C
C
H
HO HCOOH
OH
2R, 3S 2S, 3R
2R, 3R 2S, 3S
COOH
C
C
H
OHHCOOH
OHCOOH
C
C
H
HO HCOOH
HO
COOH
C
C
H
OHCOOH
HO
H
Mirror image is identical
86
H CH3
CH3 H
Cl Br
CH3 HH CH3
Br Cl
H HCH3 CH3
Br Cl
CH3CHCHCH3
Cl Br
H HCH3 CH3
Cl Br
enantiomers 1
enantiomers 2
diastereomers
S R RS
S S R R
mirror
2-Bromo-3-chlorobutane
87
H HCH3 CH3
Cl Cl
CH3CHCHCH3
Cl Cl
H HCH3 CH3
Cl Cl
CH3 HH CH3
Cl Cl
H CH3
CH3 H
Cl Cl
meso
enantiomers
diastereomers
S R
S S R R
mirror image is identical
2,3-Dichlorobutane
88
Tartaric Acid(-) - tartaric acid
[]D = -12.0o
mp 168 - 170o
solubility of 1 g 0.75 mL H2O
1.7 mL methanol 250 mL ether
insoluble CHCl3 d = 1.758 g/mL
(+) - tartaric acid[]D = +12.0o
mp 168 - 170o
solubility of 1 g 0.75 mL H2O
1.7 mL methanol 250 mL ether
insoluble CHCl3 d = 1.758 g/mL
meso - tartaric acid[]D = 0o solubility of 1 gmp 140o 0.94 mL H2Od = 1.666 g/mL insoluble CHCl3
89
Fischer Projections
90
H OH
CH3
CH2CH3Fischer ProjectionsFischer projection: a two-dimensional representation showing the configuration of a stereocenter
horizontal lines represent bonds projecting forward vertical lines represent bonds projecting to the rearthe only atom in the plane of the paper is the stereocenter
91
Fischer Projections
(R)-lactic acid
C
COOH
HOH CH3
COOH
CH3
H OH
How?
92
Fischer Projections
C
COOH
HOH CH3
COOH
CH3
H OH
93
Fischer Projections
COOH
CH3
H OH
COOH
CH3
H OH
94
Fischer Projections
1. Orient the stereocenter so that bonds projecting away from you are vertical and bonds projecting toward you are horizontal
2. Flatten it to two dimensions
(S)-2-Butanol (3-D formula)
(1) (2)
(S)-2-Butanol (Fischer projection)
CH3CH2
HCH3
OH
C
CH3
CH2CH3
OHH HC OH
CH3
CH2CH3
95
Assigning R,S Configuration
Lowest priority group goes to the top.View rest of projection.A curved arrow from highest to lowest priority groups.Clockwise - R (rectus)Counterclockwise - S (sinister)
96
Assigning R,S Configuration
1
2
3
4
H
OH
H3C COOH
s-lactic acid
97
Rules of Motion Can rotate 180°, but not 90°
because 90° disobeys the Fischer projection.
Same groups go in and out of plane
CH3
HO H
COOH
CH3
COOH
HO H180
COOH
H OH
CH3
COOH
CH3
H OH= =
98
Rules of Motion Can rotate 180°, but not 90°
because 90° disobeys the Fischer projection.
Different groups go in and out of planeThis generates an enantiomeric structure
H
H3C COOH
OH
H
OH
H3C COOH90
COOH
H OH
CH3
COOH
CH3
H OH= =
(R)-lactic acid (S)-lactic acid
99
Rules of Motion One group can be held steady and
the others rotated.
H
COOH
HO CH3same as
CH3
COOH
H OH
100
Rules of MotionTo determine if two Fischer projections represent the same enantiomer carry out allowed motions. C2H5
CH3
HO H
OH
C2H5
H CH3
H
OH
H3C C2H5
A B C
101
Rules of MotionBy performing two allowed movements on B, we are able to generate projection A. Therefore, they are identical.
H
CH3
HO
CH2CH3
CH2CH3
HHO
CH3
HO
H
CH3
CH2CH3
CH3
B A
CH3CH2
C2H5
CH3
HO H
OH
C2H5
H CH3
H
OH
H3C C2H5
A B C
102
Rules of MotionPerform one of the two allowed motions to place the group with lowest priority at the top of the Fischer projection.
180
H
CH3
OH
CH2CH3
C not A
CH3H
OH
CH2CH3
CH2CH3
HH3C
OH
OH90
C2H5
CH3
HO H
OH
C2H5
H CH3
H
OH
H3C C2H5
A B C
103
Priorities1. NH2
2. COOH3. CH3
4. H
S - stereochemistry
CH3
H
HOOC NH2
H
CH3
HOOC NH2
CH3
H2N H
HOOC
CH3
H2N H
HOOC
CH3
HOOC NH2
HCH3
104
Br Cl BrCl
Cl
Br Br
Cl
enantiomers
enantiomersdiastereomers
cis
trans
1-Bromo-2-chlorocyclohexane
105
ClBr BrCl
Cl
Br Br
Cl
enantiomers
enantiomers
cis
trans
diastereomers
R S SR
R R S S
1-Bromo-2-chlorocyclopropane
106
BrBr BrBr
Br
Br Br
Br
mirror image identical
meso
enantiomers
diastereomers
cis
trans
1,2-Dibromocyclopropane
107
Biological Significance of Stereoisomers
Structure Properties
Stereochemistry Biological effects
causes
Example•Pasteur’s plant mold metabolized (+)-tartaric acid but not (-)-tartaric acid
108
Biological Significance of StereoisomersThalidomide
•Marketed in 50 countries 1956-1962Sedative for “hysterical” pregnant womenAntiemetic to combat morning sickness
•Caused thousands of birth defects
N
N
O
O O H
O
•Sold as racemic mixture: 1:1 mixture of enantiomersR enantiomer = antiemetic (not teratogenic)S enantiomer = teratogenic (not antiemetic)
•Single-enantiomer drug not useful: quickly racemizes in body
One stereocenter
Teratogen: causes fetal abnormalities
109
Biological Significance of Stereoisomers
Another Biological Effect: Odor
Mirror image molecules do not have “mirror image effects”
enantiomers
(S)-(+)-carvone
O
H
(R)-(-)-carvone
O
H
smells like spearmint smells like caraway
110
Biological Significance of Stereoisomers
Of Hands, Gloves, and BiologyWhy do stereoisomers have different biological properties?•Many biological effects involve interaction with a cavity in enzyme or receptor•Good fit to cavity (i.e., strong binding) triggers enzyme or receptor
•Most amino acids are chiral, so protein cavity is also chiral•Metaphor: Stereoisomer = left hand or right hand Protein hole = left glove or right glove Left hand fits left glove but not right glove Left hand triggers “left protein” but not “right protein”•(R)-carvone triggers spearmint smell receptor but not caraway smell receptor
H2N
O
HR
OH•Enzymes and receptors are proteins; built from amino acids:
111
